DOI: 10.1002/anie.201102263
Asymmetric Induction
Asymmetric Autocatalysis: Triggered by Chiral Isotopomer Arising
from Oxygen Isotope Substitution**
Tsuneomi Kawasaki,* Yasushi Okano, Etsuharu Suzuki, Shizuka Takano, Shotaro Oji, and
Kenso Soai*
The substitution of the atoms in the enantiotopic moiety of an
achiral molecule by their isotopes makes the present molecule
chiral.[1,2] Isotopically labeled compounds[3] have been used to
elucidate structural information,[3b] mechanisms of organic
reactions,[3c–e] and drug kinetics,[3f] however, asymmetric syn-
thesis using the chirality generated by isotope substitution
alone is difficult because of the very low enantiomeric excess
(ee) displayed when using deuterated chiral compounds as a
source of chirality.[4] Amplification effects of the helicity in
the polyisocianates[5a] and supramolecular polymers[5b] that
Scheme 1. Asymmetric autocatalysis in the presence of chiral isotopo-
results from hydrogen isotopes (D/H) have been reported.
mer of [18O]1.
And discrimination of hydrogen isotope chirality using
spectroscopic methods[6] and HPLC analyses with a chiral
stationary phase[7] have been reported.
chiral compound created by oxygen isotope substitution
serves as the chiral trigger of asymmetric autocatalysis to
afford alkanol 3 with high ee values. The relationship between
the absolute configurations of the chiral 18O-labeled hydro-
benzoin ([18O]1) and the product alkanol 3 is reproducible.
The enantiomers of [18O]1 were synthesized from chiral
trans-stilbene oxide (4), which was obtained by resolution of
its racemate by HPLC methods using a chiral stationary
phase. The enantiomers of oxide 4 had ee values greater than
99.5% and were submitted to the epoxide-opening reaction
using [18O]H2O under basic reaction conditions (Figure 1A).
By using 2-methoxyethanol as a cosolvent, the hydrolysis of
the epoxide by [18O]H2O proceeded stereoselectively to form
the chiral [18O]1 predominantly.
The enantioenrichment of the synthesized compound 1
was confirmed by 13C NMR spectroscopic analysis of its
diastereomeric bis[(S)-MTPA] esters 6 and 7 (MTPA = a-
methoxy-a-(trifluoromethyl)phenylacetyl; Figure 1B). The
chemical shift differences for the pair of carbon atoms
bound to normal and 18O-labeled groups can be observed.
We have determined the ee value of [18O](S)-1 and [18O](R)-1
to be greater than 95%. This arises because a) the ee value of
4 is very high (> 99.5% ee), and b) the epoxide-opening
reaction proceeds in highly stereoselective manner. Addi-
tionally, the signals that would arise from the opposite form
were not detected in the 13C NMR spectra of 6 and 7. Several
samples of chiral isotopomers 1 were prepared in a different
reaction batches using different apparatus, and they were then
submitted to the asymmetric autocatalysis reaction as chiral
triggers.
Recently, we have reported asymmetric autocatalysis with
amplification of ee values[8–11] that was triggered by chiral
compounds resulting from hydrogen (D/H)[12] and carbon
isotope (13C/12C)[13] substitutions. Meanwhile, the syntheses of
chiral compounds resulting from oxygen isotope substitu-
tions[14] and oxygen kinetic isotope effects (KIEs)[15] have
been reported. However, to the best of our knowledge, there
have been no reports of asymmetric synthesis or induction
utilizing chiral compounds resulting from oxygen isotope
substitution. Therefore, asymmetric autocatalysis initiated by
chiral compounds arising from 18O/16O substitution is chal-
lenging.
We selected a meso compound as the oxygen isotope
enantiomer (Scheme 1). Achiral meso hydrobenzoin forms
chiral oxygen isotopomers 1 after 18O labeling of the hydroxy
group in an enantioselective manner. These diols should be
chiral only as a result of the oxygen isotope (18O/16O)
substitution. The enantiomer whose 18O atom is bound to
the S-configured carbon center is described as [18O](S)-1,
while the opposite is described as [18O](R)-1.
Herein we report the first asymmetric induction by chiral
compounds arising from oxygen isotope substitution in
conjunction with asymmetric autocatalysis (Scheme 1). The
[*] Dr. T. Kawasaki, Y. Okano, E. Suzuki, S. Takano, S. Oji,
Prof. Dr. K. Soai
Department of Applied Chemistry and Research Institute for
Science and Technology, Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
E-mail: tkawa@rs.kagu.tus.ac.jp
We found that the isotopic chirality in [18O]1 was
successfully utilized as a chiral trigger of asymmetric auto-
catalysis (Table 1). When iPr2Zn addition to the pyrimidine-5-
carbaldehyde 2 was performed in the presence of [18O](S)-1[16]
that was synthesized from the resolved 4, the enantioenriched
(R)-3 was formed (entry 1). When [18O](R)-1 was used as the
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the Japan Society for the Promotion of Science.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 8131 –8133
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8131