Highly Stereoselective Strecker Synthesis Induced by a Slight Modification of Benzhydrylamine from Achiral to Chiral

Article abstract of DOI:10.1002/chem.201704033

2-Methylbenzhydrylamine is a chiral variant of achiral benzhydrylamine; however, the chirality formed from the small difference between the phenyl and o-tolyl groups is not expected to induce sufficient stereoselectivity in conventional homogeneous reactions. Initiated by the spontaneous formation and asymmetric amplification of the enantioenriched N-benzhydryl-α-aminonitrile forming conglomerate, we here report that (S)- and (R)-configured title amine, upon the Strecker reaction with achiral aldehydes and HCN, afford the corresponding α-aminonitriles with up to >99.5 % diastereomeric excess, in conjunction with an enhancement of chirality in the solid state. l-Alanine with 98 % ee was synthesized from the (S)-amine by using the method discussed here. Achiral aromatic and heteroaromatic aldehydes could also be successfully utilized to afford chiral α-aminonitriles in a highly stereoselective manner. The stereodivergent synthesis of styrylglycine nitriles has also been accomplished by using racemic and enantioenriched 2-methylbenzhydrylamine. Thus, accompanied with a small rearrangement of the common substrate from achiral toward chiral, the present reactions induce an enhancement of chirality, and expands the concept of stereoselective synthesis to increase the opportunity to access highly enantioenriched compounds such as α-amino acids.

Full text of DOI:10.1002/chem.201704033

A Journal of
Accepted Article
Title: Highly Stereoselective Strecker Synthesis Induced by the Slight
Modification of Benzhydrylamine from Achiral to Chiral
Authors: Naoya Takamatsu, Shohei Aiba, Takuya Yamada, Yuji
Tokunaga, and Tsuneomi Kawasaki
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To be cited as: Chem. Eur. J. 10.1002/chem.201704033
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10.1002/chem.201704033
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Highly Stereoselective Strecker Synthesis Induced by the Slight
Modification of Benzhydrylamine from Achiral to Chiral
Naoya Takamatsu,[b] Shohei Aiba, [b] Takuya Yamada,[b] Yuji Tokunaga,[b] and Tsuneomi Kawasaki*[a]
Abstract: 2-Methylbenzhydrylamine is a chiral variant of achiral
benzhydrylamine, however, the chirality formed from the small
difference between the phenyl and o-tolyl groups is not expected to
induce sufficient stereoselectivity in conventional homogeneous
reactions. Initiated by the spontaneous formation and asymmetric
amplification of the enantioenriched N-benzhydryl-a-aminonitrile
forming conglomerate, we here report that (S)- and (R)-configured
title amine, upon the Strecker reaction with achiral aldehydes and
HCN, afford corresponding a-aminonitriles with up to >99.5%
diastereomeric excess, in conjunction with the enhancement of
chirality in solid-state. L-Alanine with 98% ee was synthesized from
the S-amine via the method discussed here. Achiral aromatic and
heteroaromatic aldehydes could also be successfully utilized to
afford chiral a-aminonitriles in highly stereoselective manner. The
stereodivergent synthesis of styrylglycine nitriles has also been
accomplished by using racemic and enantioenriched 2-
aminonitrile 4b (see figure in Table 1 for the chemical structure)
in combination with the Strecker reaction between three achiral
substrates.[18] The tiny imbalance of the enantiomorphous
aminonitriles could be greatly amplified from ca. 0.05%
enantiomeric excess (ee) to near enantiopure (>99.5% ee) by
thermal dissolution/crystallization cycles.[19,20] Although this
transformation is powerful for the synthesis of large amounts of
highly enantioenriched a-aminonitriles—the chiral intermediates
of a-amino acids—crystallization of aminonitriles in the
conglomerates is necessary.
One of the solutions to this limitation is a stereoselective
reaction, introducing chirality to the substrate, i.e., crystallization-
induced diastereomer transformations.[21] Employing this
concept, diastereoselective Strecker formations have been
reported in which chiral a-phenylglycine amide[22] and b-amino
alcohols[23] were used as chiral substrates. Diastereomeric salt
formation of aminonitriles has also been reported.[24]
methylbenzhydrylamine. Thus, accompanied with
a
small
rearrangement of the common substrate from achiral toward chiral,
present reactions including an enhancement of chirality, would
expand the concept of stereoselective synthesis to increase the
opportunity of addressing highly enantioenriched compounds such
as a-amino acids.
NH2
R
amplification of ee
RCHO 3
+
HCN
XHN
CN
*
in solid-state
(L)/(D)-4, high ee
achiral 1 (=XNH2)
slight
modification
chirality
α-amino acid*
Strecker reaction
Introduction
chiral 2 (=X*NH2)
Stereochemistry is an important research topic in the field of
organic synthesis,[1] therefore, the stereoselective synthesis of
chiral a-amino acids holds great significance.[2–5] In chemical
transformations, Strecker synthesis[6] is a simple yet powerful
strategy for the preparation of a-amino acids.[7] After pioneering
work in the asymmetric synthesis of L-alanine using (S)-
phenylethylamine, acetaldehyde, and hydrogen cyanide
(HCN),[8] further stereoselective reactions using chiral substrates
have been developed.[9,10] Catalytic asymmetric Strecker
reactions have also been developed to provide a wide variety of
enantioenriched intermediate aminonitriles.[11,12]
(
L
)/(
D
)-5, high de
NH2
RCHO 3
+
HCN
enhancement of de
R
*
in solid-state
X*HN
CN
*
Scheme 1. The concept of this work.
Here we discuss a highly stereoselective Strecker synthesis
induced by slight modification of an achiral substrate to a chiral
substrate, based on the research on the spontaneous formation
We previously reported on the spontaneous formation[13,14]
(total spontaneous resolution)[15–17] of enantioenriched a-
of chiral N-benzhydryl-a-aminonitriles
4
with significant
amplification of ee in solid-state, i.e., Viedma ripening[25]
(Scheme 1). 2-Methylbenzhydrylamine (2), which is a chiral
variant of achiral 1, can act as a highly efficient chiral parent
amine for Strecker synthesis between achiral aldehydes and
HCN, with significant enhancement of stereoselectivity in solid
state, up to >99.5% diastereomeric excess (de).
[a]
Prof. Dr. T. Kawasaki
Department of Applied Chemistry
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo, 162-8601 (Japan)
E-mail: tkawa@rs.tus.ac.jp
To our knowledge, there are no reports on the approach of
stereoselective synthesis induced by slight modification of a
common substrate from achiral to chiral, even in crystallization-
induced diastereomer transformations. Asymmetric induction
power of chiral substrate such as 2-methylbenzhydrylamine (2),
in which closely similar substituents are attached at the
[b]
Mr. N. Takamatsu, Mr. T. Yamada, Mr. S. Aiba, Prof. Dr. Y.
Tokunaga
Department of Materials Science and Engineering
University of Fukui
Bunkyo, Fukui, 910-8507 (Japan)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201704033
Chemistry - A European Journal
FULL PAPER
asymmetric carbon center without stereo-directing group, is
supposed to be small.[26] Therefore, present research would
expand the possibility of stereoselective synthesis to address
wide spectrum of enantiomerically enriched compounds such as
a-amino acids.
On the other hand, as same as the previously reported 4b
with the p-tolyl substituent (entry 2), the single crystal 4c with an
o-tolyl group belongs to the chiral space group P21 forming
conglomerate (entry 3). In the structure of 4c with the o-tolyl
group, two molecules with the same handedness were included
in the crystal lattice (figure in Table 1). The molecules 4c are
helically arranged along the b-axis through weak hydrogen
bonding between cyano and amino groups (Supporting
Results and Discussion
Information Figure S1).
A crystal of 4d with the m-tolyl
substituent and 4e with p-bromophenyl substituent crystallized in
achiral space groups, respectively (entries 4 and 5). Therefore,
crystallization-based enantioselective synthesis is applicable for
the 4c (including the previous 4b).
Single-crystal structures of
achiral benzhydrylamine (1)
a
-aminonitriles 4 formed from
Racemates of aminonitriles 4 were prepared by the Strecker
reaction between benzhydrylamine 1, the aldehydes 3a–e, and
HCN. From benzaldehyde 3a, crystal of racemic compound 4a
(achiral space group P21/c) was obtained from acetonitrile
solution after slow evaporation (Table 1, entry 1). In the crystal
structure of rac-4a (figure in Table 1), the pseudo-1,3-diaxial
conformation[27] was observed between the methine of the
benzhydryl group and the cyano group. The stability of this
conformation was indicated from the optimized structure of the
corresponding aminonitriles, including 4a, using the DFT method
(see Supporting Information Table S1). It should be noted that
this pseudo-1,3-diaxial conformation was commonly observed in
all the crystal structures of a-aminonitriles in the present study.
Spontaneous formation and asymmetric amplification of
enantioenriched N-benzhydryl-o-tolylglycine nitrile (4c)
The Strecker reaction between achiral 1, o-tolualdehyde (3c),
and HCN was conducted in
a 1.5 M solution of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in methanol (Figure 1a
and Supporting Information Table S2). As the three-component
reaction proceeded, solid 4c appeared spontaneously in
enantioenriched form; thus, total spontaneous resolution
occurred as observed in the formation of 4b.[18] To check the
distribution of the molecular handedness and the ee, further
Strecker reactions were conducted. Among the 18 experiments
carried out, solid product 4c was formed in all cases and the
absolute handedness exhibited an approximate stochastic
distribution; the L-enantiomer occurred nine times and the
opposite D-form occurred nine times. Because the reaction was
initiated by mixing only achiral reagents without the addition of
any chiral materials, the present observation, i.e., statistical
formation of L- and D-4c, constitutes one of the conditions
necessary for the spontaneous absolute asymmetric synthesis.
Table 1. Single-crystal structures of a-aminonitriles
benzhydrylamine (1).
4 derived from
R
Ph2CHNH2 1 (=XNH2)
+ RCHO 3a–e
+ HCN
single crystals
4a–e
XHN
CN
*
(a)
R
amplification of ee
Ph2CHNH2 1
(=XNH2)
XHN
CN
CN
+
RCHO 3b, c
+
DBU
spontaneous
formation
L
-4b, c
rac-4a
conglomerate 4c
MeOH
R
HCN
Substituent R
Entry
N-benzhydryl-α-aminonitrile 4
amplification of ee
(aldehyde 3)
XHN
CCDC[a]
1560341
1055257
1560325
1560343
1560344
p-tolyl (previous)
3b: R =
D
-4b, c
Space group
o-tolyl (present work)
3c:
1
phenyl (3a)
p-tolyl (3b)
4a
4b
4c
4d
4e
Achiral
Chiral
P21/c
P21
(b)
(c)
2[b]
3
100
75
50
25
0
D
-4c
L-4c
4
o-tolyl (3c)
Chiral
P21
2
0
4
m-tolyl (3d)
(p-Br)C6H4 (3e)
Achiral
Achiral
C2/c
P21/n
L
-4c
(ca. 5 to 99% ee)
5
0
2
4
6
8
10
–20
–10
0
10
20
ee [%]
time [day]
[a] Deposit number of the Cambridge Crystallographic Data Centre (CCDC).
[b] Previously reported structure. See also ref. 18.
Figure 1. (a) Spontaneous formation and asymmetric amplification of
enantioenriched aminonitriles 4b and 4c. (b) Histogram of the
enantioselectivity of spontaneous formation of L- and D-4c. (c) Asymmetric
amplification of solid-state L-4c by Viedma ripening.
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Next, we examined the amplification of crystal ee by
applying Viedma ripening.[28–30] L-Aminonitrile 4c with ca. 5% ee
was suspended in a solution of DBU (1.5 M) and HCN (2 eq) in
methanol and the resulting mixture was vigorously stirred in the
presence of glass beads (Figure 1c and Supporting Information
Table S3). The ee was amplified to 10% ee after 19 h and,
finally, 4c with 99% ee was isolated in 37% yield after 10 days
by filtration. The ee of suspended solid 4c could also be
enantiomerically improved from near racemic to 94% ee by the
heating/cooling cycle (Supporting Information Figure S2).[31]
Therefore, highly enantioenriched aminonitrile 4c could be
synthesized without any assistance of chiral materials.
slight modification was carried out toward 1 by the introduction
of one methyl group to be chiral 2-methylbenzhydrylamine (2).[34]
The chirality of 2 originates from the difference between the
phenyl and o-tolyl groups. It is not expected to induce sufficient
stereoselectivity in the homogeneous reaction.[35] We postulated
that the significant asymmetric amplification observed in 4c and
previous 4b could be successfully substituted by the
enhancement of solid state chirality in the stereoselective
synthesis.
Because of the formation of racemic compound 4a by the
reaction between achiral 1, benzaldehyde (3a) and HCN (Table
1, entry 1), the Strecker reaction of 3a was performed utilizing
chiral 2 (Figure 2). Therefore, (R)-2 with 96% ee, 3a and HCN
was reacted in 2-propanol in the presence of 0.1 M DBU as an
epimerizing reagent (Figure 2a). After precipitation of the solid
product 5a and stirring of the reaction suspension overnight
without using glass beads, syn-(L)-5a with 99% de (>99.5% ee)
was obtained in 77% isolated yield simply by filtration
(Supporting Information Table S6). The opposite, (S)-2, afforded
enantiomeric syn-(D)-5a with >99.5% de in 85% yield. The
stereochemistry of 5a was confirmed by X-ray single-crystal
structure analysis (Figure 2b).
Stereoselective Strecker synthesis using enantioenriched 2-
methylbenzhydrylamine (2).
Benzhydrylamine 1 is one of the useful parent amines in
asymmetric Strecker reactions[12a] and related stereoselective
reactions.[32] The benzhydryl substituent is removable under
acidic or reductive conditions to afford the amino group after
desired transformation. In addition, it is likely to form crystalline
derivatives.[33] Therefore, in order not to lose these properties,
(a)
PhCHO 3a
+
HCN
Ph
CN
o-Tol
Ph
CN
o-Tol
Ph
CN
o-Tol
Ph
CN
o-Tol
(S)-2 NH2
Ph o-Tol
NH2 (R)-2
o-Tol
HN
Ph
HN
Ph
HN
Ph
HN
Ph
Ph
+
+
enhancement of solid-state chirality
then filtration (up to >99.5% de)
anti-(L)-5a
syn-(D)-5a
syn-(L)-5a
anti-(D)-5a
major
major
minor
minor
(b)
(c)
100
50
0
0.1 M DBU in 2-propanol
0.01 M DBU in 2-propanol
MeOH (without DBU)
0
10
20
30
time [hour]
Figure 2. (a) Stereoselective formation of α-phenylglycine nitrile 5a. (b) Single-crystal structure of syn-(D)-5a (CCDC 1560534). (c) Continuous enhancement of
diastereomeric ratio in solid state syn-(D)-5a as a function of the reaction time.
Continuous improvement in de was monitored by sampling a
part of suspended solid 5a using (S)-2 (Figure 2c). In 0.1 M DBU
in 2-propanol, the initial low diastereoselectivity of solid product
(35% de) was significantly improved over 2 h, increasing to 89%
de. After further enhancement of de (94%/6 h and 96%/16 h),
finally syn-(D)-5a with >99.5% de was isolated as mentioned
above (Figure 2c, red-colored line). Even when the amount of
DBU was reduced to 0.01 M, syn-(D)-5a with >99.5% de was
isolated in 85% yield after the gradual enhancement of de (blue-
colored line). From the filtrate, the same configured syn-(D)-5a
with 46% de was also isolated in 9% yield after purification by
silica-gel. Since 5a can racemize in only methanol solution
without using DBU, syn-(D)-5a with 98% de was isolated from
methanol suspension in 73% yield together with syn-(D)-5a (23%
yield, 57% de) from the filtrate (green-colored line).
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10.1002/chem.201704033
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isolated by filtration in 60% yield and the same configured anti-
(L)-5f with 3% de was also isolated in 10% yield from the filtrate.
Both removal of the 2-methylbenzhydryl group and hydrolysis of
the cyanide group were conducted in a one-pot reaction under
acidic conditions to afford L-alanine with 98% ee in 96% yield
without a decrease in enantiomeric purity. Therefore, one of the
natural aliphatic a-amino acids, alanine, could be
enantioselectively synthesized based on the chirality of (S)-2-
methylbenzhydrylamine (2).
NH2
+ CH3CHO 3f
+ HCN
Ph
(S)-2
=X*SNH2
o-Tol
X*SHN
anti-(
CN
)-5f
L
(98% de)
H3O+
L-alanine
(98% ee)
Stereoselective reactions using other aromatic and
heteroaromatic aldehydes 3e and 3g-k are shown in Table 2.
Although, p-bromobenzaldehyde (3e) afforded racemic
Scheme 2. Asymmetric synthesis of L-alanine. The stereochemistry of 5f was
confirmed by X-ray single crystal structure analysis (CCDC 1560537).
compound 4e by the reaction with achiral
1 and HCN,
stereoselective synthesis could be realized by the reaction with
(R)-2 to give anti-(D)-5e with 90% de (entry 1). Even when p-
chloro- and p-methoxybenzaldehydes 3g and 3h were submitted
to the reaction, corresponding anti diastereomers 5g and 5h with
94 and 97% de have been formed after the enhancement of de,
respectively (entries 2 and 3). Additional amount of aminonitriles
5g and 5h with low to moderate de were also recovered in 9%
and 15% yield from the filtrate, respectively.
Furthermore, the present method was then applied to the
enantioselective alanine synthesis[8] (Scheme 2). Initially, the
crystalline solid of anti-(L)-alanine nitrile 5f was formed with 6%
de by the Strecker reaction between (S)-2 with >99.5% ee,
acetaldehyde (3f) (2 eq), and HCN. Subsequent stirring of the
suspension in 0.5
M
DBU in methanol improved the
diastereomeric purity to 98% de. The solid of anti-(L)-5f was
Table 2. Highly stereoselective Strecker reaction utilizing highly enantioenriched 2-methylbenzhydrylamine (2).
RCHO 3 + HCN
R
R
R
R
(S)-2
(R)-2
+
(=X*RNH2)
(=X*SNH2)
X*RHN
anti-(
X*RHN
syn-(
X*sHN
anti-(
X*sHN
syn-(
+
CN
)-5
CN
CN
CN
)-5
D
L
)-5
L
)-5
D
Enhancement of solid-state chirality
Entry[a]
Solvent
DBU (M)
Aminonitrile 5
Amine 2
substituent R
(Config.)
(aldehyde 3)
#
config.[b]
de[c]
90
Yield[d]
80
CCDC[e]
1
2
3
4
5
6
R
S
R
S
R
S
(p-Br)C6H4 (3e)
(p-Cl)C6H4 (3g)
(p-MeO)C6H4 (3h)
2-furyl (3i)
2-propanol
2-propanol
2-propanol
MeOH
0.1
0.1
0.1
–
5e
5g
5h
5i
anti-(D)
anti-(L)
anti-(D)
syn-(D)
syn-(L)
syn-(D)
1560574
1560665
1560673
1560677
1560678
1560679
94 (4)
85 (9)
76 (15)[f]
87[g]
97 (56)
99
3-pyridyl (3j)
2-propanol
2-propanol
0.1
–
5j
98 (BDL)
99 (BDL)
78 (8)
65 (28)
2-pyridyl (3k)
5k
[a] Molar ratio used 2:3 = 1:1. [b] The configuration was determined from the X-ray single-crystal structure analysis. [c] The diastereomeric excess was
determined by HPLC on a chiral stationary phase (UV detector) because the difference in the UV absorbance between diastereomers is enough small to discuss
the diastereoselectivity (see also ref. 35). The value in parentheses indicates the de of 5 isolated from the filtrate, whose configuration is the same as solid 5.
BDL: below the detectable level. [d] Isolated yield of solid 5 by filtration based on the molar amount of 2 (the same as 3). Additional recovered yield of 5 from the
filtrate indicated in parentheses. [e] Deposit number of the CCDC. [f] The yield was calculated from the amount of initially suspended solid anti-(D)-5h with 7% de.
[g] The yield was calculated based on the molar amount of (S)-imine 6i (see Scheme 4 for the chemical structure) using starting substrate.
Furthermore, heteroaromatic aldehydes 3i–k could also be
applicable for the stereoselective formation of aminonitriles 5i–k.
As shown in entry 4, the highly stereoselective Strecker reaction
of furfural (3i) was accomplished between (S)-2 and HCN to
afford syn-(D)-5i with 99% de in 87% yield, in conjunction with
the enhancement of chirality in solid-state. 3- and 2-
Pyridinecarbaldehydes (3j and 3k) were also converted to the
corresponding highly enantioenriched syn-aminonitriles 5j and
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10.1002/chem.201704033
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R
5k with 98% and 99% de in excellent chemical yields,
respectively, after only simple filtration (entries 5 and 6). A rapid
decrease in the diastereomeric ratio of 5k was observed in
RCHO 3l, HCN
(S)-2
rac-2
anti-(L)-5l
HN
Ph
CN
o-Tol
1
chloroform-d, therefore, H-NMR of syn-(D)-5k with 99% de was
reversed
diastereo-
selectivity
enhancement
of de
measured in benzene-d6, in which the epimerization rate
became slow. Crystallization-mediated synthesis offers
advantages for obtaining easily racemizable chiral compounds in
highly stereoselective manner. To our knowledge, this is the first
example of the highly stereoselective synthesis of an a-
aminonitrile with the 2-pyridyl group directly connected to the a-
position.
R
syn-rac-5l
HN
Ph
CN
o-Tol
RCHO 3l, HCN
R=trans-styryl
Therefore, 1,3-asymmetric induction has been achieved by
using 2-methylbenzhydrylamine (2) as a chiral substrate in the
Strecker reaction in conjunction with an enhancement of chirality
in solid state. The chirality of solid aminonitriles 5 has been
Scheme 3. Stereodivergent Strecker synthesis of a-styrylglycine nitrile 5l
using (S)- and rac-2-methylbenzhydrylamine (2). Stereochemistries of anti-(L)-
and syn-rac-5l were determined by X-ray single-crystal structure analysis
(CCDC 1560680 and 1560681, respectively).
continuously
improved
to
achieve
significantly
high
diastereomeric purity (up to >99.5% de) by only stirring of the
reaction suspension. The chirality of 2, generated by the
difference between phenyl and o-tolyl substituents, has been
efficiently discriminated to afford chiral intermediate, aminonitrile
with high de. Although the energy difference between the
diastereomers was calculated to be small, for example, anti-5f is
1.1 kJ/mol more stable than syn-5f by DFT calculation
(Supporting Information Table S7), such a small difference
should be integrated in the solid state to become sufficiently
large, giving high stereoselectivity observed here.
Resolution of 2-methylbenzhydrylamine (2) via imine 6i
forming conglomerate
The
methylbenzhydrylamine (2) has been reported in the
phenylboroxine and of
addition[34a] hydrogenation[34b]
asymmetric
synthesis
of
enantioenriched
2-
corresponding imine. As shown in Scheme 4, we found that the
rac-imine 6i formed from furfural (3i) crystallizes in the
conglomerate. Thus, by the seeding method, rac-6i could be
resolved to afford enantioenriched 6i. When rac-6i (70 g) was
subjected, (R)-6i (8.7 g) with 99% ee could be obtained from
(R)-seed 6i (80 mg) in a single operation. Oppositely configured
(S)-seed 6i induced the preferential crystallization of (S)-6i.
Hydrolysis of 6i by aqueous HCl proceeded in 96% yield to
afford highly enantioenriched 2 after the neutralization without
decrease of enantiomeric purity. Highly enantioenriched 2 used
in the present study was prepared by this resolution method.
Stereodivergent Strecker synthesis of -styrylglycine nitrile
a
5l by using enantioenriched and racemic 2
When trans-cinnamaldehyde (3l) was submitted to the Strecker
reaction, followed by the enhancement of chirality in solid state,
stereoselective formation of styrylglycine nitrile 5l was observed
(Scheme 3). Therefore, when enantioenriched (S)-2, aldehyde 3l,
and HCN were reacted together, L-5l was formed and
precipitated as a preferred anti-diastereomer (80% de). However,
when the rac-2 was used as the substrate, the
diastereoselectivity was reversed, i.e., syn-5l with 86% de in
racemic form was obtained as a major isomer in 85% yield.
Therefore, both anti- and syn-isomers of a-aminonitrile 5l could
be selectively synthesized under the enantiomeric and racemic
conditions, respectively. These observations, i.e., change of the
NH2
ii)
iii)
(S)-6i
(R)-6i
Ph
o-Tol
(S)-2
rac-2
(=X*NH2)
O
i)
resolution
+
3i
NH2
X*N
H
rac-6i
Ph o-Tol
(R)-2
ii)
iii)
major
stereoisomer
should
be
occurred,
because
enantioenriched and racemic compounds afford the crystals with
completely different structures and which determines the
preferable diastereomer in solid state. Because the slightly
major diastereomer in solution phase[35] may be the same under
both racemic and enantiomeric conditions, it was supposed that
the (slight) selectivity in the solution phase did not control the
direction of the enhancement of de in solid state.
Scheme 4. Resolution of 2-methylbenzhydrylamine (2): preferential
crystallization of imine 6i. Reaction conditions: (i) Na2SO4, CH2Cl2 (89%); (ii)
(S)-/(R)-seed 6i (CCDC 1564004), ethyl acetate, 60–50 °C; (iii) HCl, Et2O/H2O
(1/1, v/v) then NaHCO3 (96%). The absolute configuration of 2 was directly
determined by X-ray single crystal structure analysis of (S)-imine 6m (CCDC
1563890) formed from (S)-2 and 2-thiophenecarboxyaldehyde (3m)
(Supporting Information Figure S5).
Conclusions
The spontaneous formation and amplification of the
enantioenriched N-benzhydryl-a-o-tolylglycine nitrile (4c)
forming conglomerate were achieved. Stochastic distribution of
the absolute handedness of 4c fulfills one of the requirements
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10.1002/chem.201704033
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methanol (1.0 mL) and stirred for 122 h at room temperature. After
filtration, anti-(L)-5f (501 mg, 2.0 mmol, 98% de) was obtained in 60%
yield. The filtrate was concentrated then passed through silica gel, using
n-hexane/Et2O (1/1, v/v). The product anti-(L)-5f (84 mg, 0.34 mmol, 3%
de) was obtained in 10% yield.
for the spontaneous absolute asymmetric synthesis of a-amino
acids in combination with hydrolysis. After the modification of
achiral benzhydrylamine (1), asymmetric amplification of crystal
ee was successfully substituted by the enhancement of solid
state chirality in the stereoselective Strecker synthesis.
Therefore,
enantioenriched
(S)-
and
(R)-2-
A solution of anti-(L)-5f (50 mg, 0.2 mmol, 98% de) in a mixed solvent of
conc. HCl (0.2 mL) and trifluoroacetic acid (0.2 mL) was stirred for 20 h
at 80 °C. The reaction mixture was washed with Et2O and concentrated
under reduced pressure. The residue was purified by passing it through a
cation-exchange resin (Dowex 50WX8, 100–200 mesh, H+ form). L-
alanine (17 mg, 0.19 mmol, 98% de) was obtained in 96% yield.
methylbenzhydrylamine (2) afforded the corresponding
aminonitriles 5 with significantly high diastereoselectivity by the
reaction with achiral aldehydes and HCN, in combination with
the enhancement of chirality in solid-state. Near enantiomerically
pure L-alanine was also synthesized by the present method. To
our knowledge, this is the first report of research on the highly
stereoselective synthesis by the slight modification of a common
substrate from achiral to chiral.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP23685012, JP16K05692 and JP17J06244. T. K. thanks
Takeda Science Foundation, Mishima Kaiun Memorial
Foundation, The Naito Foundation and The Iwatani Naoji
Foundation for financial supports. S. A. thanks the JSPS
Research Fellowships for Young Scientists.
Experimental Section
Spontaneous formation of enantioenriched 4c.
HCN (121 µL, 3.0 mmol) was added to a solution of o-tolualdehyde (3c)
(116 µL, 1.0 mmol) and benzhydrylamine (1) (173 µL, 1.0 mmol) in 1.5 M
DBU in methanol (2.6 mL). After stirring for 3 days at 30 °C, followed by
filtration, L-solid 4c (122 mg, 0.39 mmol) with 18% ee was isolated in
39% yield. After concentration of the filtrate in vacuo, the residue was
purified by silica gel column chromatography (n-hexane/Et2O = 3/1, v/v).
4c (116 mg, 0.37 mmol) with ee below the detectable level was obtained
in 37% yield.
Keywords: Strecker synthesis • Chirality • Stereoselective
synthesis • a-Amino acids • a-Aminonitrile
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10.1002/chem.201704033
Chemistry - A European Journal
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Naoya Takamatsu, Shohei Aiba, Takuya
Yamada, Yuji Tokunaga, Tsuneomi
Kawasaki*
R
L
Strecker reaction
Slight
modification
NH2
NH2
X*HN
CN
NH2
RCHO
HCN
Enhancement of
solid-state chirality
up to >99.5% de
R
R
S
Ph
Ph
One methyl group
Achiral
Page No. – Page No.
X*HN
CN
Strecker reaction
Chiral
D
Highly Stereoselective Strecker
Synthesis Induced by the Slight
Modification of Benzhydrylamine
from Achiral to Chiral
Slight modification of common substrate from achiral to chiral. Highly
stereoselective Strecker synthesis using 2-methylbenzhydrylamine between achiral
aldehydes and HCN have been achieved by the enhancement of chirality in solid-
state to afford aminonitriles with significantly high diastereoselectivity (up to >99.5%
de).
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