Asymmetric autocatalysis initiated by chiral ephedrine immobilized on silica gel in a diisopropylzinc addition to pyrimidine-5-carbaldehyde

Article abstract of DOI:10.1246/bcsj.77.1587

5-Pyrimidyl alkanol with up to 97% ee was formed using chiral ephedrine immobilized on silica gel in the enantio-selective addition of diisopropylzinc to pyrimidine-5-carbaldehyde in conjunction with asymmetric autocatalysis.

Full text of DOI:10.1246/bcsj.77.1587

Short Articles
Bull. Chem. Soc. Jpn., 77, 1587–1588 (2004) 1587
Me
N
Ph
O
O
O
SiO2
Si
OH
Asymmetric Autocatalysis
Initiated by Chiral Ephedrine
Immobilized on Silica Gel in a
Diisopropylzinc Addition to
Pyrimidine-5-carbaldehyde
n
Me
(
(
1R,2S)-2a (n=3)
1R,2S)-2b (n=5)
N
OH
CHO
Asymmetric
Autocatalysis
N
N
t-Bu
(R)-3
N
O
O
O
Me
Ph
OH
t-Bu
1
SiO2
Si
N
n
+
Me
i-Pr Zn
2
(1S,2R)-2a (n=3)
1S,2R)-2b (n=5)
N
OH
(
Asymmetric
Autocatalysis t-Bu
N
(
S)-3
Itaru Sato, Masako Shimizu, Tsuneomi Kawasaki,
ꢀ
Scheme 1. Highly enantioselective asymmetric autocatalysis
using ephedrine immobilized on silica gel.
and Kenso Soai
Department of Applied Chemistry, Faculty of Science,
Tokyo University of Science, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601
Table 1. Highly Enantioselective Synthesis of Pyrimidyl
Alkanol 3 in the Presence of Inorganic–Organic Hybrid
Materials 2a, b
aÞ
Received March 8, 2004; E-mail: soai@rs.kagu.tus.ac.jp
Entry
Hybrid silica
Pyrimidyl alkanol 3
bÞ
Yield/%
Ee/%
Config.
1
2
3
4
5
6
7
8
(1R,2S)-2a
(1R,2S)-2a
(1S,2R)-2a
(1S,2R)-2a
(1R,2S)-2b
(1R,2S)-2b
(1S,2R)-2b
(1S,2R)-2b
(1S,2R)-2b
86
90
91
93
86
87
84
85
88
93
92
95
93
97
90
93
93
95
R
R
S
5
-Pyrimidyl alkanol with up to 97% ee was formed us-
ing chiral ephedrine immobilized on silica gel in the enantio-
selective addition of diisopropylzinc to pyrimidine-5-carbal-
dehyde in conjunction with asymmetric autocatalysis.
S
R
R
S
S
The enantioselective addition of dialkylzincs to aldehydes
using chiral catalysts is a useful method for the preparation
of enantioenriched sec-alcohols. Homogeneous chiral cata-
bÞ
9
S
1
a) For detailed reaction conditions, see the Experimental. b)
Recovered hybrid silica 2b from Entry 8 was used.
lysts such as ꢀ-amino alcohols have been employed most often.
Although heterogeneous chiral catalysts have been developed
for the enantioselective addition of dialkylzincs to aldehydes,
most of them are polystyrene-bound and organic polymer based
chiral catalysts. Meanwhile, silica gel is an easily available
inorganic compound and has been widely used as the chiral
and achiral stationary phases in chromatographic separations.
However, it has rarely been employed as a support of chiral cat-
alysts in asymmetric carbon–carbon bond forming reactions.
In 1990, we reported the first use of silica gel as a support of
chiral catalysts for the enantioselective addition of dialkylzincs
quent immobilization of (1R,2S)- and (1S,2R)-ephedrine on
the functionalized silica gels afforded chiral inorganic–organic
hybrid materials 2a and 2b bearing tri- and penta-methylene
chains, respectively.
1
,2
In the presence of chiral inorganic–organic hybrid materials,
the enantioselective addition of i-Pr2Zn to 2-alkynylpyrimi-
dine-5-carbaldehyde 1 was examined (Scheme 1). As shown
in Table 1, in the presence of (1R,2S)-2a, (R)-5-pyrimidyl alka-
nol 3 with 92–93% ee was formed (Entries 1 and 2). In sharp
contrast, in the presence of (1S,2R)-2a, (S)-5-pyrimidyl alkanol
3 with 93–95% ee was obtained in 91–93% yields (Entries 3
and 4). The length of the methylene chains of inorganic–organ-
ic hybrid materials didn’t have a considerable effect on the
enantiomeric excess of product 3. The reaction in the presence
of hybrid silica (1R,2S)-2b gave (R)-5-pyrimidyl alkanol 3 with
90–97% ee (Entries 5 and 6), whereas the reaction in the pres-
ence of (1S,2R)-2b gave (S)-5-pyrimidyl alkanol 3 with 93% ee
(Entries 7 and 8). As shown in Table 1, the reproducibility of
the reaction is confirmed by 4 pairs of experiments carried
out under the same conditions (Entries 1, 2 and 3, 4 and 5, 6
and 7, 8). Hybrid silica is recoverable and can be used without
any loss of enantioselectivity (Entries 8 and 9).
3
to aldehydes. Since then, chiral catalysts supported on meso-
porous silica and silica gel have been developed by several
4
groups. However, compared to the chiral catalysts bound to or-
1
,2
5
ganic polymers and dendrimers, the enantioselectivity ob-
served in the dialkylzinc addition to aldehydes has remained
low to moderate by the use of these chiral catalysts immobi-
lized on silica gel. Meanwhile, we have been studying asym-
metric autocatalysis with amplification of ee6 in which the
chiral product acts as the chiral catalyst for its own production.
We here report a successful use of chiral inorganic–organic
hybrid materials, i.e., ephedrine immobilized on silica gel, as a
chiral catalyst and initiator in asymmetric autocatalysis: highly
enantioenriched 5-pyrimidyl alkanol with the corresponding
absolute configurations to those of chiral inorganic–organic hy-
brid materials was achieved.
,7
In summary, we demonstrated a highly enantioselective
asymmetric autocatalysis in the presence of chiral inorganic–
organic hybrid materials. 5-Pyrimidyl alkanol with up to 97%
ee was obtained with the absolute configuration corresponding
to that of the hybrid silica used as a chiral initiator.
Chiral inorganic–organic hybrid materials were prepared as
follows: activated silica gel was functionalized with either 3-
chloropropylsilyl or 5-bromopentylsilyl groups.3 The subse-
,8
Published on the web August 6, 2004; DOI 10.1246/bcsj.77.1587

1
588 Bull. Chem. Soc. Jpn., 77, No. 8 (2004)
Ó 2004 The Chemical Society of Japan
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT).
Experimental
Silica gel 60 (0.063–0.210 mm) (70–230 mesh ASTM) was pur-
chased from Kanto. Chiral hybrid silica 2a was synthesized accord-
ing to the literature.3,8
Preparation of (5-Bromopentyl)trimethoxysilane: 2-Propa-
nol solution (0.6 mL) of hydrogen hexachloroplatinate hexahydrate
References
1
a) K. Soai and S. Niwa, Chem. Rev., 92, 833 (1992).
(
and 5-bromo-1-pentene at 0 C. The mixture was refluxed at 140
C for 7 d, and was cooled to r.t. (5-Bromopentyl)trimethoxysilane
was obtained by distillation. A colorless oil; 13.34 g, yield 30%; bp
0.06 g, 0.12 mmol) was added to the mixture of trimethoxysilane
ꢁ
ꢁ
b) L. Pu and H.-B. Yu, Chem. Rev., 101, 757 (2001). c) R.
Noyori and M. Kitamura, Angew. Chem., Int. Ed. Engl., 30, 49
(1991).
2
For the early examples, a) S. Itsuno and J. M. Frechet,
ꢁ
1
1
1
10 C (2 mmHg). H NMR (CDCl3) ꢁ 0.65 (2H, m), 1.45 (4H, m),
J. Org. Chem., 52, 4140 (1987). b) K. Soai, S. Niwa, and M.
Watanabe, J. Org. Chem., 53, 927 (1988).
3 K. Soai, M. Watanabe, and A. Yamamoto, J. Org. Chem.,
55, 4832 (1990).
1
3
.84 (2H, m), 3.40 (2H, t, J ¼ 6:8 Hz), 3.57 (9H, s); C NMR (75
MHz, CDCl3) ꢁ 9.0, 21.9, 31.5, 32.4, 33.8, 50.5; IR (neat) 2949,
ꢂ1
1
458, 1192, 1091 cm ; Anal. Found: C, 35.60; H, 7.02%. Calcd
for C8H19BrO3Si: C, 35.43; H, 7.06%.
Preparation of (5-Bromopentyl)silyl-Functionalized Silica
4
a) M. Lasperas, N. Bellocq, D. Brunel, and P. Moreau,
Tetrahedron: Asymmetry, 9, 3053 (1998). b) S. J. Bae, S.-W.
Kim, T. Hyeon, and M. B. Kim, Chem. Commun., 2000, 31. c)
A. Heckel and D. Seebach, Angew. Chem., Int. Ed., 39, 163
(2000) d) Y.-M. Chung and H.-K. Rhee, C. R. Chimie, 6, 695
(2003). e) J. M. Fraile, J. A. Mayoral, J. Serrano, M. A. Peric a´ s,
L. Sol a´ , and D. Castellnou, Org. Lett., 5, 4333 (2003).
Gel:
gel was prepared from silica gel (silica gel was activated by reflux-
(5-Bromopentyl)trimethoxysilane immobilized on silica
9
ing in concd. hydrochloric acid for 4 h) and (5-bromopentyl)tri-
8
methoxysilane according to a literature procedure. Anal. Found:
C, 7.64; H, 1.64%.
Preparation of (1R,2S)- or (1S,2R)-Ephedrine Immobilized
on Silica Gel 2b: The chiral hybrid silica 2b was prepared by
the reaction of (5-bromopentyl)silyl-functionalized silica gel (2
g) and (1R,2S)- or (1S,2R)-ephedrine (0.582 g, 3.5 mmol), respec-
tively, in refluxing toluene for 20 h in the presence of triethylamine
5
6
Review: K. Soai and I. Sato, C. R. Chimie, 6, 1097 (2003).
a) K. Soai, T. Shibata, H. Morioka, and K. Choji, Nature,
378, 767 (1995). b) T. Shibata, H. Morioka, T. Hayase, K. Choji,
and K. Soai, J. Am. Chem. Soc., 118, 471 (1996). c) T. Shibata,
J. Yamamoto, N. Matsumoto, S. Yonekubo, S. Osanai, and K. Soai,
J. Am. Chem. Soc., 120, 12157 (1998). d) T. Shibata, S. Yonekubo,
and K. Soai, Angew. Chem., Int. Ed., 38, 659 (1999). e) K. Soai, S.
Osanai, K. Kadowaki, S. Yonekubo, T. Shibata, and I. Sato, J. Am.
Chem. Soc., 121, 11235 (1999). f) I. Sato, K. Kadowaki, and K.
Soai, Angew. Chem., Int. Ed., 39, 1510 (2000). g) I. Sato, R.
Yamashima, K. Kadowaki, J. Yamamoto, T. Shibata, and K. Soai,
Angew. Chem., Int. Ed., 40, 1096 (2001). h) I. Sato, H. Urabe, S.
Ishiguro, T. Shibata, and K. Soai, Angew. Chem., Int. Ed., 42,
315 (2003). i) I. Sato, K. Kadowaki, H. Urabe, J. H. Jung, Y.
Ono, S. Shinkai, and K. Soai, Tetrahedron Lett., 44, 721 (2003).
j) I. Sato, K. Kadowaki, Y. Ohgo, and K. Soai, J. Mol. Catal. A,
in press.
(
collected by filtration, washed with ether and methanol, and dried
0.49 mL, 3.5 mmol). After cooling the reaction mixture, 2b was
ꢁ
in vacuo at 40 C for 3 h. Chiral hybrid silica 2b was obtained (1.65
g). Elemental analysis showed that 0.60–0.63 mmol of ephedrine
was immobilized on 1 g of 2b. Anal. Found: C, 17.06; H, 2.73;
N, 0.88%.
Representative Procedure for the Enantioselective Addition
of Diisopropylzinc to Pyrimidine-5-carbaldehyde in the Pres-
ence of Chiral Hybrid Silica (1S,2R)-2b (Table 1, Entry 7):
To an ice cooled mixture of hybrid silica (1S,2R)-2b (60 mg,
ephedrine content: 0.63 mmol/g) and a toluene solution (1.0 M)
of i-Pr2Zn (0.12 mmol) was added a toluene (0.1 mL) solution of
aldehyde 1 (4.7 mg, 0.025 mmol) over a period of 30 min. The mix-
7
Reviews on asymmetric autocatalysis with amplification of
ꢁ
ture was stirred for 16 h at 0 C. Toluene (1.9 mL), i-Pr2Zn (0.2
ee: a) K. Soai, Enantiomer, 4, 591 (1999). b) K. Soai, T. Shibata,
and I. Sato, Acc. Chem. Res., 33, 382 (2000). c) K. Soai, I. Sato,
and Shibata, Chem. Record, 1, 321 (2001). d) C. Bolm, F.
Bienewald, and A. Seger, Angew. Chem., Int. Ed. Engl., 35,
1657 (1996). e) M. Avalos, R. Babiano, P. Cintas, J. L. Jim e´ nez,
and J. C. Palacios, Chem. Commun., 2000, 887. f) H. Buschmann,
R. Thede, and D. Heller, Angew. Chem., Int. Ed., 39, 4033 (2000).
g) M. H. Todd, Chem. Soc. Rev., 31, 211 (2002). Reviews includ-
ing both autocatalytic and non-autocatalytic reactions with ampli-
fication of ee: h) C. Girard and H. B. Kagan, Angew. Chem., Int.
Ed., 37, 2922 (1998). i) K. Mikami and M. Yamanaka, Chem.
Rev., 103, 3369 (2003).
mmol, 0.2 mL of 1.0 M toluene solution) and a toluene (1.0 mL)
solution of aldehyde 1 (18.8 mg, 0.10 mmol) were added succes-
sively, and the reaction mixture was stirred for 4 h. Toluene (7.5
mL), i-Pr2Zn (0.8 mmol, 0.8 mL of 1.0 M toluene solution) and
a toluene (2.0 mL) solution of aldehyde 1 (75.3 mg, 0.40 mmol)
were then added successively, and the mixture was stirred at 0
ꢁ
C for an additional 3 h. The reaction was quenched by adding 1
M hydrochloric acid (2.2 mL), and the mixture was neutralized
by adding satd. aq. sodium hydrogencarbonate (6.6 mL). The mix-
ture was filtered using Celite, and the filtrate was extracted with
ethyl acetate. The combined organic layers were dried over anhy-
drous sodium sulfate, and evaporated under reduced pressure. Pu-
rification of the residue by silica gel thin-layer chromatography
8
L. A. Carpino, E. M. E. Mansour, and J. Knapczyk, J. Org.
Chem., 48, 666 (1983).
J. S. Fritz and J. N. King, Anal. Chem., 48, 570 (1976).
(developing solvent, hexane:ethyl acetate = 2:1 v/v) gave (S)-pyr-
imidyl alkanol 3 with 93% ee in an isolated yield of 84% (0.103 g).
9