Asymmetric Strecker Reaction Arising from the Molecular Orientation of an Achiral Imine at the Single-Crystal Face: Enantioenriched l- and d-Amino Acids

Article abstract of DOI:10.1002/anie.201611128

Strecker synthesis has long been considered one of the prebiotic reactions for the synthesis of α-amino acids. However, the correlation between the origin of chirality and highly enantioenriched α-amino acids through this method remains a puzzle. In the r

Full text of DOI:10.1002/anie.201611128

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International Edition: DOI: 10.1002/anie.201611128
German Edition: DOI: 10.1002/ange.201611128
Chirality
Asymmetric Strecker Reaction Arising from the Molecular Orientation
of an Achiral Imine at the Single-Crystal Face: Enantioenriched l- and
d-Amino Acids
Shinobu Miyagawa, Koji Yoshimura, Yusuke Yamazaki, Naoya Takamatsu, Tetsuya Kuraishi,
Shohei Aiba, Yuji Tokunaga, and Tsuneomi Kawasaki*
Abstract: Strecker synthesis has long been considered one of
the prebiotic reactions for the synthesis of a-amino acids.
However, the correlation between the origin of chirality and
highly enantioenriched a-amino acids through this method
remains a puzzle. In the reaction, it may be conceivable that the
handedness of amino acids has been determined at the
formation stage of the chiral intermediate a-aminonitrile, that
is, the enantioselective addition of hydrogen cyanide to an
imine. Herein, an enantiotopic crystal surface of an achiral
imine acted as an origin of chirality for the enantioselective
formation of a-aminonitriles by the addition of HCN. In
conjunction with the amplification of the enantiomeric excess
and multiplication of enantioenriched aminonitrile, a large
amount of near enantiopure a-amino acids, with the l- and d-
handedness corresponding to the molecular orientation of the
imine, is reported.
fore, the synthesis of a 5-pyrimidyl alkanol with greater than
99.5% ee was triggered by the treatment of the enantiotopic
crystal face of an achiral aldehyde with a dialkylzinc vapor.[11]
The Strecker reaction has been considered one of the
mechanisms for prebiotic synthesis of amino acids. Therefore,
the enantioselective addition of hydrogen cyanide (HCN) to
an achiral imine would be a challenge and could become one
of the approaches towards discovering the origin of chiral
amino acids. In this presentation (Scheme 1), an achiral
O
ne of the mysteries of the origin of life is the origin and
amplification leading to biological homochirality, that is, how
biology is almost predominantly composed of l-amino acids
and d-sugars.[1] Chiral factors[2] have been suggested as
candidates for the origin of chirality, such as circularly
polarized light,[3] the chiral surface of minerals,[4] chiral
crystallization,[5] spontaneous absolute asymmetric synthe-
sis,[6] and extra-terrestrial factors such as enantioenriched
meteoritic compounds.[7] Even if the initially induced chiral
compounds by these factors have extremely small enantio-
meric excess (ee), the compounds might acquire overwhelm-
ing enantioenrichment, as seen in l-amino acids, by the
appropriate amplification and multiplication processes.[8]
Among the proposed chiral factors, the enantioselective
reactions at the enantiotopic surface of an achiral compound
should also be an entry because enantioenriched compounds
could be synthesized from achiral compounds,[9] as exempli-
fied by oxidation[10a] and reduction[10b] to give enantiomeri-
cally imbalanced chiral products. Moreover, highly enantio-
Scheme 1. The concept of this work: enantioselective Strecker amino
acid synthesis induced by the molecular orientation of a prochiral
intermediate imine.
intermediate imine, prepared from a carbonyl compound and
amine, provides its own molecular orientation as a source of
asymmetric HCN addition to give an enantioenriched chiral
intermediate a-aminonitrile. In conjunction with enhance-
ment of the ee value and the amount of enantioenriched
aminonitrile, a large amount of near enantiopure a-amino
acid could be synthesized by hydrolysis. Different from the
suggested external chiral factors, such as those mentioned
above, the present method approaches the internal origin of
chiral amino acids, thus, an achiral imine with an enantiotopic
crystal face acts as both substrate and source of chirality
inside the prebiotic mechanism, that is, Strecker amino acid
synthesis.[12] To our knowledge, this is the first example of the
direct link between the molecular orientation of a prochiral
imine and l- and d-amino acids with high enantioenrichment
mediated by the asymmetric Strecker reaction.
À
selective C C bond formation has been achieved in combi-
nation with asymmetric autocatalysis (Soai reaction). There-
[*] S. Miyagawa, K. Yoshimura, Y. Yamazaki, N. Takamatsu, T. Kuraishi,
S. Aiba, Prof. Dr. Y. Tokunaga, Prof. Dr. T. Kawasaki
Department of Materials Science, University of Fukui
Bunkyo, Fukui, 910-8507 (Japan)
Previously, we reported the significant amplification of a-
aminonitrile 2[13a] (for structure see Scheme 2) in the solid
state from about 0.05% ee to near enantiopure by thermal
dissolution/recrystallization cycles, and the replicative forma-
tion of a-p-tolylglycine has been achieved in which l- and d-
E-mail: tk@u-fukui.ac.jp
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201611128.
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amino acids induce the amplification of its own l- and d-
intermediate 2, respectively.[13b] Herein, we show the asym-
metric addition of HCN to the enantiotopic single-crystal face
of achiral imine 1 to afford the corresponding l- and d-
aminonitrile 2 with up to greater than 99.5% ee, in combi-
nation with the asymmetric amplification and multiplication
of the solid product, which can be hydrolyzed to give l- and d-
amino acids without a decrease in enantiopurity (Scheme 2).
Scheme 2. The asymmetric addition of hydrogen cyanide (HCN) to the
imine 1 at the enantiotopic surface to afford the corresponding l- and
d-aminonitriles 2.
Figure 1. Single crystal of achiral imine 1. a) Microscope image of
a single crystal 1 from the (100) and its back side of (À100) planes
with enantiotopic parallelogram face shapes. See also Figure S1. b) A
packing diagram of imine 1. The red and blue planes correspond to
the enantiotopic (100) and (À100) faces, respectively. The hydrogen
atoms other than those of the imino group were removed for clarity.
See also Figure S1. c) Microscope image of single crystals 1. One
crystal was coated with a resin other than the indicated (100) face and
the other crystal was coated with a resin except for the indicated
(À100) face. d) Asymmetric addition of HCN at the enantiotopic faces.
The achiral imine 1 was prepared by dehydrative con-
densation between achiral p-tolualdehyde and benzhydryl-
amine, and its well-defined single crystals could be synthe-
sized by recrystallization from the mixed solvent of n-hexane
and toluene by slow concentration (Figure 1a). Single-crystal
X-ray structure analysis demonstrated that the crystal
ꢀ [14]
1 belongs to the achiral space group P1. When molecule
1 was projected along the a-axis in the packing diagram, the
Re face of the imino group was oriented towards the red-
colored a-face on the outside of the crystal (Figure 1b). In
turn, the Si face was oriented towards the opposite blue-
colored face. The X-ray analysis showed reproducibly the
single-crystal surfaces having the largest surface areas to be
enantiotopic (100) or its back side (À100) faces. These crystal
planes were parallelograms with an acute angle of about 608,
which could be absolutely differentiated and defined mor-
phologically to be (100) or (À100) planes based on the non-
superimposable parallelogram face shapes as indicated,
respectively (Figures 1a; see Figure S1 in the Supporting
Information). The single crystal 1, other than the single
reactive (100) or (À100) faces, was coated with an epoxy resin
to select one enantiotopic face from which HCN could
approach (Figure 1c), thus leading to enantioselective addi-
tion. It was assumed that racemic transformation would
proceed when the cyanide addition occurred at both enantio-
topic faces with the same probability.
The enantiotopic (100) and (À100) faces were independ-
ently reacted with HCN to form enantioenriched l- and d-
aminonitriles 2, respectively (Figure 1d and Table 1). Upon
treatment of HCN at the enantiotopic (100) face (area:
8.0 mm2) of the single crystal 1 (crystal A, 0.026 mmol) in
a methanol suspension of rac-2 (lot number I), the enan-
tioenriched l-aminonitrile 2 with 99% ee was synthesized in
the yield of 0.195 mmol after the amplification of the solid-
state ee value (Table 1, entry 1). In contrast, when the
opposite (À100) plane of 1 (crystal B) was reacted with
HCN in the suspension of rac-2 with the same lot number I,
the oppositely configured d-2 with an amplified ee value of
98% was obtained in a yield of 0.198 mmol by filtration
(entry 2). Although the eevalue of the suspended 2 was below
the detectable level after finishing the asymmetric HCN
addition, and before the thermal cycles, the initial tiny
enantiomorphic imbalance of 2 could be enhanced signifi-
cantly to afford highly enantioenriched 2 by the thermal
heating/cooling cycles.[13b] The suspensions of the rac-2 used in
each asymmetric reaction were prepared by dividing a solu-
tion of rac-2, obtained from a homogeneous reaction of 1 and
HCN (see the Supporting Information). The original solution
was identified with the indicated lot numbers I–VI. Further
reactions disclosed that cyanide addition at the morpholog-
ically defined (100) and (À100) faces of 1 (crystals C, D, E,
and F) reproducibly gives l- and d-aminonitrile 2, respec-
tively, with high ee values (entries 3–6). Because the stereo-
chemical relationships are constant between the absolute
configuration of the produced 2 and the parallelogram face
shape of the reacting single crystal of 1, the molecular
orientation of prochiral 1 in the crystal should correlate to the
handedness of the parallelogram face. Therefore, the absolute
orientation of the imino group at the crystal surface can be
determined from the absolute configuration of 2.[15]
Moreover, for the purpose of making sure of the
stereochemical outcomes further experiments were con-
2
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Table 1: Stereochemical correlations between the enantiotopic face of 1 and absolute handedness of 2.
Entry[a] Single-crystal 1
No. Amount (mmol) Face index Area (mm2) pre-suspended rac-2[b] ee [%][c] (config.) Amount[d] (mmol) thermal cycles[e]
Reactive surface
Lot No. of
2
Number of
1
2
3
4
5
6
7
8
A
B
C
D
E
0.026
0.028
0.0084
0.01
0.019
0.036
0.033
0.026
0.022
0.023
0.126
0.093
(100)[f]
(À100)[f]
(100)
8.0
8.8
2.0
3.2
7.0
6.0
10.5
9.6
7.0
I
I
99 (l)
98 (d)
90 (l)
92 (d)
93 (l)
0.195
0.198
0.130
0.227
0.232
0.170
10
10
9
II
II
II
II
I
(À100)
9
(100)
11
14
6
13
7
7
7
8
F
(À100)
(100)
92 (d)
G
G
H[h]
H[h]
I
>99.5 (l)
>99.5 (d)
97 (l)
84 (d)
91 (l)
0.198 (0.652)[g]
0.130 (0.698)[g]
0.278
(À100)
I
9
(100)
III
III
IV
IV
10
11
12
(À100)
(100)
(À100)
8.3
0.221
n.d.[i]
n.d.[i]
n.d.[i]
I
95 (d)
n.d.[i]
[a] In a 5 mL screw vial, the single crystal 1, coated with resin except for one enantiotopic face, was added to a suspension of rac-2 (ca. 0.5 mmol) in
methanol (1 mL) and includes HCN (0.036 mL, 0.85 mmol) at room temperature for entries 1, 2, 7, 8, 11, and 12 or 08C for entries 3–6, and 9 and 10.
After gentle stirring for 1–2 h, the single crystal 1 disappeared and the resin was removed. After the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU; 0.2 mL), the resulting mixture was submitted to a heating/cooling cycle to afford the enantioenriched 2 by filtration. See also the Supporting
Information for the details. [b] The rac-2 was synthesized by HCN addition to 1 in a homogeneous toluene solution in the presence of a catalytic
amount of DBU. See also the Supporting Information for the details. [c] Determined by high-performance liquid chromatography (HPLC) on a chiral
stationary phase. [d] The amount of isolated 2 by filtration. Near rac-2 from the filtrate was not included in this value. [e] The ee value before the
thermal amplification cycles was below the detectable level from the HPLC analysis of a part of the suspended solid 2. [f] Photos of the single crystal A
coated with a resin except for the (100) face and single crystal B coated with a resin except for the (À100) face are shown in Figure 1c. [g] The amount
of enantioenriched 2 could be increased by reactive crystallization. See also Ref. [13b]. [h] Photos of both the (100) and (À100) faces of the crystal H,
which was cut and submitted to the reaction after coating with resin, are shown in Figure 1a. [i] Not determined.
ducted using both enantiotopic faces originating from one
specific single crystal, which was cut into two pieces. The (100)
face of almost one-half of the crystal G was reacted with HCN
to afford l-2 with greater than 99.5% ee, after the amplifi-
cation of the ee value (entry 7). In contrast, the reaction at the
opposite (À100) face of the same crystal G gave the
oppositely configured d-2 with greater than 99.5% ee
(entry 8). It should be noted that further Strecker reaction
between achiral HCN, p-tolualdehyde, and benzhydrylamine
using the obtained 2 as a seed could increase the amount of
near enantiomerically pure 2, as shown here.[13b] The repro-
ducibility of the formation of the major enantiomer was also
checked by using pieces of the single crystals H and I to afford
the highly enantioenriched 2 with the corresponding molec-
ular handedness (entries 9–12). Therefore, the present enan-
tioselectivity of HCN addition would be induced by the direct
reaction of HCN at a single-crystal face, either Re or Si
enantioface, of the imino group because the dissolution of
1 causes disappearance of the chirality. Because the reaction
proceeds at one specific plane of the crystal, the direction of
the preferential approach of cyanide to the Re and Si faces
can be absolutely controlled.
riched solid 2, as observed here. Therefore, a larger molar
amount of 2 than that of the submitted 1 could be isolated by
filtration in a highly enantioselective manner. The present
thermal cycle is a highly sensitive and efficient method to
amplify the tiny enantio-imbalance induced by the asymmet-
ric HCN addition on the crystal surface of imine.
In addition, it should be noted that the absence of any
chiral factors which can chirally influence the asymmetric
amplification was confirmed by checking the pre-existing rac-
2 (see Table S1). Therefore, the present results support that
the asymmetric Strecker reaction solely arose from the two-
dimensional molecular orientation of the achiral imine 1.
In summary, we have demonstrated the enantioselective
addition of HCN to the enantiotopic surface of the imine 1 to
form the a-aminonitriles 2 in enantioenriched form with the
absolute configurations corresponding to the prochirality of 1.
In conjunction with the amplification of the solid-state
ee value and multiplication of the enantioenriched intermedi-
ate 2, a large amount of near enantiopure l- and d-amino
acids could be synthesized. Therefore, a possible origin for
chiral amino acids has been found by using the suggested
Strecker reaction.
During the HCN addition reaction, pre-suspended l- and
d-2 (racemic conglomerate) were grown according to the
formation of 2 because the solution was saturated in rac-2. It
was supposed that the crystals of l- and d-2 grew depending
on the enantioenrichment of newly formed 2. Therefore, the
enantioselectivity of HCN addition to 1 could be caught as an
imbalance of the l- and d-enantiomorphs 2. After finishing
the HCN addition, that is, the disappearance of the single
crystal 1, the enantiomerically imbalanced solid 2, including
initially added racemic conglomerate, was subjected to
thermal amplification[13b] thus affording the highly enantioen-
Acknowledgements
This work was financially supported by a Grant-in-Aid for
Scientific Research from the Japan Society for the promotion
of Science (JSPS KAKENHI Grant Numbers 23685012 and
16K05692), Daiichi-Sankyo foundation of life science, Nagase
science and technology foundation, Takeda Science Founda-
tion and Cooperative Program of Advanced Medicine and
Engineering Research of University of Fukui. T.K. thanks the
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& Technology, Tokyo University of Science for the research
resources.
Conflict of interest
The authors declare no conflict of interest.
Keywords: amino acids · asymmetric amplification · chirality ·
enantioselectivity · structure elucidation
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Manuscript received: November 14, 2016
Revised: December 3, 2016
Final Article published: && &&, &&&&
4
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Communications
Chirality
Face off: The correlation between the
molecular orientation of an achiral imine
and highly enantioenriched amino acids
has been achieved for the Strecker syn-
thesis. A highly enantioenriched amino-
nitrile was formed by the asymmetric
addition of HCN at one surface of a single
crystal of the imine, in combination with
amplification of the ee value and multi-
plication of the enantioenriched product.
Therefore, a possible entry for the origin
of chiral amino acids has been found by
using the Strecker reaction.
S. Miyagawa, K. Yoshimura, Y. Yamazaki,
N. Takamatsu, T. Kuraishi, S. Aiba,
Y. Tokunaga,
T. Kawasaki*
&&&& — &&&&
Asymmetric Strecker Reaction Arising
from the Molecular Orientation of an
Achiral Imine at the Single-Crystal Face:
Enantioenriched l- and d-Amino Acids
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