Self-Replication and Amplification of Enantiomeric Excess of Chiral Multifunctionalized Large Molecules by Asymmetric Autocatalysis

Article abstract of DOI:10.1002/anie.201405441

Self-replication of large chiral molecular architectures is one of the great challenges and interests in synthetic, systems, and prebiotic chemistry. Described herein is a new chemical system in which large chiral multifunctionalized molecules possess asymmetric autocatalytic self-replicating and self-improving abilities, that is, improvement of their enantioenrichment in addition to the diastereomeric ratio. The large chiral multifunctionalized molecules catalyze the production of themselves with the same structure, including the chirality of newly formed asymmetric carbon atoms, in the reaction of the corresponding achiral aldehydes and reagent. The chirality of the large multifunctionalized molecules controlled the enantioselectivity of the reaction in a highly selective manner to construct multiple asymmetric stereogenic centers in a single reaction.

Full text of DOI:10.1002/anie.201405441

Angewandte
Chemie
DOI: 10.1002/anie.201405441
Asymmetric Amplification
Self-Replication and Amplification of Enantiomeric Excess of Chiral
Multifunctionalized Large Molecules by Asymmetric Autocatalysis**
Tsuneomi Kawasaki, Mai Nakaoda, Yutaro Takahashi, Yusuke Kanto, Nanako Kuruhara,
Kenji Hosoi, Itaru Sato, Arimasa Matsumoto, and Kenso Soai*
Abstract: Self-replication of large chiral molecular architec-
tures is one of the great challenges and interests in synthetic,
systems, and prebiotic chemistry. Described herein is a new
chemical system in which large chiral multifunctionalized
molecules possess asymmetric autocatalytic self-replicating
and self-improving abilities, that is, improvement of their
enantioenrichment in addition to the diastereomeric ratio. The
large chiral multifunctionalized molecules catalyze the pro-
duction of themselves with the same structure, including the
chirality of newly formed asymmetric carbon atoms, in the
reaction of the corresponding achiral aldehydes and reagent.
The chirality of the large multifunctionalized molecules
controlled the enantioselectivity of the reaction in a highly
selective manner to construct multiple asymmetric stereogenic
centers in a single reaction.
autocatalytically formed from completely achiral substrates
and reactants. Herein, we report the elaboration of large
chiral molecular architectures with autocatalytic self-replicat-
ing ability. In addition, we evaluate their function of self-
improvement, that is, improvement of their enantiopurity. In
our replication system, the large molecule is formed from
a branched alkylsilane backbone and the periphery of the
structure has a pyrimidine moiety with an asymmetric carbon
atom. Such chiral molecules catalyze the production of
molecules with the same structure, including the chirality of
newly formed asymmetric carbon atoms, in the reaction of the
corresponding achiral aldehydes and achiral dialkylzinc
reagent. It is noteworthy that the ratio of the diastereomers,
including enantiomers, and enantioenrichment continuously
increased, finally forming a nearly enantiopure product. Thus,
these molecules contain the functionalities of both self-
replication and self-improvement of enantioenrichment.
We have previously reported the asymmetric autocatal-
ysis[6,7] of 5-pyrimidyl alkanols with a significant amplification
of the enantiomeric excess (ee),[8] which enables the amplifi-
cation of chirality from extremely low values to near
enantiopure values (> 99.5% ee).[9–11] We have found here
that chiral macromolecules possessing a hexameric multi-
functionalized structure with as many as six asymmetric
carbon centers automultiply in a manner of asymmetric
autocatalysis. Even when large molecules with low isomeric
and enantiomeric purities were used as the initial catalyst, five
consecutive asymmetric autocatalysis events multiplied the
number of molecules (homoisomer: by a factor of ca. 900000
times) and amplified the diastereomeric ratio and ee value,
based upon the homoisomer of the newly formed chiral
molecules, to achieve greater than 99.5% ee.
We designed the large chiral molecules based upon 5-
pyrimidyl alkanols, which act as highly efficient asymmetric
autocatalysts in the addition reaction of diisopropylzinc to the
corresponding pyrimidine-5-carbaldehyde, as shown in
Figure 1. The hexakis(2-ethynyl-5-pyrimidyl alkanol)hexaal-
kylsilane 1 was synthesized from an alkylsilane backbone with
terminal acetylene and pyrimidyl alkanol as the monomeric
moiety by a coupling reaction (see Scheme S1 in the
Supporting Information). Its isopropylzinc alkoxide was
assumed to be the actual catalytic species. When racemic
alkanol was used as the coupling partner of the alkylsilane,
the same number of (S)- and (R)-pyrimidyl alkanols were
introduced to the terminals of the skeleton almost randomly,
that is, seven isomers of 1 were formed in the stochastic
racemic ratio with the binomial distribution.[12,13] Six equiv-
alents of asymmetric carbon atoms produce seven diastereo-
meric and enantiomeric isomers because of the six absolute
T
he creation of huge synthetic molecules possessing remark-
able self-replicating and self-improving functionalities
remains a great challenge in organic, prebiotic, and systems
chemistry.[1] To date, self-replications of oligonucleotides,[2]
oligopeptides,[3] and complementary artificial molecules[4] in
synthetic chemical systems have been demonstrated.[5] In
these chemical systems, the molecules replicate by a non-
enzymatic template-directed synthesis. Thus, these chemical
approaches are considered to be nice models for prebiotic
replicating reactions. In contrast, the chirality in the repli-
cated products in previously reported chemical systems is
based upon the pre-existing chirality of each building block.
To the best of our knowledge, there has been no report of an
efficient chemical process in which large chiral molecules are
[*] Prof. Dr. T. Kawasaki,[+] M. Nakaoda, Y. Takahashi, Y. Kanto,
N. Kuruhara, K. Hosoi, Prof. Dr. I. Sato,[++] Prof. Dr. K. Soai
Department of Applied Chemistry, Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
E-mail: soai@rs.kagu.tus.ac.jp
Homepage: http://www.rs.kagu.tus.ac.jp/soai/index.html
Prof. Dr. T. Kawasaki,[+] Prof. Dr. K. Soai
Research Center for Chirality, Research Institute for Science and
Technology (RIST), Tokyo University of Science (Japan)
[+] Present address: Department of Materials Science and Engineering
University of Fukui, Bunkyo, Fukui, 910-8507 (Japan)
[
++] Present address: Graduate School of Science and Engineering
Ibaraki University, Bunkyo, Ibaraki, 310-8512 (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific Research
from Japan Society for the Promotion of Science (JSPS) and MEXT-
Supported Program for the Strategic Research Foundation at Private
Universities, 2012–2016.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405441.
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Figure 1. Replication and self-improvement of the ee value and diastereomeric ratio of chiral molecules (S6)-1. a) The consecutive addition of
diisopropylzinc to the hexaaldehyde 2 in the presence of the chiral macromolecule 1. For the typical procedure of asymmetric autocatalysis, see
the Supporting Information. b) The continuous multiplication of the chiral molecule (S6)-1 and improvement of the isomeric ratio and
enantioenrichment of (S6)-1. c) Analysis of the seven isomers of the compound 1 by HPLC using a chiral stationary phase.
configurations (S or R) of the terminal pyrimidine moieties.
When a pyrimidyl alkanol having the S configuration with
high ee value was subjected to the coupling reaction, (S6)-
1 was obtained in almost enantiopure form. The correspond-
ing achiral hexaaldehyde 2 could be prepared by a similar
synthetic method using pyrimidine-5-carbaldehyde as the
monomeric coupling partner.
The experimental results of the asymmetric autocatalysis
using the hexamer 1 are shown in Figures 1a–c and Table S1.
Using these large synthetic molecules, we performed the
asymmetric autocatalytic reaction and determined the dia-
stereomeric ratio and ee value of the formed molecules 1.
Initially, the addition of diisopropylzinc to 2 was conducted in
the presence of the initial catalyst 1 (eehomo based on the
homoisomers (S6)-1/(R6)-1 was 59%; isomer ratios:
(S6)/(S5,R)/(S4,R2)/(S3,R3)/(S2,R4)/(S,R5)/(R6)-1 =
Then, the product 1 (including initial catalyst) was submitted
to the next autocatalytic reaction as the catalyst. After three
additional cycles of reaction, we observed further improve-
ment of the eehomo value and isomer ratio. The ratio of (S6)-
1 was significantly increased to 93% and the multiplication
factor of the homoisomer 1 from the initial catalyst was
achieved to greater than 12500 times, and the eehomo value of
1 was significantly amplified to greater than 99.5% ee. One
more cycle of the asymmetric autocatalytic reaction using
10 mol% of the catalyst 1 afforded the chiral molecule 1 as
the final product with a yield of 60% as the newly formed
product. The ratio of (S6)-1 was increased to 98%, the
eehomo value amplified to greater than 99.5% ee, and the
isomer ratio improved to (S6)/(S5,R)/(S4,R2)/(S3,R3)/(S2,R4)/
(S,R5)/(R6)-1 = 98:2:–:–:–:–:–). Thus, (S6)-1 has exclusively
increased by a factor of more than 92000 times during these
steps, and the ratio of other isomers containing the R confi-
guration almost disappeared, except for 2% of (S5,R)-1. That
is to say, self-replication of the large chiral molecule (S6)-1 has
been obtained in this autocatalytic system and additionally,
6:11:23:29:21:8:2). The isopropylation of each aldehyde
moiety proceeded readily to afford the hexaalkylated product
1 as a mixture with the initial catalyst 1. The eehomo value was
found to be enhanced to 75% ee, including the initial catalyst.
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Table 1: Asymmetric autocatalysis of (S4)-tetrakis(5-pyrimidyl alkanol)tetraalkylsilane 3.
Run[a]
Catalyst 3
Mixture of catalyst 3 and product 3
ratio[b,f]
Multiplication
eemono eehomo yield factor for
Product 3
ratio[b]
ratio[b]
amount
eemono eehomo
yield
[%][g]
(mol%)[c] [%][d] [%][e]
[%][d] [%][e]
[%]
(S4)-3
1[h]
2
6:25:38:25:6
20
0.06
24
0.5
52
28:26:21:16:9 24
97
4.9
34:26:17:14:9 77
52
96
28:26:21:16:9 20
74:14:7:4:1
77
106
26
84:12:3:1:–
86
3
4
5
74:14:7:4:1
96:3:1:–:–
97:2:1:–:–
5
5
5
77
97
98
96
>99.5
>99.5
96:3:1:–:–
97:2:1:–:–
98:1:1:–:–
97
98
99
>99.5 94
>99.5 91
>99.5 96
483
8795
168870
97:2:1:–:–
97:2:1:–:–
98:1:1:–:–
89
86
91
[a] A typical procedure for asymmetric autocatalytic replication is described in the Supporting Information. For the synthesis of 3 and 4, see
Scheme S2. [b] The isomeric ratios of (S4)/(S3,R)/(S2,R2)/(S,R3)/(R4)-3 are described. The ratio was determined by HPLC using a chiral stationary
phase. [c] The value is given for the amount of the tetraaldehyde 4 used. [d] The ee value of the monomeric pyrimidine part, assuming that all
peripheral pyrimidine functionalities in 3 were subtracted. [e] The ee value is based on the homoisomers (S4)-3 and (R4)-3. [f] The values are described
for a mixture of the initial catalyst 3 used in this reaction and the newly formed product 3. [g] The yield was calculated by subtracting the amount of the
autocatalyst 4 loading from the amount of isolated 4. [h] Initial catalyst was prepared by mixing a small amount of (S4)-3 and a stochastically
distributed racemic mixture of 3.
the improvement of the isomeric ratio and amplification of
enantioenrichment, that is, self-improvement, was observed
during this chemical replication cycle.
replication cycles (runs 2–5), the final compound 3 was
obtained with an eehomo value of greater than 99.5% and an
isomeric ratio of (S4)/(S3,R)/(S2,R2)/(S,R3)/(R4)-3 = 98:1:1:–:–.
The homoisomer (S4)-3 was automultiplied by about 170000
times to reach near enantiopure form. The amounts of (S,R3)-
3 and (R4)-3 were below the detection level in HPLC analysis.
In this chemical system, (S4)-3 replicated significantly with
improvement of its diastereomeric and enantiomeric ratio
during the continuing reaction cycles. The portion of the
isomers 3 containing R-asymmetric carbon was greatly
reduced in the mixture.
As described, these reactions are asymmetric autocatal-
ysis of large chiral molecules with an amplification of the
chirality. Thus, the asymmetric autocatalysis of 5-pyrimidyl
alkanol with amplification of the ee value[8] can work on the
large branched molecules with many reaction points. In
addition, it is the first example of a real chemical reaction,
that is, large chiral molecules catalyzing the production of
chiral molecules, having the same structure and same config-
uration, from an achiral substrate and reagent. The enantio-
selectivity of this reaction was controlled by the chirality of
the large multifunctionalized molecules. The synthetically
important aspect of this reaction is that in a single reaction,
The replication and improvement of the tetrakis(pyri-
midyl alkanol)tetraalkylsilane 3 was examined and the results
are summarized in Table 1. The initial catalyst 3, with a small
imbalance of enantiomers, was prepared by adding (S4)-3 to
the compound 3 with a stochastic racemic mixture of isomers.
The eehomo value of (S4)-3 was calculated to be 0.5% from the
amount of its enantiomer (R4)-3 and the eemono value (ee of the
monomeric pyrimidine part) was calculated to be 0.06%
assuming that all of the terminal pyrimidine functionalities
were taken off. In run 1, the above indicated compound 3 with
a small excess of enantiomer was utilized initially to perform
the addition of diisopropylzinc to the tetrakis(pyrimidine-5-
carbaldehyde)tetraalkylsilane 4. After the tetraalkylation of
4, 3 (eehomo = 52%, isomeric ratio: (S4)/(S3,R)/(S2,R2)/(S,R3)/
(R4)-3 = 28:26:21:16:9) was isolated as a mixture, containing
the initial catalyst 3, in 97% yield. The eehomo and eemono values
of (S4)-3 amplified significantly, reaching 52 and 24%,
respectively. The obtained mixture of initial catalyst and the
product 3 was subjected to the next replication cycle as the
starting catalyst for run 2. After an additional four runs of the
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multiple asymmetric centers are constructed with high
selectivity.
Received: May 20, 2014
Published online: September 3, 2014
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Chem. Soc. 2005, 127, 3274 – 3275.
Keywords: asymmetric amplification · asymmetric catalysis ·
autocatalysis · chirality · enantioselectivity
.
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[12] The seven isomers of the hexamer 1 are described for a number
of each S- and R-asymmetric carbon atoms as follows:
(S,S,S,S,S,S)-1 [abbreviated as (S6)-1], (S,S,S,S,S,R)-1 [abbrevi-
ated as (S5,R)-1], (S,S,S,S,R,R)-1 [abbreviated as (S4,R2)-1],
(S,S,S,R,R,R)-1 [abbreviated as (S3,R3)-1], (S,S,R,R,R,R)-
1 [abbreviated as (S2,R4)-1], (S,R,R,R,R,R)-1 [abbreviated as
(S,R5)-1], and (R,R,R,R,R,R)-1 [abbreviated as (R6)-1]. The
isomer of the tetramer 3 is also shown in the same manner.
[13] The isomer ratio of the stochastic racemic mixture of the
hexamer 1 was (S6)/(S5,R)/(S4,R2)/(S3,R3)/(S2,R4)/(S,R5)/(R6)-1 =
1:6:15:20:15:6:1. The ratio of seven isomers of compound
1 (except for the isomers caused by the asymmetric silicon
atoms and substitution pattern of (S)- and (R)-pyrimidyl
alkanols on the branches) can be analyzed using HPLC on
a chiral stationary phase.
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