Replication of α-amino acids: Via Strecker synthesis with amplification and multiplication of chiral intermediate aminonitriles

Article abstract of DOI:10.1039/c6cc05544c

Replication of chiral l- and d-α-(p-tolyl)glycine has been achieved in combination with the asymmetric induction, amplification and multiplication of their own chiral intermediates, l- and d-aminonitriles, in the solid-phase via the Strecker reaction between three achiral components, which is a plausible prebiotic mechanism for amino acid synthesis.

Full text of DOI:10.1039/c6cc05544c

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DOI: 10.1039/C6CC05544C
Amino acid triggers the amplification and multiplication of its own chiral intermediate
aminonitrile in the replicative Strecker reaction.
H3O+
p-Tol
CN
p-Tol
H2N CO2H
Replicate
Achiral:
HCN
+
p-TolCHO
+
RHN
L
L
Amplify
&
Multiply
Strecker
Reaction
Chiral
>99.5% ee
induction Large amount
RNH2
p-Tol
p-Tol
Replicate
RHN
CN
H2N
CO2H
D
D
R = Ph2CH–
H3O+

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DOI: 10.1039/C6CC05544C
Journal Name
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Replication of α-amino acid via Strecker synthesis with
amplification and multiplication of chiral intermediate
aminonitrile†
Received 00th January 20xx,
Accepted 00th January 20xx
Shohei Aiba, Naoya Takamatsu, Taichiro Sasai, Yuji Tokunaga, and Tsuneomi Kawasaki*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Replication of chiral L- and D-α-(p-tolyl)glycine has been achieved
in combination with the asymmetric induction, amplification and
multiplication of its own chiral intermediates, L- and D-amino
nitriles in solid-phase via the Strecker reaction between achiral
three components, which is a plausible prebiotic mechanism for
amino acids synthesis.
Carbonyl
compound
+
Amine
–H2O
Chiral induction
HCN
Imine
α-Aminonitrile*
α-Amino acid*
Replicate
The origin and amplification leading to biological homochirality,
as exemplified by the L-amino acids and D-sugars, has attracted
Amplification
&
Multiplication
H3O+
much attention. Starting from the discovery of molecular
chirality,1 original researches2 toward the origin of chirality
have been achieved including the effect of chiral physical
factors3 such as circularly polarized light,4 chiral surface of
inorganic crystals5 such as quartz, chiral crystallization of
achiral compounds6 including stereospecific solid-state
reactions2d,7 and the spontaneous absolute asymmetric
synthesis.8 The induced small chirality by the suggested
mechanisms should be significantly enhanced toward high
enantioenrichment as seen in biological compounds by the
appropriate mechanisms9 including the phenomenon of self-
disproportionation of enantiomers.10 Asymmetric autocatalysis
with amplification of enantiomeric excess (ee)2e,11 should be
strongly correlated to the homochirality of organic compounds.
In addition, it has been reported that chiral amino acids
including meteoritic compounds12 could act as a source of
chirality to synthesize the enantioenriched compounds13 such
as sugars and related compounds.14
*Chiral compound
Fig. 1
Concept of the present research: replicative Strecker amino acid synthesis.
Here we report the selective formation of a nearly
enantiomerically pure α-aminonitrile, which is chiral
a
intermediate of the Strecker amino acid synthesis. It is
produced by the reaction between hydrogen cyanide (HCN),
carbonyl compound and an amine. We found that an amino
acid could induce the enantiomeric imbalance toward the
formation of its own chiral intermediate (Fig. 1). Therefore, as
a result of the combination of the amplification and
multiplication of aminonitrile, more near enantiopure amino
acid could be newly synthesized after hydrolysis of
aminonitrile. The present reactions demonstrate one of the
models in which the chiral intermediate α-aminonitrile plays a
key role in the generation and evolution of homochirality of
amino acids via the Strecker synthesis.
We have previously reported18 the formation of
enantioenriched α-(p-tolyl)glycine nitrile 1 via spontaneous
crystallization8b,19 after a three-component Strecker reaction
between achiral HCN, p-tolualdehyde (3) and benzhydrylamine
(4). The stochastic distribution in the formation of
enriched enantiomorphs 1 was observed. In this work, the
formation of a selected enantiomer between - and -α-(p-
tolyl)glycine nitrile 1 was achieved by using chiral amino acids,
i.e., - and -α-(p-tolyl)glycine (2), as a source of chirality (Fig.
2). As the enantiomeric imbalance of 1 induced by amino acid
On the other hand, the Strecker reaction15 (Fig. 1) has long
been considered as one of the methods of synthesis of α-
amino acids on the primitive Earth before the origin of life.16
Therefore, replicative generation of highly enantioenriched
amino acids via this mechanism is an emerging research
subject in the fields of prebiotic, synthetic, and systems
chemistry,17 and which could be one of the possible
approaches to achieving biological homochirality.
L- and D-
L
D
L
D
2
can
be
significantly
enhanced
by
the
dissolution/crystallization-mediated amplification of ee,20,21
and the amount of enantioenriched 1 can also be multiplied, a
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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large amount of near enantiomerically pure amino acid 2, with subsequently differentiates the rate of crystalVigewroAwrtitchle Oannlinde
the same molecular handedness as that of the original subject, dissolution between and
-enDaOntI:io10m.1o03rp9/hCs6CC10.5544ACs
could be newly synthesized in a highly enantioselective enantioenriched 1 can be hydrolyzed to 2 without a decrease
L
-
D
manner after the hydrolysis of aminonitrile 1.
in enantiopurity, and the molecular handedness of the source
and product are the same; replication of amino acid 2 is
subsequently achieved.
HCN
+
p-Tolualdehyde (3)
Table 1 Stereochemical relationship between α-aminonitrile 1 and α-amino acid 2 in
the formation and amplification of enantiomorphs 1.
+
RNH2
4
R = Ph2CH–
Entrya
Amino acid 2
% ee Config.
Aminonitrile 1
% eeb
Config.
% yieldc
p-Tol
p-Tol
1d
2e
3
97
97
L
D
L
D
L
D
L
D
>99.5
>99.5
99
L
D
L
D
L
D
L
D
45
44
42
48
27
38
21
20
DBU, MeOH
RHN
CN
RHN
CN
Strecker
reaction
D-Aminonitrile 1
L-Aminonitrile 1
ca. 50
ca. 50
ca. 10
ca. 10
ca. 50
ca. 50
p-Tol
CO2H
4f
5g
6
98
p-Tol
Amplification &
multiplication
>99.5
>99.5
75
H2N
CO2H
D-2
H2N
L-2
7h
8h
H3O+
Solid D-1
(>99.5% ee)
Solid L-1
(>99.5% ee)
H3O+
47
a
The molar ratio used was 2:3:4:HCN = 1:2:2:3 (mmol). The reactions were
Fig. 2
Replicative formation of L- and D-α-(p-tolyl)glycine (2) via asymmetric
performed in a 1.0 M DBU solution in methanol in the presence of stir bar
induction in the formation of enantioenriched conglomerate of aminonitrile 1.
without using grass beads. Amino acid 2 completely dissolves in the reaction
b
medium containing DBU. The ee value was determined by high performance
liquid chromatography (HPLC), employing a chiral stationary phase. c The isolated
yield of solid product 1 by the filtration. d L-1 with 75% ee was obtained after four
cycles of amplification; an additional two cycles enhanced the ee to >99.5% ee.
Near racemic 1 was isolated from the solution-phase (filtrate) in 24% yield. e D-1
with 71% ee was obtained after three cycles of amplification; an additional one
cycle enhanced the ee to >99.5% ee. Near racemic 1 was isolated from the
solution-phase (filtrate) in 28% yield. f Eight cycles of amplification of solid-phase
In the presence of
L- or D-α-(p-tolyl)glycine (2), the
formation and amplification of enantiomorphic aminonitrile 1
was performed via a Strecker reaction between three achiral
substrates: HCN, aldehyde 3, and amine 4 (Fig. 2 and Table 1).
When highly enantioenriched
L-2 with 97% ee was used as a
source of chirality, -aminonitrile 1 with >99.5% ee was
L
g
ee were performed. Eleven cycles of amplification of solid-phase ee were
isolated in 45% yield by the filtration after the amplification of
solid-phase ee (entry 1). Near racemic 1 was isolated from the
solution-phase (filtrate) in 24% yield. On the other hand,
amino acid 2 led to the formation of near enantiopure
performed. h The thermal cycle was started after the dissolution of amino acid 2
in a suspension of racemic conglomerate 1.
D-
D
-1
Table 2 Stereochemical relationships between α-amino acids and aminonitrile 1.
after four amplification cycles (entry 2). No other compounds
such as the product of benzoin condensation of p-
tolualdehyde could be isolated from the filtrate except for
highly polar materials.
The enantiomeric purity of suspended solid 1 was
enhanced by the following heating/cooling cycle. After partial
dissolution of suspended solid 1 (ca. 80–90%) in the reaction
mixture at 45–50 °C, the remaining conglomerate 1 regrew
during the gradual cooling to room temperature over a period
Amino acids*
L-1
DBU
Chiral induction,
amplification and
multiplication
Enantiomer
HCN + 3 + 4
MeOH
D-1
Amino acids*
Aminonitrile 1b
Entrya
Amino acid
% ee
Config.
Yield
of
1
hour.
The
repetition
of
this
thermal
1
2
3
4
5
6
7
8
L
-Alanine
-Alanine
-Phenylalanine
-Phenylalanine
-Valine
-Valine
-Phenylglycine
-Phenylglycine
92
>99.5
99
99
99
99
99
98
L
D
L
D
D
L
54
50
54
49
58
45
41
32
dissolution/crystallization cycle amplified the ee of solid 1
significantly to afford 1 with up to >99.5% ee.
D
L
Even when
10% ee were provided as chiral triggers, highly
enantioenriched - and -solids 1 could be isolated with the
same stereochemical relationships, respectively (entries 3–6).
Therefore, -amino acid 1 induced the production of
aminonitrile 1 and -2 initiated the propagation of -1. When
- and -2 were dissolved in a prepared suspension of racemic
conglomerate 1, crystalline solid 1 acquired - and -excess,
L- and D-2 with as low as approximately 50 and
D
L
L
D
D
L
L
D
L
L-
D
D
D
a
The molar ratio used was amino acid:3:4:HCN = 1:2:2:3 (mmol). The reactions
were performed in a 1.0 M DBU solution in methanol. All amino acids completely
dissolve in the reaction medium containing DBU. b The ee value was determined
by HPLC, employing a chiral stationary phase.
L
D
L
D
respectively, after an adequate number of thermal cycles
(entries 7 and 8). Stereoselective adsorption22 of amino acid 2
at the crystal surface of conglomerate 1 would be included as a
source of asymmetric induction and amplification, which
It should be noted that amino acids other than α-(p-
tolyl)glycine (2) could also work as chiral triggers for the
2 | J. Name., 2012, 00, 1-3
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formation of enantioenriched 1 (Table 2). Therefore,
aminonitrile 1 was formed by the Strecker reaction in the
presence of -alanine after the amplification of solid-phase ee
between HCN, aldehyde 3 and primary amine 4 (entry 1). Thus,
the opposite -alanine induced the formation of -1 (entry 2).
- and -Phenylalanine also acted as a source of chirality for
the production of - and -1, respectively (entries 3 and 4).
When valine was submitted to this reaction, L-enantiomer
affords -1 and -valine gave -enantiomorph of 1 (entries 5
and 6). Unnatural phenylglycine that is demethyl derivative of
2 also worked as efficient chiral trigger form the production of
1 (entries 7 and 8). In these reactions, chiral inducers, i.e.,
amino acids completely dissolved in the reaction medium
L-
View Article Online
DOI: 10.1039/C6CC05544C
(L)
(a)
100
80
L
Initial ee of L-1
ca. 5%
60
0.5%
D
D
40
0.05%
L
D
20
L
D
1
2
3
4
5
Number of thermal
cycles (times)
0
20
D
D
L
Initial ee of D-1
ca. 5%
40
0.5%
60
0.05%
80
100
including DBU as same as the case using L- and D-2.
(D)
Next, we demonstrate the amplification of solid-phase ee
from extremely low ee (ca. 0.05% ee) to a near enantiopure
state (Fig. 3 and Table S1). The solid 1 with indicated ee was
prepared by mixing racemic conglomerate 1 and near
(b)
L-Solid 1
D-Solid 1
enantiopure L- or D-conglomerates 1, and the resulting 1 (with
Cycles
Cooling
Heating
indicated ee) was suspended in a 1 M DBU solution in
methanol in the presence of stir bar without grass beads. This
mixture was then subjected to the repetition of
dissolution/crystallization-induced amplification as mentioned
Dissolution
Crystallization
Initial low ee
>99.5% ee (L)
above. When
cycle, the ee was amplified to 26% ee (L). The next cycle
afforded -solid 1 with 91% ee; finally, >99.5% ee (L) was
achieved. The recovered yield of 1 was 54%. The opposite D-1
with ca. 5% ee could also be amplified to 96% ee (D) after four
thermally controlled amplifications. Even when the
enantioenrichment was reduced to ca. 0.5% ee, the initially
existing major enantiomorph 1 dominated; up to >99.5% ee
was achieved after five heating/cooling cycles. Furthermore,
L-1 with ca. 5% ee was subjected to the thermal
Fig. 3
(a) Amplification of solid-phase ee of L- and D-α-aminonitrile 1 from
extremely low ee (ca. 0.05% ee) to near enantiopurity (>99.5% ee) by the
heating/cooling cycles. (b) Simplified model for the production of highly
enantioenriched solid 1 (L-enantiomorph).
L
In addition, reactive crystallization of selected enantiomer
1 was realized; thus, seed crystal 1 gave a further amount of a
near enantiomerically pure crystalline solid 1 by the portion-
wise addition of three achiral reagents (Fig. 4 and Table S2).
For example, using
consecutive additions of HCN, aldehyde 3, and amine 4 were
conducted to precipitate -1 (46.5 g) with >99.5% ee in 76%
isolated yield, without thermal amplification. On the other
hand, the amount of -1 with >99.5% ee could also be
increased as a result of the three-component Strecker reaction.
Therefore, automultiplication of near enantiopure - and -α-
L-1 (0.08 g) with >99.5% ee as a seed, five
the initial very small L- and D-imbalances, approximately 0.05%
ee, were also significantly enhanced during five amplification
cycles; up to >99.5% ee was achieved.
L
A linear relationship was observed between the initial ee
and the number of thermal cycles required to achieve high ee,
therefore, it was assumed that near racemate 1 dissolved
during the heating step to afford a reduced amount of
suspended solid 1 with amplified ee (Fig 3b). In turn, cooling-
induced deracemization may occur during gradual crystal
growth without a decrease in the amplified ee. In the simple
calculations (Fig S1), dissolution of 80% of rac-1 from
enantioenriched solid 1 with 5% ee (er = 52.5/47.5) affords
solid 1 with 25% ee (er = 12.5/7.5). After the ideal
deracemization of 1 (er = 62.5/37.5, 25% ee), next cycle
affords near enantiomerically pure solid (er = 100/0, 100% ee).
It was calculated that four and five thermal cycles afford
enantiopure solids starting from the solid 1 with 0.5% ee and
0.05% ee, respectively. Since the initial very low ee (ca. 0.05%)
could be enhanced to become near enantiopure state, it was
supposed that exact racemic dissolution during heating step
and efficient deracemization during cooling step are the key of
this process. Therefore, this practically perfect thermal cycle is
a highly sensitive and powerful method to improve an
D
L
D
aminonitrile 1 has been achieved in a highly stereospecific
manner. To the best of our knowledge, it is the first example of
highly enantioselective reactive crystallization of three
component reaction involving C–C bond formation.
L-1
L-1
Seed
>99.5% ee
(Small amount)
Large amount
>99.5% ee
HCN + 3 + 4
D-1
D-1
Fig. 4
Amplification of solid-phase ee of L- and D-α-aminonitrile 1 from extremely
low ee (ca. 0.05% ee) to near enantiopurity (>99.5% ee) by the heating/cooling cycles.
In summary, we have demonstrated one of the reaction
models for the replication of chiral α-amino acids via the
proposed prebiotic mechanism—the Strecker synthesis. Amino
extremely small imbalance of L- and D-enantiomorphs of 1
toward a near enantiopure state (>99.5% ee).
acids, i.e.,
L
- and
D
-α-(p-tolyl)glycine 2, acting as a source of
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chirality, asymmetric
Journal Name
Shoji, D. Hashizume and H. Koshino, Angew. Chem. Int. Ed.,
induction,
amplification,
and
View Article Online
2006, 45, 4593; (f) R. Breslow and M. S. Levine, Proc. Natl.
DOI: 10.1039/C6CC05544C
multiplication, were realized at the formation stage of the
chiral intermediate α-aminonitrile 1 and amino acid 2 with the
same structure and configuration as that of the original amino
acid was newly synthesized by the following hydrolysis. Even if
a small amount of amino acid with low ee was induced by the
proposed origin of chirality initially, it is possible to obtain both
quantitatively and enantiomerically enhanced amino acids by
the reaction sequence discussed here. These results should
contribute to one of the approaches toward understanding the
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This work was supported by JSPS KAKENHI, Takeda Science
Foundation and Cooperative Program of Advanced Medicine
and Engineering Research of University of Fukui. T.K. thanks to
Research Center for Chirality, Research Institute for Science &
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