Asymmetric Synthesis of α-Amino Acids by Organocatalytic Biomimetic Transamination

Article abstract of DOI:10.1021/acs.orglett.9b00588

A biomimetic enantioselective transamination of α-keto ester derivatives can be realized under mild conditions by using chiral quaternary ammonium arenecarboxylates in the absence of base additives. The corresponding α-amino acids can be used as versatile intermediates for further synthetic transformations that furnish chiral pyrrolidine and octahydroindolizine derivatives.

Full text of DOI:10.1021/acs.orglett.9b00588

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Synthesis of α‑Amino Acids by Organocatalytic
Biomimetic Transamination
Qi-Kai Kang,† Sermadurai Selvakumar,† and Keiji Maruoka*,†,‡
†Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
‡School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China
S
* Supporting Information
ABSTRACT: A biomimetic enantioselective transamination of α-keto ester derivatives can be realized under mild conditions
by using chiral quaternary ammonium arenecarboxylates in the absence of base additives. The corresponding α-amino acids can
be used as versatile intermediates for further synthetic transformations that furnish chiral pyrrolidine and octahydroindolizine
derivatives.
Scheme 1. Biomimetic Enantioselective Transamination of
α-Keto Esters
he development of new catalytic asymmetric trans-
1
Tformations based on chiral metal-free catalysts in the
absence of acid and/or base additives is one of the most
desirable approaches in current asymmetric synthesis,
especially from the viewpoint of green sustainable chemistry.
We have thus been interested in the possibility of realizing
such asymmetric transformations and studied the environ-
mentally benign asymmetric organocatalytic transamination2 of
α-keto esters into the corresponding α-amino acid derivatives
under very mild conditions. Although ordinary phase-transfer
reactions using quaternary ammonium salts as phase-transfer
catalysts are generally believed to require base additives,3 we
found that even in the absence of any external base additives4
the enantioselective phase-transfer transamination of α-keto
esters into the corresponding α-amino acid derivatives
proceeds smoothly and with high enantioselectivity in the
presence of chiral quaternary ammonium carboxylates (Q+X)
under mild conditions in organic solvents (Scheme 1).
aromatic carboxylates, 2,4,6-trimethylbenzoate exhibited the
best performance in this transamination (entry 4 vs entries 3
and 5). Among the solvents tested, dichloromethane (DCM)
and tert-butyl methyl ether (TBME) decreased the enantiose-
lectivity (entries 6 and 7). In contrast, aromatic solvents such
as o-xylene and mesitylene slightly increased the enantiose-
lectivity (entries 8 and 9). Dilution of the reaction mixture
enhanced the enantioselectivity to 86% ee (entry 10), while the
use of 1.5 equiv of 2a improved the chemical yield without loss
of enantioselectivity (entry 11). We also examined different
amine donors 2, and similar or less satisfactory results were
obtained from using p-(methoxycarbonyl)benzylamine (2b), p-
cyanobenzylamine (2c), or p-(aminomethyl)pyridine (2d)
(entries 12−14). Biphenyl- and spiro-type phase-transfer
Initially, the asymmetric transamination of α-keto ester 1a
with p-nitrobenzylamine (2a) as the amine donor was carried
out in the presence of simplified Maruoka catalyst (S)-4a in
toluene to furnish the corresponding product (3a) in 33% yield
and 17% ee (entry 1, Table 1). We then examined the effect of
the counteranion of the phase-transfer catalysts (S)-4a in order
to influence the reactivity and selectivity on the asymmetric
transamination.5 When acetate was used as the anion, both the
chemical yield and the enantioselectivity of the product 3a
improved (entry 2), while the use of benzoate (S)-4c
accelerated the transamination (entry 3). Among several
Received: February 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Reaction Conditions for the
Table 2. Substrate Scope for the Biomimetic
Enantioselective Transamination of α-Keto Esters 1
a
Biomimetic Enantioselective Transamination of α-Keto
a
Esters
b
c
entry
PTC
solvent
amine time (h) % yield (% ee)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
(S)-4a
(S)-4b
(S)-4c
(S)-4d
(S)-4e
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-5
toluene
toluene
toluene
toluene
toluene
DCM
TBME
o-xylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2a
2a
2a
36
36
36
24
24
12
12
12
12
12
12
12
12
12
12
12
24
33 (17)
48 (42)
58 (40)
60 (74)
52 (58)
59 (14)
51 (63)
53 (76)
79 (78)
63 (86)
80 (86)
72 (85)
44 (78)
65 (85)
87 (88)
93 (89)
70 (91)
d
de
,
de
,
de
,
de
,
def
,
,
deg
,
,
(S,S)-6
(S,S)-6
deg h
,
, ,
a
Unless otherwise specified, the asymmetric transamination of 1a (0.1
mmol) was carried out at room temperature in the specified solvent
(0.5 mL) with benzylic amine (1.0 equiv) and MS 4 Å (20 mg) in the
b
1
presence of the chiral PTC (5 mol %). Determined by H NMR
spectroscopy using TCE as the internal standard after derivatization
c
of the product. Determined by chiral HPLC after derivatization of
d
e
the product. 2.0 mL of solvent was used. 1.5 equiv of benzylamine
f
g
a
was used. PTC (S)-5 (5 mol %) was used. PTC (S,S)-6 (5 mol %)
was used. The reaction was carried out at 10 °C.
Unless otherwise specified, the asymmetric transamination of 1 (0.05
mmol) was carried out at room temperature in mesitylene (1.0 mL)
with 2a (0.075 equiv) and MS 4 Å (20 mg) in the presence of PTC (5
h
b
c
mol %). Isolated yield. The enantioselectivity was determined by
catalysts (S)-5 and (S,S)-6 exhibited an increased enantiose-
lectivity (entries 15 and 16). Lowering the reaction temper-
ature in the presence of (S,S)-6 further improved the
enantioselectivity (entry 17).
As shown in Table 2, α-keto esters 1b−e, which contain
CC bonds, showed moderate reactivity and good
enantioselectivity (entries 3−7). Functional groups such as
tert-butoxycarbonyl and benzyloxy substituents were also
tolerated under the optimized conditions (entries 8 and 9).
Alkyl-substituted α-keto esters 1h−j furnished the correspond-
ing amino ester derivatives in 40−72% yield and 76−86% ee
(entries 10−13). Unfortunately, phenyl-substituted α-keto
ester 1 (R = Ph) afforded only trace amounts of the target
product 3 (R = Ph).
d
chiral HPLC analysis. The reaction was carried out at 10 °C.
catalytic transamination conditions, we carried out the reaction
in the presence of 7a and 7b (Scheme 2), which afforded 3a in
90% (89% ee) and 80% yields (88% ee), respectively. Under
the applied reaction conditions, 95% of 7a and 90% of 7b
survived.
The obtained transamination products can be easily
derivatized. For example, 3b was readily transformed into
pyrrolidine derivative 8 under concomitant slight loss of
enantioselectivity via a halogen-mediated cyclization (Scheme
3A). Moreover, ozonolysis of product 3e generated 9, which
could be converted into (+)-monomorine, which is a trail
pheromone of the tropical pharao ant Monomorium pharaonis
L. (Scheme 3B).6,7
In order to examine the tolerance of acid- or base-labile
substrates under the previously determined optimized organo-
B
DOI: 10.1021/acs.orglett.9b00588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
quaternary ammonium carboxylate (S)-4d and (S,S)-6, which
proceeds in the absence of base additives. The reaction exhibits
good reactivity and affords high enantioselectivity under mild
conditions. Further applications of this catalytic system are
currently under investigation in our group, and the
corresponding results will be reported in due course.
Scheme 2. Tolerance of Acid- or Base-Labile Substrates
under the Applied Mild Reaction Conditions
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00588.
Details of the effect of PTC counteranion; effect of
solvent and its concentration; PTC screening and effect
of temperature; synthesis of catalysts; general procedure
for transamination; general procedure for checking
tolerance of acid- or base-labile substrates under
standard conditions; general procedure for transforma-
tion of product; 1H NMR and 13C NMR spectra; HPLC
spectra (PDF)
Scheme 3. Subsequent Transformations of the Obtained
Transamination Products
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: maruoka@kuchem.kyoto-u.ac.jp. Fax: (+81) 75-753-
4041
ORCID
Keiji Maruoka: 0000-0002-0044-6411
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Nos.
JP26220803 and JP17H06450 (Hybrid Catalysis).
■
Based on the absolute configuration of the transamination
products (3),8 a plausible structure for the transition state is
proposed in Scheme 4. First, the α-keto ester would be
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(8) Given the specific rotation of 3a ([α]D
20.0
= +13.0 (c 1.12,
CHCl3), 88% ee), the absolute configuration was assigned as S by
20.0
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DOI: 10.1021/acs.orglett.9b00588
Org. Lett. XXXX, XXX, XXX−XXX