Asymmetric Autocatalysis as a Relay for Remote Amplification of Chirality of Target Molecules Used as Triggers

Article abstract of DOI:10.1021/acs.orglett.6b00742

Nearly racemic target molecules are enantiomerically enriched through an asymmetric autocatalytic relay for a remote amplification of chirality. Target alkynols with very low initial ee act as chiral triggers for asymmetric amplification of the Soai autocatalyst, which in turn enables the formation of the same alkynols with greater enantiomeric purity. Additionally, the stereochemical correlation between the trigger/target and autocatalyst molecules is discussed.

Full text of DOI:10.1021/acs.orglett.6b00742

Letter
pubs.acs.org/OrgLett
Asymmetric Autocatalysis as a Relay for Remote Amplification of
Chirality of Target Molecules Used as Triggers
Matías Funes-Maldonado, Bora Sieng, and Mohamed Amedjkouh*
Department of Chemistry, University of Oslo, Postboks 1033 Blindern, 0315 Oslo, Norway
S
* Supporting Information
ABSTRACT: Nearly racemic target molecules are enantiomerically enriched
through an asymmetric autocatalytic relay for a remote amplification of chirality.
Target alkynols with very low initial ee act as chiral triggers for asymmetric
amplification of the Soai autocatalyst, which in turn enables the formation of the
same alkynols with greater enantiomeric purity. Additionally, the stereochemical
correlation between the trigger/target and autocatalyst molecules is discussed.
generated from 2, was also able to propagate the amplified
he chiral homogeneity of biomolecules is considered to be
Tdirectly related to the origin and evolution of life and
continues to fascinate scientists.1 Homochirality might have
preceded the origin of life, but it remains intriguing how and
when biomolecules achieved high enantioenrichment. Once
generated, even with a small imbalance, complex chemical
systems are required for amplification and propagation of
homochirality.2 In this context, asymmetric autocatalysis is
particularly interesting; as such, a chemical system may
combine self-replication with amplification of chirality.
However, addressing this matter with direct autocatalytic
processes is far from obvious for most chemical reactions.
Alternatively, a nonenzymatic bias would provide a platform
toward one absolute sense of chirality.
chirality, which can be considered as a “read out” for transfer of
chirality to other alkanols and alkynols from azaaryl aldehydes
4−7.9,10 This observation offers opportunities toward the
design of responsive chemical systems by a judicious choice of
sequences of chemical reactions, one of which could be an
asymmetric autocatalytic reaction as the bias.
The proposed functioning of such a chemical system offers a
complementary model for homochirality to rise and become
ubiquitous without chiral templates, as illustrated in Figure 1.
Herein, we describe an unprecedented remote amplification
of chirality by taking advantage of the singularity of asymmetric
autocatalysis. The Soai reaction offered the first, and to date the
only, example of an asymmetric autocatalytic reaction to
provide spectacular chiral amplification.3 It is described as a
Frank-like1a reaction network operating in a closed system to
give rise to absolute asymmetric synthesis under kinetic control
with nonlinear amplification of ee.4 Remarkably, this reaction is
highly responsive to discrete chiral external stimuli prior to
initiation of the reaction, such as surfaces of inorganic crystals5
and circularly polarized light.6 In other responsive chiral
catalytic systems reactivity or selectivity can be modulated by
external signals.7 However, this chirality is already within the
described catalysts. Perhaps more interesting, chiral compounds
including alcohols, amino acids, epoxides, and [Cr(acac)3] can
serve as external stimuli to induce asymmetric autocatalysis of
1.6a,8
Figure 1. Strategies toward remote self-replication.
The overall process enables copy catalysis of stereochemical
information, chirality, with improved enantiopurity. We
demonstrate that a chiral target molecule TM, the external
signal, is able to trigger asymmetric amplification of autocatalyst
Zn−1 that operates as a chiral relay generated in situ by role
conversion from product to catalyst, propagating chirality in
newly formed TM. In other words, a nearly racemic target
molecule would be able to trigger the formation of its own chiral
catalyst for remote amplification of chirality.
As such, the reaction is an extremely sensitive qualitative
sensor for chirality and therefore can be considered as a tool for
a “read in” of a tiny optical activity. Besides, inspired by the
work of Soai et al., we recently reported that autocatalyst 1,
Received: March 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00742
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Organic Letters
Letter
To exemplify the basic principles described above, we noted
the advantage of alkynols 8−12 as target molecules in the
designed chemical system, as a model reaction, because they are
not capable of asymmetric amplification. The example depicted
in Scheme 1 illustrates a general protocol where a target chiral
with inversion of configuration. Therefore, we set out to
examine the structural features that could allow retention of
configuration as well as the extent of the asymmetric
amplification from very low initiator ee in these coupled
chemical systems. Thus, formation of 1 through autocatalytic
amplification was subjected to the external chiral stimulus of
various chiral alkynols 8−12. Withdrawn samples were used to
monitor product formation, and enantiomeric ratio and
absolute configurations of product 1 and 8−12 were
determined by chiral HPLC. For further experimental details,
see the Supporting Information.
Scheme 1. General Protocol for Remote Amplification of
Alkynols 8−12
Initially, the amplification process was carried out as
illustrated in Scheme 2, with chiral trigger/target compound
Scheme 2. Remote Asymmetric Amplification of Alkynols 8−
12
alcohol 8−12 with enantiopurity as low as 2% ee could be
amplified remotely. Thus, in the first step, 0.2 mol % of
molecule 8−12 triggers the asymmetric amplification of the
Soai autocatalyst Zn−1 to reach >98% ee. In the second step,
Soai autocatalyst induces (catalyzes) the formation of the target
alkynol 8−12 from its precursors.
However, the chiral sign may be dependent upon that of the
chiral initiator. Thus, the resulting process may lead to opposite
absolute configuration along the course of asymmetric
amplification. Shibata et al. have previously reported the
correlation of absolute configuration of initiator and Soai
alcohol.11 Therefore, before carrying out the remote
enantioselective amplification reactions, the correlation be-
tween the absolute configuration of the chiral propargylic
alcohols and the pyrimidyl alkanol has to be established and
may be quantified too.
We began our investigations by examining the asymmetric
autocatalytic amplification of the pyrimidyl alkanol 1 in the
presence of the trigger/target molecule (or chiral initiator, as
named by Soai et al.). Preliminary experimentation revealed
that starting with (S)-pyridyl alkynol 8 at 64% ee, autocatalytic
amplification of (S)-pyrimidyl alkanol 1 was observed up to
88% ee. Thus, pyridyl alkynol 8 is able to trigger the
amplification of alkanol 1. Surprisingly, as we could notice,
the absolute configuration of product 8 obtained through this
process was opposite to the absolute configuration of the
trigger molecule of the same chemical structure, i.e., its
enantiomer.
For example, it is Soai’s autocatalyst (R)-pyrimidyl alkanol 1
which induces formation of (S)-pyridyl alkynol 8. Thus, it is
reasonable to expect this stereochemical relationship to be
retained during the trigger step; i.e., (S)-8 would initiate
autocatalysis of (R)-1. A similar reversal phenomenon has been
observed for Soai autocatalysis with other chiral initiators.12 In
fact, the reversal phenomenon observed here occurs during the
trigger step and could be interpreted as a consequence of a
difference between the two reactions involved in this chemical
system, i.e., alkylation vs alkynylation. These two reactions
would proceed through distinct mechanisms as a result of
interactions between zinc alkoxides aggregates, which form the
catalytically active species. However, it was proposed that the
correlation of absolute configuration could be analyzed on the
basis of the bulkiness of various substituents in trigger
molecules.11
8−12 with ca. 10% ee and aldehyde 2 (catalytic amount) in the
presence of i-Pr2Zn in toluene at 0 °C. This way, high
amplification of chirality ensued after three to four autocatalytic
cycles to reach nearly enantiopure values of >98% ee for
product 1. Subsequently, the resulting mixture was added to a
solution of alkynylzinc reagent 3 followed by addition of
aldehyde 4−7.
(R)-Pyridyl alkynol 8 was used as chiral source with 8% ee to
induce asymmetric autocatalysis of (R)-1. Analyses of the
reaction mixture revealed that (R)-1 was amplified to 95% ee
after four consecutive autocatalytic cycles and then added to a
solution of alkynylzinc reagent 3 followed by addition of
aldehyde 4. In response, the (R)-1-catalyzed alkynylation
reaction provided 84% of (S)-product 8 with 67% ee (Table
1, entry 1). It should be noted that again this reaction sequence
proceeded with inversion of configuration from trigger to
product molecules. Similarly, when asymmetric amplification of
(R)-1 (98% ee after three cycles) was triggered by (S)-9 with
10% ee, reversal occurred to provide the opposite configured
(R)-9 with 82% ee (Table 1, entry 2).
Using quinoline or substituted pyridine as trigger/target
molecule resulted in improved remote amplification. Indeed,
compound (R)-11 with 10% ee was able to catalyze its own
remote amplification affording an excellent yield of 84% with
67% ee (entry 4). Interestingly, during this reaction sequence,
This result was encouraging as it provides evidence for the
functioning of the remote amplification of chirality, although
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DOI: 10.1021/acs.orglett.6b00742
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Table 1. Remote Asymmetric Amplification of Triggers 8−
12 through Soai Asymmetric Autocatalysis of 1
products 8−12
c
chiral
trigger
trigger’s initial
abs
conf 1
%
yield
% ee
a
b
d
entry ald
ee
(conf)
1
2
3
4
5
6
7
4
4
5
6
7
4
7
(R)-8
(S)-9
8
10
12
10
11
2
R
R
R
R
R
S
84
74
58
86
83
88
88
67 (S)
82 (R)
84 (R)
67 (R)
68 (R)
68 (R)
71 (S)
(S)-10
(R)-11
(R)-12
(S)-8
(S)-12
2
S
a
Reactions were carried out under nitrogen. The molar ratio in the
amplification step of chiral trigger-aldehyde 2- i-Pr2Zn = 0.01:1:1.4.
Figure 3. Amplification of Soai autocatalyst triggered with chiral seeds
8−12.
b
c
Isolated product after column chromatography. ee values were
d
determined by HPLC analysis. Absolute configuration was
determined by analysis of the corresponding Mosher ester H NMR
1
spectrum.
and (R)-11 (10% ee) prompted remarkable amplification of
(R)-1 to 62% and 74% ee within only the first cycle,
respectively.
formation of the (R) enantiomer of autocatalyst 1 was
observed, showing consecutive retention of configurations. In
an analogous reaction sequence, the target compound (R)-12
with an initial 11% ee amplified significantly by remote
replication to 68% ee (entry 5). Here again, the chiral relay
(R)-1 was identified during the replication process.
Finally, the reliability of this chemical system in remote
amplification of chirality was confirmed in translating very low
initial ee of trigger compounds. Figure 2 reveals the remarkable
In contrast, starting with similar initial ee, (S)-9 and (R)-10
were only capable of triggering amplification of (R)-1 in the
range of 17−22% ee. Notice that lower initial ee of the trigger
molecule also results in low amplification in the first cycle as,
for example, in the case of (S)-8 (2% ee). Interestingly, higher
levels of enantiopurity of 1 in the range of 72−94% ee are
reached with all trigger molecules 8−12 after the second
autocatalytic cycle. The most significant amplification of 1 was
observed in the case of (S)-8 with 11% ee after the first
autocatalytic cycle to increase up to 87% ee after the second
cycle.
The present study described a responsive chemical system
for a two-way communication of chirality with amplification of
ee. A target organic molecule with low ee, or nearly racemic, is
used as a chiral inducer/trigger of asymmetric autocatalysis that
can be translated into the remote asymmetric amplification of
the target molecules by use of Soai’s autocatalyst. Thus, chiral
information is restored with amplification to deliver a copy of
the target molecule with high fidelity, although high
amplification is also observed with opposite absolute
configuration for other substrates. Additionally, the latter can
be considered as amplification of minor enantiomer. This is not
necessarily a drawback for the present concept; this observation
reminds us of the challenging complexity in communicating
chirality as chemical information. As such, the results presented
here provide a new concept to make homochirality ubiquitous
and offer a first demonstration of a responsive chemical system
for a remote amplification of chirality by read-in and read-out of
chiral information from an external trigger using an
autocatalyst, generated in situ, as a chiral bias.
Figure 2. (a) Remote amplification of chirality with inversion of
configuration and (b) with retention of configuration.
amplification of autocatalyst (S)-1 to >98% ee triggered by 0.2
mol % of chiral target alkynols (S)-8 or (S)-12, initially with ca.
2% ee, into enantioenriched molecules as depicted in Table 1
(entries 6 and 7). Under identical conditions, enantiomer (R)-8
amplified to 68% ee at the expense of trigger (S)-8 (Figure 2a),
while (S)-12 improved itself notably to 71% ee (Figure 2b).
The autocatalytic amplification of 1 was examined as a
function of the structure and chirality of the chiral trigger
compound, as shown in Figure 3. Examination of this plot
reveals a clear structure dependence of asymmetric amplifica-
tion of 1 for the first autocatalytic cycles. Indeed, (R)-8 (8% ee)
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00742.
1
Detailed experimental procedures, H and 13C NMR
spectra, and other characterization data for the materials
(HPLC, HRMS) (PDF)
C
DOI: 10.1021/acs.orglett.6b00742
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T.; Sato, M.; Ishiguro, S.; Saito, T.; Morishita, Y.; Sato, I.; Nishino, H.;
Inoue, Y.; Soai, K. J. Am. Chem. Soc. 2005, 127, 3274.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mamou@kjemi.uio.no.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the Research Council of Norway
(FRIPRO Grant No. 205271), the University of Oslo, and
COST Action “Emergence and Evolution of Complex
Chemical Systems” (CM 1304).
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