Chiral secondary alcohol-induced asymmetric autocatalysis: correlation between the absolute configuration of the chiral initiators and the product

Article abstract of DOI:10.1016/j.tetasy.2007.07.030

In the presence of various chiral secondary alcohols as chiral initiators, an enantioselective alkylation of a pyrimidine-5-carbaldehyde using diisopropylzinc was examined: a pyrimidyl alkanol was obtained in high yield and enantiomeric excess. The correl

Full text of DOI:10.1016/j.tetasy.2007.07.030

Tetrahedron: Asymmetry 18 (2007) 1759–1762
Chiral secondary alcohol-induced asymmetric autocatalysis:
correlation between the absolute configuration
of the chiral initiators and the product
Takanori Shibata,a,* Kimiko Iwahashi,a Tsuneomi Kawasakib and Kenso Soaib
aDepartment of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University,
Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
bDepartment of Applied Chemistry, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 16 June 2007; accepted 28 July 2007
Abstract—In the presence of various chiral secondary alcohols as chiral initiators, an enantioselective alkylation of a pyrimidine-5-carb-
aldehyde using diisopropylzinc was examined: a pyrimidyl alkanol was obtained in high yield and enantiomeric excess. The correlation
between the absolute configuration of the chiral secondary alcohols and the pyrimidyl alkanol is discussed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
In fact, when the isopropylation of 2-(tert-butylethynyl)
pyrimidine-5-carbaldehyde 1 was examined in the presence
of (S)-2-butanol 3 with ca. 0.1% ee, (S)-pyrimidyl alkanol 2
with 83% ee was obtained. (R)-2-Butanol 3 surely induced
(R)-pyrimidyl alkanol 2 (Scheme 1). These correlations
between the absolute configuration of the chiral secondary
alcohol and pyrimidyl alkanol 2 are derived from the chi-
rality in 2-butanol 3, that is, discrimination of the bulkiness
of the ethyl and methyl groups (Et > Me).
When the alkylation of a prochiral carbonyl compound is
examined in the presence of a small amount of a chiral sub-
stance, an enantiomeric imbalance most certainly appears
in the alkylated product. In most cases, however, the enan-
tiomeric imbalance (enantiomeric excess) is very slight and
a commonly used apparatus, such as HPLC using chiral
stationary phase, cannot detect it. We have comprehen-
sively studied an asymmetric autocatalysis with the ampli-
fication of the enantiomeric excess in the enantioselective
alkylation of pyrimidine-5-carbaldehyde using diisopropyl-
zinc (i-Pr2Zn), in which a slight enantiomeric imbalance is
drastically amplified by the consecutive asymmetric auto-
catalytic reaction,1–3 its mechanism study using physical
models has been reported by several groups including
us.4 When the asymmetric autocatalytic reaction is exam-
ined in the presence of a chiral substance (we named it as
a ‘chiral initiator’), a slight enantiomeric imbalance could
be induced, then it is amplified by the consecutive asym-
metric autocatalysis, finally highly enantiomerically
enriched pyrimidyl alkanol is obtained. The absolute
configuration of the product is dependent upon that of
the chiral initiator.5,6
In other words, the correlation of the absolute configura-
tions of chiral secondary alcohols and product 2 elucidates
the steric discrimination of the substituents (RL > RS) of a
OH
RS
RL
N
OH
N
(S)-2
[83% ee from (S)-3]
3: Rs=Me, RL=Et
CHO
t-Bu
N
N
1
+
OH
t-Bu
N
OH
RL
RS
i-Pr2Zn
N
(R)-2
[90% ee from (R)-3]
3: Rs=Me, RL=Et
t-Bu
Scheme 1. The concept of steric discrimination in the enantioselective
alkylation of 1 using chiral secondary alcohols as chiral initiators.
*
Corresponding author. E-mail: tshibata@waseda.jp
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.07.030

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T. Shibata et al. / Tetrahedron: Asymmetry 18 (2007) 1759–1762
chiral secondary alcohol in the present enantioselective
alkylation (Scheme 1). We here examined the enantioselec-
tive isopropylation of pyrimidine-5-carbaldehyde 1 using
various chiral secondary alcohols as chiral initiators. The
correlation of the absolute configurations is comprehen-
sively studied and the discrimination on the basis of the
bulkiness of various substituents is discussed.
To ensure the absolute configuration of alcohol 7, X-ray
single crystal analysis was performed to the crystalline
derivative. (À)-Alcohol 7 obtained from the resolution,
was transformed into the ferrocene carboxylate. The X-
ray crystal structure shown in Figure 1 clearly indicated
the absolute configuration of (À)-7 to be (R) (CCDC
618865).
Based on the concept depicted in Scheme 1, these results in
Table 1 could be explained as follows: in the alkylation of
pyrimidine-5-carbaldehyde 1 using i-Pr2Zn, phenyl was dis-
tinguished as a more bulky group than methyl and cyclo-
propyl, and as a less bulky one than isopropyl and tert-
butyl (Scheme 2).13 Therefore, isopropyl is surely more
bulky than cyclopropyl, as expected.
2. Results and discussion
We prepared chiral secondary alcohols of ca. 10% ee and
used them as chiral initiators of asymmetric autocatalysis.
First, alkyl-substituted benzyl alcohols were submitted to
the asymmetric autocatalysis as the chiral initiator7 (Table
1). When the alkylation was examined in the presence of
(S)-methyl phenyl carbinol 4, (S)-pyrimidyl alkanol 2 was
obtained in high ee and yield (entry 1) and vice versa (entry
2).8 The correlation [(S)-secondary alcohol induces (S)-2]
was the same as 2-butanol 3. On the contrary, in the case
of isopropyl phenyl carbinol 5,9 the correlation was oppo-
site: (S)-secondary alcohol 5 induced (R)-2 (entries 3 and
4). When the isopropyl group was replaced by a more
bulky tert-butyl group, that is, tert-butyl phenyl carbinol
610 was subjected to the asymmetric autocatalysis, the cor-
relation was the same as the results of 5 (entries 5 and 6).
When alcohol 711 with a cyclopropyl group instead of iso-
propyl substitution was used, the correlation was the oppo-
site (entries 7 and 8), which means that the correlation was
the same as the case of methyl phenyl carbinol 4.
Next, the unsaturated group-substituted benzyl alcohols
were used (Table 2): in the case of phenyl isopropenyl car-
binol 8,14 the correlation was the same as phenyl isopropyl
carbinol 5 (entries 1 and 2). Conversely, phenyl vinyl carb-
inol 915 brought about the opposite correlation (entries 3
and 4). These results imply that branched substituents play
a pivotal role for the bulkiness (Scheme 3).
Finally, b-branched alkyl group-substituted benzyl alco-
hols were examined (Table 3): when isobutyl phenyl carbi-
nol 1016 was used as a chiral initiator, (S)-alcohol 10
induced (S)-pyrimidyl alkanol 2 and the correlation was
the same as methyl phenyl carbinol 4 (entries 1 and 2).
Even if the isobutyl group was replaced with a more bulky
Table 1. Alkyl-substituted benzyl alcohols as chiral initiators
OH
∗
OH
CHO
N
N
Ph
ca. 10% ee
R
N
1
N
2
toluene, 0 °C
+
t-Bu
t-Bu
i-Pr2Zn
Entrya
Chiral initiatorb
Pyrimidyl alkanol 2
Yielde (%)
ee (%)
eec,d (%)
OH
1
2
4f
10 (S)
8 (R)
93 (S)
96 (R)
88
97
Ph
Ph
Me
OH
OH
OH
3
4
5
6
7
9 (S)
12 (R)
94 (R)
92 (S)
91
91
5
6
11 (S)
10 (R)
80 (R)
87 (S)
90
89
Ph
7
8
10 (S)
10 (R)
88 (S)
96 (R)
98
93
Ph
a The molar ratio of sec-alcohol–aldehyde 1–i-Pr2Zn = 0.02:2.1:5.
b sec-Alcohol with ca. 10% ee was prepared by thorough mixing of optically active and racemic ones. Ee was determined by HPLC on a chiral stationary
phase.
c The ee value was determined by HPLC on a chiral stationary phase (Daicel Chiralcel OD).
d See Ref. 12.
e Isolated yield.
f Enantiomerically pure and racemic 4 are commercially available.

T. Shibata et al. / Tetrahedron: Asymmetry 18 (2007) 1759–1762
1761
Table 3. b-Branched alkyl-substituted benzyl alcohols as chiral initiators
Entrya
Chiral initiatorb
Pyrimidyl alkanol 2c
ee (%)
ee (%)d
Yield (%)
OH
OH
1
2
10 (S)
10 (R)
96 (S)
96 (R)
92
96
10
11
Ph
3
4
12 (S)
8 (R)
95 (S)
93 (R)
90
97
Ph
Ph
OH
5
6
12
12 (S)
13 (R)
91 (S)
87 (R)
89
87
a See Table 1, footnote a.
b See Table 1, footnote b.
c See Table 1, footnote c and d.
d See Ref. 12.
Figure 1. X-ray crystal structure of ferrocenyl derivative of (À)-cycloprop-
yl(phenyl)methanol 7.
OH
OH
OH
OH
Ph
(R)-5
Ph
(R)-6
α
α
Ph
(R)-5
Ph
Ph
(S)-2
(R)-2
(R)-6
1
(S)-2
(R)-2
OH
OH
1
+
OH
OH
α
Ph
(R)-
Ph
(R)-
7
+
α
β
β
i-Pr2Zn
4
Ph
i-Pr2Zn
(R)-
10
(R)-11
Scheme 2. The steric discrimination of Me, i-Pr, t-Bu, c-Pr versus Ph
Scheme 4. The steric discrimination of isobutyl and neopentyl groups
group.
versus Ph group.
Table 2. Unsaturated group-substituted benzyl alcohols as chiral
tre causes steric bulkiness while the influence of the branch
initiators
at b-position is relatively small. (Scheme 4).
Entrya
Chiral initiatorb
Pyrimidyl alkanol 2c
ee (%)
eed (%)
Yield (%)
3. Conclusion
OH
1
2
10 (S)
11 (R)
94 (R)
86 (S)
87
92
8
9
We have studied the asymmetric induction using various
chiral secondary alcohols as chiral initiators in the alkyl-
ation of pyridine-5-carbaldehyde 1 by i-Pr2Zn. Based on
the correlation of the absolute configurations of 2-butanol
3 and pyrimidyl alkanol 2, the bulkiness of various substit-
uents was determined in comparison with the phenyl
group. In conclusion, it can be ascertained that branching
of the substituent and its position determines the bulkiness.
Ph
Ph
OH
3
4
12 (S)
13 (R)
97 (S)
96 (R)
94
96
a See Table 1, footnote a.
b See Table 1, footnote b.
c See Table 1, footnote c and d.
d See Ref. 12.
Acknowledgement
OH
OH
Ph
(R)-5
Ph
(R)-8
This research was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
(S)-2
1
OH
+
Ph
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initiator and alkylated product, asymmetric autocatalysis is
necessary for amplification of ee.
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autocatalysis using the obtained pyrimidyl alkanol as a chiral
catalyst (Ref. 3c).
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imply that the total effect of steric and electronic factors
determined ‘bulkiness’ in the enantioselective alkylation using
diisopropylzinc and the estimation of bulkiness discrimina-
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present system could achieve it.
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´
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isomer using modified Mosher method. See the literature in
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7. In a typical experiment, a secondary alcohol (0.02 mmol, ca.
10% ee) in a toluene (0.6 mL) and i-Pr2Zn (0.2 mL of 1 M