Chiral lithium binaphtholate for enantioselective amination of acyclic α-alkyl-β-keto esters: Application to the total synthesis of L-carbidopa

Article abstract of DOI:10.1016/j.tet.2017.08.015

A chiral lithium binaphtholate catalyzes the enantioselective amination of α-alkyl-β-keto esters with azodicarboxylates to produce optically active α,α-disubstituted α-amino acid derivatives in high yields and with good to high enantioselectivities. A stoichiometric amount of lithium hydroxide efficaciously improved both the reactivity and enantioselectivity of amination. The resulting aminated product is readily convertible to L-carbidopa.

Full text of DOI:10.1016/j.tet.2017.08.015

Accepted Manuscript
Chiral lithium binaphtholate for enantioselective amination of acyclic α-alkyl-β-keto
esters: Application to the total synthesis of L-carbidopa
Toshifumi Asano, Miyuki Moritani, Makoto Nakajima, Shunsuke Kotani
PII:
S0040-4020(17)30835-9
10.1016/j.tet.2017.08.015
TET 28909
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 June 2017
Revised Date: 2 August 2017
Accepted Date: 10 August 2017
Please cite this article as: Asano T, Moritani M, Nakajima M, Kotani S, Chiral lithium binaphtholate
for enantioselective amination of acyclic α-alkyl-β-keto esters: Application to the total synthesis of L-
carbidopa, Tetrahedron (2017), doi: 10.1016/j.tet.2017.08.015.
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Chiral lithium binaphtholate for enantioselective
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Toshifumi Asano, Miyuki Moritani, Makoto Nakajima, Shunsuke Kotani*

1
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Tetrahedron
journal homepage: www.elsevier.com
Chiral lithium binaphtholate for enantioselective amination of acyclic α-alkyl-β-keto esters:
Application to the total synthesis of -carbidopa
L
Toshifumi Asano,a Miyuki Moritani,a Makoto Nakajima,a Shunsuke Kotania,b*
a Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
b Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A chiral lithium binaphtholate catalyzes the enantioselective amination of α-alkyl-β-keto
esters with azodicarboxylates to produce optically active α,α-disubstituted α-amino acid
derivatives in high yields and with good to high enantioselectivities. A stoichiometric
amount of lithium hydroxide efficaciously improved both the reactivity and
Available online
enantioselectivity of amination. The resulting aminated product is readily convertible to
carbidopa.
L-
Keywords:
Asymmetric catalysis
Amination
2017 Elsevier Ltd. All rights reserved
.
Chiral binaphtholate
Enantioselectivity
β-Keto ester
esters catalyzed by chiral lithium binaphtholate,10 and the
1. Introduction
asymmetric short-step synthesis of
enantioselective amination as a key step.
L-carbidopa using
Optically active amino acids are one of the most representative
constituents of living organisms. However, α,α-disubstituted α-
amino acids are found only in unnatural amino acids, some of
which possess unique biologically activity.1 Therefore, a number
of asymmetric transformations for synthesizing such optically
active α,α-disubstituted α-amino acids have been developed over
the past several decades.2 One conventional strategy to generate
optically active α,α-disubstituted α-amino acids is the
asymmetric addition of a tertiary carbanion equivalent to an
electrophilic nitrogen.3 In 2003, Jørgensen and co-workers were
the first to demonstrate a chiral Ph-bis(oxazoline)copper complex
catalyzed enantioselective amination of α-alkyl-β-keto esters
with azodicarboxylates to produce optically active α,α-
disubstituted α-amino acids in high enantioselectivity.4 Recent
advances on metal catalyses and organocatalyses have also
provided us with many asymmetric variations.5-8 Indeed, cyclic
α-alkyl-β-keto esters such as cyclohexanone carboxylates and 1-
indanone carboxylates afforded high stereoselectivity, however,
less attention has been paid to acyclic α-alkyl-β-keto esters,
except for acetylpropionates. In this regard, our group has
explored the utilities of the conjugate base of binaphthol (i.e.,
binaphtholate) and has recently reported asymmetric conjugate
additions of acyclic α-alkyl-β-keto esters using dilithium
binaphtholate catalysis.9,10 In this publication, we report the full
details of the enantioselective amination of acyclic α-alkyl-β-keto
2. Results and discussion
2.1. Enantioselective amination of α-alkyl-β-keto esters
catalyzed by chiral lithium binaphtholate
We began examining the asymmetric amination of β-keto
ester 1a with various azodicarbonyl compounds 2a-f in the
presence of 10 mol % of (R)-3,3'-Br2-BINOL (3a) as a
precatalyst and 20 mol % of lithium hydroxide (LiOH) in diethyl
ether at –23 ºC (Table 1). Azodicarboxylate esters 2a-e showed
sufficient reactivity to afford the corresponding aminated adducts
4aa-ae in high yields (entries 1–5). tert-Butyl azodicarboxylate
2c gave the best enantioselectivity of 74% ee (entry 3).
Azodicarbamate 2f was less reactive under these reaction
conditions, yielding no product (entry 6).
_____
* Corresponding author. Tel.: +81963714394; E-mail address: skotani@gpo.kumamoto-
u.ac.jp

2
Tetrahedron
a All the reactions were performed by treating 1a (0.5 mmol) with 2c
Table 1. Enantioselective amination of 1a with 2 catalyzed by
ACCEPTED MANUSCRIPT
chiral lithium binaphtholate under various reaction conditions.a
(1.05 equiv) in the presence of (R)-3 (10 mol %) and LiOH (20 mol %)
in Et2O (4 mL) at –23 °C
.
b Determined by HPLC analysis.
To investigate the effect of the bases, we examined the reaction
with various alkali metals (Table 3). Other lithium bases such as
butyllithium and lithium tert-butoxide afforded good
enantioselectivities (entries 2 and 3). Sodium hydroxide and
potassium hydroxide gave the lower yields and selectivities
(entries 4 and 5). These results implied that the enantio-
determining step involves lithium metals.
Table 3. Screening of alkali metals.a
Entry
X
OMe
Yield, %
ee, %b
62
2
1
2
3
4
5
6
96
96
98c
92
89
0
2a
2b
2c
2d
2e
2f
OEt
OtBu
64
74
54d
OBn
Entry
1
alkali metal
LiOH
Time, h
0.5
Yield, %
98
ee, %b
74
OCH2CCl3
4
NMe2
–
a All the reactions were performed by treating 1a (0.5 mmol) with 2 (1.05
equiv) in the presence of (R)-3a (10 mol %) and LiOH (20 mol %) in Et2O (4
mL) at –23 °C.
2
3
4
5
nBuLi
LiOtBuc
NaOH
KOH
1
1
1
1
96
99
54
34
68
71
8
b Determined by HPLC analysis.
c For 0.5 h.
d The absolute configuration is R.
4
a
Unless otherwise noted, the reactions were performed by treating 1a
(0.5 mmol) with 2c (1.05 equiv) in the presence of (R)-3a (10 mol %)
To improve the enantioselectivities, we next examined the
amination reaction with various BINOLs 3a-f (Table 2). Parent
(R)-BINOL (3b) and (R)-3,3'-Ph2-BINOL (3c) were ineffective,
and an alkari metal (20 mol %) in Et2O (4 mL) at –23 °C
.
b Determined by HPLC analysis.
c 1.0 M LiOtBu/THF was used.
giving very low selectivities (entries
2 and 3). Higher
enantioselectivities were obtained with (R)-3,3'-dihaloBINOLs,
with a significant acceleration of the reaction rate (entries 1, 4,
and 5). To clarify the effects of the halogeno groups, we
conducted the amination reaction with (R)-3,3'-(C6F5)2-BINOL
(3f, entry 6). Similar to (R)-3,3'-Ph2-BINOL (3c), low
enantioselectivity (8% ee) was obtained, despite the higher
conversion. This result indicates that the steric effect of the 3,3'-
substituents affect the asymmetric induction, whereas the
electron deficiency increased the catalytic activity.
We next investigated solvent effects (Table 4). Less polar
solvents such as dichloromethane and toluene were ineffective
for both the yields and selectivities (entries 2 and 3). Regarding
coordinative solvents, tetrahydrofuran afforded the aminated
adduct 4ac in good enantioselectivity, albeit in low yield (entry
4). Acyclic ethers such as tert-butyl methyl ether (TBME) and
cyclopentyl methyl ether (CPME) afforded good yields and
enantioselectivities (entries 5 and 6). In contrast, 1,4-dioxane and
1,2-dimethoxyethane (DME) decreased selectivity (entries 7 and
8). Bidentate coordination might prevent substrates from
accessing lithium atom, resulting in lower enantioselectivities.
Table 2. Screening of (R)-BINOLs.a
Table 4. Screening of solvents.a
Entry
Solvent
Et2O
Time, h
Yield, %
98
ee, %b
74
1
2
3
4
5
6
7
8
0.5
2
CH2Cl2
toluene
THF
22
2
Entry
3
Time, h
Yield, %
98
ee, %b
2
22
11
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
0.5
1
74
5
2
35
65
95
TBME
CPME
1,4-dioxane
DME
1
92
54
1
92
4
1
90
71
0.5
0.5
1
97
61
64
8
2
82
17
97
2
18
10
92

3
a All the reactions were performed by treating 1a (0.5 mmol) with 2c
promote the formation of highly active dilithium binaphtholate,
which can be employed in the asymmetric amination.
ACCEPTED MANUSCRIPT
(1.05 equiv) in the presence of (R)-3a (10 mol %) and LiOH (20 mol %)
in a solvent (4 mL) at –23 °C.
bDetermined by HPLC analysis.
Table 6. Investigation of LiOH equivalents.a
We performed the amination at various temperatures (Table 5).
At 0 °C, the reaction was completed within 10 min, but the
enantioselectivity was decreased (entry 2). Thus, conducting the
reaction at lower temperatures increased the enantioselectivities
(entries 3-5). At –60 °C, the highest enantioselectivity (80% ee)
was obtained (entry 4), whereas, at –78 °C, both reactivity and
enantioselectivity decreased (entry 5).
Entry
Z, mol %
10
Yield, %
98
ee, %b
77
1
2
3
4
5
6
Table 5. Effect of temperatures.a
20
99
80
30
91
82
50
99
86
100
130
90
87
99
86
a All the reactions were performed by treating 1a (0.5 mmol) with 2c (1.05
Entry
Temp., °C
Time, h
0.5
Yield, %
ee, %b
74
equiv) in the presence of (R)-3a (10 mol %) and LiOH (Z mol %) in Et2O (4
mL) at –60 °C.
1
2
3
–23
0
98
99
99
b Determined by HPLC analysis.
10 min
24
61
With the optimum reaction conditions in hand, we examined
the enantioselective amination of keto esters
–40
79
1
with
4
5
–60
–78
24
24
99
55
80
60
azodicarboxylate 2c (Table 7). Keto ester 1b bearing an electron-
withdrawing group slightly decreased the enantioselectivity
relative to benzoyl ester 1a (entry 2). In contrast, keto esters 1c-e
with electron-donating functional groups on the phenyl group
maintained higher enantioselectivities (entries 3–5). However,
introducing an o-methoxy group on the phenyl group diminished
enantioselectivity (entry 6). It is possible that the o-methoxy
group coordinates to the lithium complex in the transition
structure, resulting in a reduction of enantioselectivity. Although
alkyl ketones 1g-i were reactive and the reactions completed in 2
(entries 7-9), but the products afforded lower
enantioselectivities than those of aryl ketones. In examination of
R2 groups, the azodicarboxylate 2a
gave higher
enantioselectivities than 2c (entries 10-12). α-butyl-β-keto ester
1j gave the product 4ja in 68% yield and 58% ee (entry 10). Keto
ester 1k bearing an allyl group gave the product 4ka in
quantitative yield and with 82% ee (entry 11). Benzylated keto
a All the reactions were performed by treating 1a (0.5 mmol) with 2c
(1.05 equiv) in the presence of (R)-3a (10 mol %) and LiOH (20 mol %)
in Et2O (4 mL).
b Determined by HPLC analysis.
Next, we examined the effect of LiOH by varying the amounts
of equivalents (Table 6). Interestingly, increasing LiOH
equivalents improved the enantioselectivities, and the use of a
stoichiometric amount of LiOH afforded 4ac in 90% yield with
87% ee (entry 5). Excess amounts of LiOH did not improve the
enantioselectivity (entry 6). As for facilitating progression of the
reaction, formation of monolithium binaphtholate (see
binaphtholate 5 in Figure 1) may be superior to that of dilithium
binaphtholate due to the production of lithiated 4ac. Overall, it is
clear that a stoichiometric amount of LiOH is sufficient to
h
Table 7. Enantioselective amination catalyzed by lithium binaphtholate 3aa
Entry
1
R1
Ph
R2
R3
Et
2
R4
Temp., °C
–60
Time, h
24
Yield, %
ee, %b
87
1
2
3
4
1a
1b
1c
1d
Me
Me
Me
Me
2c
2c
2c
2c
tBu
tBu
tBu
tBu
90
98
96
93
4-F-C6H4
Me
Me
Me
–60
24
78
4-MeO-C6H4
3,5-(MeO)2-4-Br-C6H2
–40
24
80
–23
24
88
5
1e
3,4-(MeO)2-C6H3
Me
Me
2c
tBu
–30
24
95
89c
6
7
1f
1g
1h
1i
2-MeO-C6H4
Me
Me
Me
Me
nBu
allyl
Bn
Et
Et
2c
2c
2c
2c
2a
2a
2a
tBu
tBu
tBu
tBu
Me
Me
Me
–60
–60
–60
–60
–60
–60
–60
24
2
62
93
83
85
68
86
82
4
Me
nPr
iPr
Ph
Ph
Ph
47
13
54
58
82
95
8
Et
2
9
Et
2
10
11
12
1j
Me
Et
24
24
24
1k
1l
Et
a All the reactions were performed by treating 1 (0.5 mmol) with 2 (1.05 equiv) in the presence of (R)-3a (10 mol %) and LiOH (1.0 equiv) in Et2O (4 mL).
b Determined by HPLC analysis.
c The absolute configuration is R.

4
Tetrahedron
ACCEPTED MANUSCRIPT
ester 1i afforded the best enantioselectivity of 95% ee (entry
To demonstrate the synthetic utility of the lithium
binaphtholate-catalyzed asymmetric amination in organic
synthesis, we attempted the total synthesis of -carbidopa, which
is a drug used to treat Parkinson’s disease.11
-Carbidopa acts as
an inhibitor of the peripheral aromatic -amino acid
decarboxylase, an enzyme responsible for the metabolism of
levodopa to dopamine. In combination with -dopa, -carbidopa
12).
L
The proposed catalytic cycle is shown in Figure 1. First,
L
lithium binaphtholates 5 and 6 are formed from (R)-3,3'-Br2-
BINOL (3a) and LiOH, entering a state of equilibrium in the
reaction media. Since the use of a stoichiometric amount of
LiOH improved both the yield and enantioselectivity, we expect
that dilithium binaphtholate 6 is an aptly active species in this
asymmetric amination. Next, toward dilithium binaphtholate 6, a
lithium enolate of keto ester (1-Li) coordinates to form chiral
complex A, which may well be stabilized by the coordination of
ether solvent based on the solvent investigations (Table 4).
Azodicarboxylate 2 then approaches complex A from its Re-face,
undergoing carbon-nitrogen bond formation via transition state B
L
L
L
temporarily diminishes the disease’s motor symptoms.
Vallribera and co-workers demonstrated in 2013 the asymmetric
synthesis of
Despite the convenience of their synthetic route, the use of
sterically congested ester motifs was essential to obtain high
stereoselectivity. Consequently, an expensive reducing reagent
was required for the carbonyl reduction. However, it is possible
L
-carbidopa using enantioselective amination.12
to synthesize
L-carbidopa more conveniently with the
to give complex
C
as the R-isomer.4a Finally, lithium
enantioselective amination catalyzed by lithium binaphtholate
presented herein, as it affords aminated adducts with high
enantioselectivity from α-alkyl-β-keto esters.
binaphtholate 5 is eliminated along with lithiated product (4-Li).
At an early stage of the catalytic cycle, reformation of dilithium
binaphtholate 6 from 5 occurs efficiently, with growing tendency
to form monolithium binaphtholate 5 as the reaction progresses.
LiOH successfully moves the equilibrium to dilithium
binaphtholate 6, resulting in regeneration of the active catalyst.
To this end, we performed asymmetric amination of methyl
keto ester 1e with azodicarboxylate 2c in the presence of 10 mol
% of (S)-3a to give the aminated adduct (S)-4ec in 99% yield and
with 88% ee (Scheme 1). After recrystallization from
hexane/EtOAc, the enantioselectivity of the mother liquid
increased to >99% ee. The next three-step conversion to 7ec must
be pursued as
a one-pot procedure because hydrazine
intermediate 5ec steadily decomposes.13 Aminated adduct 4ec
was treated with trifluoroacetic acid (TFA) to remove two tert-
butoxycarbonyl groups, and the subsequent addition of N,N-
diisopropylethylamine and carbobenzoxy chloride afforded 6ec.
The one-pot procedure allowed the conversion of 4ec to 6ec in
quantitative yield, and improved the synthesis efficiency. After
evaporation, the obtained residue of hydrazide 6ec was treated
with triethylsilane in TFA, leading to α-aminoester 7ec in 62%
yield. Following Vallribera’s derivatization procedure, we
performed demethylation of 7ec with BBr3 to obtain
carbidopa·hydrobromide salt, which was nuetlized by
diethylamine, leading to
-carbidopa·monohydrate.12 The
synthesized -carbidopa was identical to the commercially
available authentic material with respect to all experimental data.
Thus, we achieved asymmetric total synthesis of -carbidopa in 7
L-
L
L
L
steps (42% yield) from commercially available materials.
3. Conclusion
We have demonstrated that chiral lithium binaphtholate
Scheme 1. Total synthesis of L-carbidopa
Figure 1. Plausible reaction mechanism of the lithium
binaphtholate-catalyzed asymmetric amination
prepared from (R)-3,3'-Br2-BINOL and lithium hydroxide
catalyzes the enantioselective amination of α-alkyl-β-keto esters
with azodicarboxylates to produce optically active α,α-
2.2. Asymmetric synthesis of L-carbidopa

5
disubstituted α-amino acid derivatives with good to high
enantioselectivities. The use of a stoichiometric amount of
lithium hydroxide strongly increased the catalytic activity to
improve the enantioselectivities. Using this amination as a key
3.35-4.05 (m, 6H), 4.26-4.42 (m, 2H), 6.27-6.72 (m, 1H), 7.36-
ACCEPTED MANUSCRIPT
7.58 (m, 3H), 7.95-8.59 (m, 2H); Due to the distinct presence of
rotameric isomers, the 13C NMR contained multiple
peaks.13C{1H} NMR (100 MHz, CHCl3): δ 13.9, 14.1, 20.1, 53.3,
53.8, 54.0, 54.4, 54.7, 62.3, 62.6, 128.2, 128.5, 129.2, 129.8,
133.0, 134.0, 157.3, 157.6, 169.9, 190.7; IR (ATR): 3297, 2959,
1720, 1687, 1229 cm–1; LRMS (FAB): m/z 353 (M+H)+; HRMS
(FAB): Calcd for C16H21N2O7 353.1349, found 353.1354. The
enantiomeric excess was determined to be 62% ee by HPLC with
Daicel Chiralcel AD-H column [eluent: hexane/IPA = 19/1; flow
rate: 1.0 mL/min; detection: 254 nm; tR: 41.6 min (major), 44.1
min (minor)].
step, we achieved the asymmetric total synthesis of
L-carbidopa
in 7 steps (42% yield) from commercially available materials. A
one-pot procedure allows conversion of
yields.
L-carbidopa into higher
Acknowledgments
This work was supported by JSPS KAKENHI Grant Number
16K08168 from The Ministry of Education, Culture, Sports,
Science and Technology, Japan.
4.2.2. (–)-1-[1-Benzoyl-2-ethoxy-1-methyl-2-
oxoethyl] -1,2-hydradinedicarboxylic acid 1,2-
diethyl ester (4ab)
4. Experimental Section
Colorless amorphous; 182.1 mg; 96% yield; TLC: Rf 0.44
30
4.1. General experimental details
(hexane/EtOAc = 2/1, stained white with anisaldehyde); [α]D
1
1H and 13C NMR spectra were measured in CDCl3 with a
JEOL JNM-ECX400 spectrometer. Tetramethylsilane (TMS) (δ
= 0 ppm) and CDCl3 (δ = 77.0 ppm) served as an internal
standard for 1H and 13C, respectively. Infrared spectra were
recorded on a Perkin Elmer Frontier. Mass spectra were
measured with a JEOL JMS-700MStation and BRUKER Impact
II. Optical rotations were recorded on a JASCO P-1010
polarimeter. High-performance liquid chromatography (HPLC)
was performed on a JASCO P-2080 and UV-2075. Thin-layer
chromatography (TLC) analysis was performed using Merck
silica gel plates. Visualization was accomplished with UV light,
–109.2 (c 1.05, CHCl3) for 64% ee; H NMR (400 MHz,
CDCl3): δ 0.82-1.58 (m, 9H), 1.79-1.96 (m, 3H), 3.92-4.36 (m,
6H), 6.27-6.50 (m, 1H), 7.46-7.52 (m, 3H), 8.11-8.51 (m,
2H); Due to the distinct presence of rotameric isomers, the 13C
NMR contained multiple peaks.13C{1H} NMR (100 MHz,
CDCl3): δ 13.2, 13.8, 14.0, 14.1, 14.4, 20.1, 20.7, 62.3, 62.5,
63.2, 63.6, 128.1, 128.4, 129.2, 129.4, 129.7, 132.7, 132.9,
133.8, 134.1, 156.8, 157.0, 157.6, 169.6, 169.8, 190.8, 191.9;
IR (ATR): 3286, 2996, 1687 cm–1; LRMS (ESI): m/z 403
(M+Na)+; HRMS (ESI): Calcd for C18H25N2NaO7 403,1476,
found 403.1481. The enantiomeric excess was determined to
be 64% ee by HPLC with Daicel Chiralpak AD-H column
[eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min; detection:
254 nm; tR: 19.6 min (major), 25.3 min (minor)].
phosphomolybdic
acid,
and/or
anisaldehyde.
Column
chromatography was performed using Kanto Chemical Silica Gel
60N (spherical, 63–210 ꢀm). (R)-3,3'-disubstituted BINOLs were
synthesized according to literature procedures.14 β-Ketoꢀ esters
1 was synthesized according to literatures.15 Purified lithium
hydroxide was prepared by recrystallization in H2O and then
4.2.3. (–)-1-[1-Benzoyl-2-ethoxy-1-methyl-2-
oxoethyl] -1,2-hydradinedicarboxylic acid 1,2-di-
tert-butyl ester (4ac).
dried at 70 °C under reduced pressure. Authentic L-carbidopa
was purchased from Tokyo Kasei Industries. Dehydrated
stabilizer-free diethyl ether and tetrahydrofuran were purchased
from Kanto Chemical Co. Inc. All other solvents and chemicals
were purified based on standard procedures or used as received,
unless otherwise noted.
Pale yellow amorphous; 197.0 mg; 90% yield; TLC: Rf 0.25
27
(hexane/EtOAc = 4/1, stained yellow with anisaldehyde); [α]D
–
1
106.5 (c 1.05, CHCl3) for 87% ee; H NMR (400 MHz, CDCl3):
δ 1.05-1.95 (m, 24H), 4.25-4.40 (m, 2H), 5.95-6.47 (m, 1H),
7.30-7.58 (m, 3H), 8.11-8.65 (m, 2H); Due to the distinct
presence of rotameric isomers, the 13C NMR contained multiple
peaks.13C{1H} NMR (100 MHz, CDCl3): δ 14.1, 20.2, 20.9, 27.2,
27.8, 28.2, 62.0, 62.2, 76.3, 77.5, 81.3, 81.5, 82.1, 82.9, 83.1,
85.0, 128.0, 128.2, 128.3, 128.9, 129.2, 129.8, 129.9, 132.4,
132.8, 134.0, 134.6, 155.7, 156.4, 169.5, 169.8, 170.0, 191.0,
191.2, 192.0; IR (ATR): 2980, 1734, 1714, 1688, 1154 cm–1;
LRMS (FAB): m/z 459 (M+Na)+; HRMS (FAB): Calcd for
C22H32N2NaO7 459.2107, found 459.2085. The enantiomeric
excess was determined to be 87% ee by HPLC with Daicel
Chiralpak AD-H column [eluent: hexane/IPA = 9/1; flow rate:
1.0 mL/min; detection: 254 nm; tR: 8.5 min (minor), 17.9 min
(major)].
4.2. Typical procedure for lithium binaphtholate catalyzed
enantioselective amination
To a suspension of (R)-3,3'-Br2-BINOL (3a, 22.2 mg, 0.05
mmol) and LiOH (12.0 mg, 0.5 mmol) in diethyl ether (1 mL)
was added a diethyl ether solution of β-keto ester 1 (0.25 M, 2
mL, 0.50 mmol) at 23 °C under an argon atmosphere. The
reaction mixture was cooled to the desired temperature, and then
a solution of azodicarboxylate 2 in diethyl ether (0.525 M, 1 mL,
0.525 mmol) was added. The mixture was further stirred for 24 h
at the same temperature. The reaction was quenched with
aqueous saturated NH4Cl (5 mL), and the aqueous layer was
extracted with ethyl acetate (3 × 10 mL). The combined organic
layer was washed with brine (15 mL) and then dried over
Na2SO4. Concentration and column chromatographic purification
gave the corresponding adduct 4. The enantiomeric excess was
determined by HPLC equipped with a chiral column.
4.2.4. (–)-1-[(1R)-1-Benzoyl-2-ethoxy-1-methyl-2-
oxoethyl] -1,2-hydradinedicarboxylic acid 1,2-
dibenzyl ester (4ad).4 a
Pale yellow amorphous; 232.1 mg; 92% yield; TLC: Rf 0.28
19
(hexane/EtOAc = 4/1, stained yellow with anisaldehyde); [α]D
–
4.2.1. (–)-1-[1-Benzoyl-2-ethoxy-1-methyl-2-
oxoethyl] -1,2-hydradinedicarboxylic acid 1,2-
dimethyl ester(4aa)ꢀ
Colorless amorphous; 170.7 mg; 96% yield; TLC: Rf 0.48
(hexane/EtOAc = 4/1, stained yellow with anisaldehyde); m.p.;
58.0-100.5 °C; [α]D25 –95.9 (c 1.05, CHCl3) for 62% ee; 1H NMR
(400 MHz, CDCl3): δ 1.21-1.39 (m, 3H), 1.78-1.97 (m, 3H),
25
34.5 (c 1.29, CH2Cl2) for 54% ee [lit. [α]D –82.7 (c 0.98,
CH2Cl2) for 98% ee (R)]; H NMR (100 MHz, CDCl3): δ 1.16-
1
1.29 (m, 3H), 1.74-2.02 (m, 3H), 4.18-4.33 (m, 2H), 4.88-5.29
(m, 4H), 6.33-6.66 (m, 1H), 7.05-7.58 (m, 13H), 8.07-8.54 (m,
2H). The enantiomeric excess was determined to be 54% ee by
HPLC with Daicel Chiralpak AS-H column [eluent: hexane/IPA

6
Tetrahedron
hydradinedicarboxylic acid 1,2-di-tert-butyl ester
= 9/1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 27.7 min
ACCEPTED MANUSCRIPT
(4dc).
(minor, S), 63.7 min (major, R)].
Colorless amorphous; 595.0 mg; 93% yield; TLC: Rf 0.50
4.2.5. (–)-1-[1-Benzoyl-2-ethoxy-1-methyl-2-
oxoethyl] -1,2-hydradinedicarboxylic acid 1,2-
bis(2,2,2-trichloroethyl) ester (4ae).
25
(hexane/EtOAc = 4/1, stained yellow with anisaldehyde); [α]D
–
1
120.2 (c 1.09, CHCl3) for 88% ee; H NMR (400 MHz, CDCl3):
δ 1.17-1.64 (m, 18H), 1.80-1.95 (m, 3H), 3.87 (s, 3H), 4.00 (s,
6H), 6.26 (brs, 1H), 7.80-7.86 (m, 2H); Due to the distinct
presence of rotameric isomers, the 13C NMR contained multiple
peaks. 13C{1H} NMR (100 MHz, CDCl3): δ 20.2, 20.8, 27.3, 27.8,
28.0, 28.4, 29.6, 53.0, 53.1, 56.7, 56.9, 57.1, 76.3, 77.5, 81.5,
81.6, 83.3, 85.3, 105.4, 105.9, 106.3, 106.8, 134.1, 134.4, 155.6,
155.8, 156.2, 156.9, 157.0, 170.2, 170.4, 190.5, 191.3; IR (ATR):
3308, 2980, 1726, 1689, 1241, 1120 cm–1; LRMS (FAB): m/z
585, 583 (M+Na)+; HRMS (FAB): Calcd for C23H33BrN2NaO9
583.1267, found 583.1275. The enantiomeric excess was
determined to be 88% ee using HPLC equipped with a Daicel
Chiralpak AD-H column [eluent: hexane/IPA = 9/1; flow rate:
1.0 mL/min; detection: 254 nm; tR: 4.7 min (minor), 11.7 min
(major)].
Colorless amorphous; 261.2 mg; 89% yield; TLC: Rf 0.39
(hexane/EtOAc = 4/1, stained white with anisaldehyde); [α]D
31
–3.6 (c 0.90, CHCl3) for 4% ee; 1H NMR (400 MHz, CDCl3):
δ 1.36-1.39 (m, 3H), 1.87-1.99 (m, 3H), 4.28-5.23 (m, 6H),
6.63-7.05 (m, 1H), 7.37-7.55 (m, 3H), 7.96-8.47 (m, 2H); Due
to the distinct presence of rotameric isomers, the 13C NMR
contained multiple peaks.13C{1H} NMR (100 MHz, CDCl3): δ
13.9, 14.1, 14.2, 19.9, 20.2, 62.7, 63.0, 63.1, 75.2, 75.4, 75.7,
75.9, 94.3, 94.5, 128.3, 128.5, 129.0, 129.2, 130.0, 133.1,
133.5, 133.8, 134.1, 153.8, 154.4, 154.9, 155.0, 155.4, 169.2,
169.5, 190.3; IR (ATR): 1746, 1720, 1688 cm–1; LRMS
(FAB): m/z 585, 587, 589, 591 (M+H)+; HRMS (FAB): Calcd
for C18H19Cl6N2O7 584.9333, found 584.9323. The
enantiomeric excess was determined to be 4% ee by HPLC
with Daicel Chiralpak AD-H column [eluent: hexane/IPA =
4/1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 11.9 min
(major), 34.6 min (minor)].
4.2.9. (–)-1-[(1R)-1-(3,4-Dimethoxybenzoyl)-2-
methoxy-1-methyl-2-oxoethyl] -1,2-
hydradinedicarboxylic acid 1,2-di-tert-butyl ester
(4ec).1 2
Colorless; 228.6 mg; 95% yield; TLC: Rf 0.31 (hexane/EtOAc =
18
4.2.6. (–)-1-[1-(4-Fluorobenzoyl)-2-methoxy-1-
methyl-2-oxoethyl] -1,2-hydradinedicarboxylic acid
1,2-di-tert-butyl ester (4bc).
2/1, stained yellow with anisaldehyde); [α]D –137.7 (c 1.08,
CHCl3) for 89% ee; 1H NMR (400 MHz, CDCl3): δ 1.12-1.98 (m,
21H), 3.86 (s, 3H), 3.93-3.96 (m, 6H), 6.00-6.51 (m, 1H), 6.92-
7.01 (m, 1H), 7.71-8.43 (m, 2H). The enantiomeric excess was
determined to be 89% ee using HPLC equipped with a Daicel
Chiralpak AD-H column [eluent: hexane/IPA = 4/1; flow rate:
1.0 mL/min; detection: 254 nm; tR: 5.7 min (minor, S), 22.2 min
(major, R)].
Pale yellow amorphous; 215.8 mg; 98% yield; TLC: Rf 0.42
19
(hexane/EtOAc = 4/1, stained yellow with anisaldehyde); [α]D
–
90.7 (c 0.80, CHCl3) for 78% ee; 1H NMR (400 MHz, CDCl3): δ
1.07-1.97 (m, 21H), 3.87 (s, 3H), 5.96–6.52 (m, 1H), 7.02–7.23
(m, 2H), 8.22–8.66 (m, 2H); Due to the distinct presence of
rotameric isomers, the 13C NMR contained multiple peaks.
13C{1H} NMR (100 MHz, CDCl3): δ 20.3, 20.9, 27.3, 27.8, 28.2,
53.0, 53.2, 76.4, 77.6, 81.5, 81.6, 83.3, 85.3, 115.3, 115.4, 115.6,
130.3, 130.8, 131.6, 131.96, 132.04, 132.6, 155.6, 155.8, 156.5,
164.0, 164.2, 166.6, 166.7, 170.3, 170.5, 190.0, 190.8; IR (ATR):
2981, 1720, 1688, 1599, 1154 cm–1; LRMS (FAB): m/z 463
(M+Na)+; HRMS (FAB): Calcd for C21H29FN2NaO7 463.1856,
found 463.1864. The enantiomeric excess was determined to be
78% ee using HPLC equipped with a Daicel Chiralpak AD-H
column [eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min;
detection: 254 nm; tR: 7.3 min (minor), 45.6 min (major)].
4.2.10. (–)-1-[2-Ethoxy-1-(2-methoxybenzoyl)-1-
methyl-2-oxoethyl] -1,2-hydradinedicarboxylic acid
1,2-di-tert-butyl ester (4fc).
Colorless amorphous; 172.5 mg; 62% yield; TLC: Rf 0.47
(hexane/EtOAc = 2/1, stained yellow with anisaldehyde);
32
1
[α]D +0.1 (c 1.13, CHCl3) for 4% ee; H NMR (400 MHz,
CDCl3): δ 1.15-1.83 (m, 24H), 3.83 (s, 3H), 4.11-4.31 (m, 2H),
6.07-6.51 (m, 1H), 6.85-7.06 (m, 2H), 7.23-7.50 (m, 2H); Due
to the distinct presence of rotameric isomers, the 13C NMR
contained multiple peaks.13C{1H} NMR (100 MHz, CDCl3): δ
13.9, 14.2, 19.9, 20.1, 27.8, 27.9, 28.1, 55.2, 55.8, 56.2, 61.6,
80.8, 81.0, 81.3, 82.2, 111.0, 120.6, 120.9, 128.6, 129.1, 129.7,
130.7, 131.1, 131.9, 132.1, 154.5, 154.8, 155.6, 155.9, 168.3;
IR (ATR): 3321, 2979, 1708, 1244 cm–1; LRMS (FAB): m/z
489 (M+Na)+; HRMS (FAB): Calcd for C23H34N2NaO8
489.2213, found 489.2234. The enantiomeric excess was
determined to be 4% ee by HPLC with Daicel Chiralpak AD-
H column [eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min;
detection: 254 nm; tR: 12.5 min (minor), 18.0 min (major)].
4.2.7. (–)-1-[2-Methoxy-1-(4-methoxybenzoyl)-1-
methyl-2-oxoethyl] -1,2-hydradinedicarboxylic acid
1,2-di-tert-butyl ester (4cc).
Pale yellow amorphous; 217.2 mg; 96% yield; TLC: Rf 0.22
19
(hexane/EtOAc = 4/1, stained yellow with anisaldehyde); [α]D
–
1
99.2 (c 0.80, CHCl3) for 80% ee; H NMR (400MHz, CDCl3): δ
1.11-1.95 (m, 21H), 3.81-3.94 (m, 6H), 5.94-6.50 (m, 1H), 6.83-
7.05 (m, 2H), 8.14-8.66 (m, 2H); Due to the distinct presence of
rotameric isomers, the 13C NMR contained multiple peaks.
13C{1H} NMR (100 MHz, CDCl3): δ 20.5, 21.1, 27.2, 27.8, 28.1,
52.7, 52.9, 53.0, 55.3, 76.5, 77.7, 81.2, 81.4, 82.0, 82.9, 83.1,
84.8, 113.5, 126.9, 127.3, 131.2, 131.5, 132.1, 132.5, 155.8,
156.5, 162.8, 163.1, 170.5, 170.8, 190.4, 191.0; IR (ATR): 3303,
2980, 1721, 1679, 1601, 1243, 1153 cm–1; LRMS (FAB): m/z
475 (M+Na)+; HRMS (FAB): Calcd for C22H32N2NaO8 475.2056,
found 475.2066. The enantiomeric excess was determined to be
80% ee using HPLC equipped with a Daicel Chiralpak AD-H
column [eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min;
detection: 254 nm; tR: 13.8 min (minor), 45.8 min (major)].
4.2.11. (+)-1-[1-Acetyl-2-ethoxy-1-methyl-2-
oxoethyl] -1,2-hydradinedicarboxylic acid 1,2-di-
tert-butyl ester (4gc).
Pale yellow amorphous; 174.7 mg; 93% yield; TLC: Rf
0.32 (hexane/EtOAc = 4/1, stained yellow with anisaldehyde);
[α]D30 +13.3 (c 1.02, CHCl3) for 47% ee; 1H NMR (400 MHz,
CDCl3): δ 1.29 (t, 3H, J = 7.4 Hz), 1.32-1.78 (m, 21H), 2.21-
2.43 (m, 3H), 4.21-4.37 (m, 2H), 5.94-6.37 (m, 1H); Due to
the distinct presence of rotameric isomers, the 13C NMR
contained multiple peaks.13C{1H} NMR (100 MHz, CDCl3): δ
13.9, 14.0, 18.9, 19.7, 24.2, 25.7, 27.6, 27.8, 28.0, 61.7, 61.9,
75.2, 75.5, 76.2, 81.2, 81.7, 82.7, 84.7, 155.0, 155.4, 156.2,
4.2.8. (–)-1-[1-(4-Bromo-3,5-dimethoxybenzoyl)-2-
methoxy-1-methyl-2-oxoethyl] -1,2-

7
168.9, 169.2, 198.9, 199.5, 200.6, 202.2; IR (ATR): 3321,
hexane/IPA = 9/1; flow rate: 1.0 mL/min; detection: 254 nm;
tR: 12.8 min (minor), 16.1 min (major)].
ACCEPTED MANUSCRIPT
2980, 1710, 1151 cm–1; LRMS (ESI): m/z 397 (M+Na)+;
HRMS (ESI): Calcd for C17H30N2NaO7 397.1951, found
397.1949. The enantiomeric excess was determined to be 47%
ee by HPLC with Daicel Chiralpak AD-H column [eluent:
hexane/IPA = 19/1; flow rate: 1.0 mL/min; detection: 220 nm;
tR: 15.5 min (major), 21.8 min (minor)].
4.2.15. (–)-1-[1-Allyl-2-ethoxy-1-benzoyl-2-
oxoethyl] -1,2-hydradinedicarboxylic acid 1,2-
dimethyl ester (4ka).
Colorless amorphous; 163.1 mg; 86% yield; TLC: Rf 0.38
26
(hexane/EtOAc = 4/1, stained red with anisaldehyde); [α]D
–
34.5 (c 1.05, CHCl3) for 82% ee; 1H NMR (400 MHz, CDCl3): δ
1.15-1.48 (m, 3H), 2.91-3.32 (m, 2H), 3.33-3.98 (m, 6H), 4.15-
4.43 (m, 2H), 4.68-5.13 (m, 2H), 5.76-5.89 (m, 2H), 6.30-6.68
(m, 1H), 7.38-7.58 (m, 3H), 8.16-8.55 (m, 2H); Due to the
distinct presence of rotameric isomers, the 13C NMR contained
multiple peaks.13C{1H} NMR (100 MHz, CDCl3): δ 13.6, 13.9,
38.6, 39.0, 39.4, 53.2, 53.6, 54.0, 54.3, 62.2, 62.5, 79.5, 118.9,
119.7, 128.0, 128.4, 128.9, 131.6, 132.7, 133.5, 135.1, 156.0,
157.0, 157.5, 167.3, 168.9, 169.3, 189.7, 191.0; IR (ATR): 3300,
2959, 1719, 1686, 1218 cm–1; LRMS (FAB): m/z 379 (M+H)+;
HRMS (FAB): Calcd for C18H23N2O7 379.1505, found 379.1523.
The enantiomeric excess was determined to be 82% ee by HPLC
with Daicel Chiralpak AD-H column [eluent: hexane/IPA = 9/1;
flow rate: 1.0 mL/min; detection: 254 nm; tR: 15.1 min (minor),
18.4 min (major)].
4.2.12. (+)-1-[1-Butyryl-2-ethoxy-1-methyl-2-
oxoethyl] -1,2-hydradinedicarboxylic acid 1,2-di-
tert-butyl ester (4hc).
Pale yellow amorphous; 166.6 mg; 83% yield; TLC: Rf 0.21
(hexane/EtOAc = 4/1, stained yellow with anisaldehyde);
29
1
[α]D +3.9 (c 0.97, CHCl3) for 13% ee; H NMR (400 MHz,
CDCl3): δ 0.89-0.99 (m, 3H), 1.26-1.80 (m, 26H), 2.44-2.87
(m, 2H), 4.18-4.32 (m, 2H), 5.88-6.42 (m. 1H); Due to the
distinct presence of rotameric isomers, the 13C NMR contained
multiple peaks.13C{1H} NMR (100 MHz, CDCl3): δ 13.6,
13.9, 14.0, 14.1, 17.5, 19.4, 19.6, 20.2, 20.4, 27.9, 28.0, 28.1,
380, 39.4, 61.8, 62.0, 75.8, 81.3, 81.8, 82.8, 84.6, 155.5,
155.6, 156.3, 169.6, 170.0, 201.6, 202.2, 203.2, 204.5; IR
(ATR): 3298, 2970, 1748, 1718, 1152 cm–1; LRMS (ESI): m/z
425 (M+Na)+; HRMS (ESI): Calcd for C19H34N2NaO7
425.2264, found 425.2264. The enantiomeric excess was
determined to be 13% ee by HPLC with Daicel Chiralpak
AD-H column [eluent: hexane/IPA = 19/1; flow rate: 1.0
mL/min; detection: 220 nm; tR: 10.4 min (major), 15.3 min
(minor)].
4.2.16. (+)-1-[1-Benzoyl-1-benzyl-2-ethoxy-2-
oxoethyl] -1,2-hydradinedicarboxylic acid 1,2-
dimethyl ester (4la).
Pale yellow amorphous; 175.9 mg; 82% yield; TLC: Rf 0.38
27
(hexane/EtOAc = 4/1, stained orange with anisaldehyde); [α]D
+14.7ꢁ(c 1.04, CHCl3) for 95% ee; 1H NMR (400 MHz, CDCl3):
δ 0.95-1.75 (m, 3H), 3.45–4.42 (m, 10H), 5.10-6.60 (m, 1H),
6.98–7.55 (m, 8H), 8.08–8.65 (m, 2H); Due to the distinct
presence of rotameric isomers, the 13C NMR contained multiple
peaks. 13C{1H} NMR (100 MHz, CDCl3): 13.6, 13.8, 14.0, 39.3,
39.9, 52.8, 53.2, 54.0, 54.2, 62.6, 80.2, 80.5, 126.7, 127.6, 128.0,
128.4, 129.0, 129.2, 129.6, 130.3, 130.7, 132.6, 134.4, 135.1,
135.6, 136.0, 155.9, 156.4, 157.2, 157.6, 165.8, 166.1, 169.3,
189.5, 190.0; IR (ATR): 3302, 2958, 1719, 1688, 1222 cm–1;
LRMS (FAB): m/z 429 (M+H)+; HRMS (FAB): Calcd for
C22H25N2O7 429.1662, found 429.1653. The enantiomeric excess
was determined to be 95% ee by HPLC with Daicel Chiralpak
AD-H column [eluent: hexane/IPA = 9/1; flow rate: 1.0 mL/min;
detection: 254 nm; tR: 18.1 min (major), 20.7 min (minor)].
4.2.13. (–)-1-[2-Ethoxy-1-isobutyryl-1-methyl-2-
oxoethyl] -1,2-hydradinedicarboxylic acid 1,2-di-
tert-butyl ester (4ic).
Pale yellow amorphous; 170.1 mg; 85% yield; TLC: Rf 0.34
(hexane/EtOAc = 4/1, stained yellow with anisaldehyde); [α]D
29
–
10.1 (c 1.08, MeOH) for 54% ee; 1H NMR (400 MHz, CDCl3): δ
1.05-1.85 (m, 30H), 3.18-3.70 (m, 1H), 4.15-4.34 (m, 2H), 5.90-
6.36 (m, 1H); Due to the distinct presence of rotameric isomers,
the 13C NMR contained multiple peaks. 13C{1H} NMR (100
MHz, CDCl3): δ 14.0, 14.1, 19.6, 19.9, 20.3, 20.6, 21.9, 22.3,
27.8, 34.5, 34.9, 36.3, 61.6, 61.9, 75.9, 76.1, 81.2, 81.7, 82.6,
155.5, 155.7, 169.3, 169.5, 169.9, 206.6, 207.3, 209.5; IR (ATR):
3319, 2979, 1710, 1150 cm–1; LRMS (FAB): m/z 425 (M+Na)+;
HRMS (FAB): Calcd for C19H34N2NaO7 425.2264, found
425.2264. The enantiomeric excess was determined to be 54% ee
by HPLC with Daicel Chiralpak AD-H column [eluent:
hexane/IPA = 19/1; flow rate: 1.0 mL/min; detection: 220 nm; tR:
11.2 min (major), 12.3 min (minor)].
4.3. Preparation of Enantiomerically Pure (S)-(+)-4ec
To a suspension of (S)-3,3'-Br2-BINOL (88.8 mg, 0.2 mmol) and
LiOH (48.2 mg, 2 mmol) in diethyl ether (1 mL) was added an
diethyl ether solution of β-keto ester 1e (0.25 M, 2 mL, 2 mmol)
at 23 °C under argon atmosphere. A solution of azodicarboxylate
2c in diethyl ether (0.525 M, 1 mL, 2.1 mmol) at the described
temperature was added to the reaction mixture, which was further
stirred for 24 h at the same temperature. The reaction was
quenched with aqueous saturated NH4Cl (20 mL), and the
aqueous layer was extracted with ethyl acetate (3 x 40 mL). The
combined organic layer was washed with brine (20 mL), and
dried over Na2SO4. Concentration and column chromatographic
purification gave the corresponding adduct 4ec (955.4 mg, 99%
yield, 87% ee), which was then dissolved in hexane/ethyl acetate
(20:1, 20 mL) to furnish the racemic crystal. After filtration, the
mother liquid was evaporated to obtain (S)-4ea with >99% ee.
The enantiomeric excess was determined to be >99% ee by
HPLC with Daicel Chiralpak AD-H column [eluent: hexane/IPA
= 4/1; flow rate: 1.0 mL/min; detection: 254 nm; tR: 5.5 min
(major, S), 19.7 min (minor, R)].
4.2.14. (–)-1-[1-Benzoyl-1-butyl-2-methoxy-2-
oxoethyl] -1,2-hydradinedicarboxylic acid 1,2-
dimethyl ester (4ja).
Yellow amorphous; 129.8 mg; 68% yield; TLC: Rf 0.25
(hexane/EtOAc = 2/1, stained yellow with anisaldehyde);
[α]D28 –54.3 (c 0.96, CHCl3) for 58% ee; 1H NMR (400 MHz,
CDCl3): δ 0.68-0.88 (m, 3H), 0.95-2.58 (m, 6H), 3.35-4.00
(m, 9H), 6.28-6.79 (m, 1H), 7.39-7.58 (m, 3H), 7.95-8.62 (m,
2H); Due to the distinct presence of rotameric isomers, the 13C
NMR contained multiple peaks.13C{1H} NMR (100 MHz,
CDCl3): δ 13.5, 23.1, 26.4, 26.9, 33.9, 34.3, 35.1, 53.2, 53.3,
54.1, 54.5, 79.9, 128.2, 128.6, 128.7, 128.9, 132.9, 135.2,
135.5, 157.4, 157.7, 170.7, 190.1; IR (ATR): 3300, 2958,
1721, 1684, 1228 cm–1; LRMS (ESI): m/z 403 (M+Na)+;
HRMS (ESI): Calcd for C18H24N2NaO7 403.1481, found
403.1475. The enantiomeric excess was determined to be 58%
ee by HPLC with Daicel Chiralpak AD-H column [eluent:
4.4. One-pot manipulation for derivatization of 4ec into 7ec

8
Tetrahedron
ACCEPTED MANUSCRIPT
4ec (241.4 mg, 0.5 mmol, >99% ee) was treated with TFA
(s, 3H), 2.62 (d, 1H, J = 13.6 Hz), 2.73 (d, 1H, J = 13.6 Hz),
(0.31 mL, 4.0 mmol, 8.0 equiv) at 23 °C under argon atmosphere.
After stirring for 6 h at the same temperature, the reaction
mixture was then cool to 0 °C. To the reaction mixture were
added carbobenzoxy chloride (0.079 mL, 0.55 mmol, 1.1 equiv)
and N,N-diisopropylethylamine (0.87 mL, 5.0 mmol, 10 equiv),
respectively. The reaction was completed in 30 min, and then the
mixture was evaporated under reduce pressure to afford a crude
material of 6ec. The obtained residue was dissolved in TFA (1.9
mL, 25 mmol, 50 equiv) at 23 °C, and triethylsilane (1.2 mL, 7.5
mmol, 15 equiv) was added to the solution. The mixture was
heated at 35 °C for 30 h. The reaction mixture was diluted with
dichloromethane (3 mL) and quenched with sat. NaHCO3 (15
mL). After stirring for 1 hour, the two-layers mixture was
separated, and the water layer was extracted with
dichloromethane (4 x 15 mL). The combined organic layer was
washed with brine and dried over anhydrous Na2SO4. After
filtration and concentration, the obtained crude material was
purified by column chromatography to give the amino acid
derivative 7ec.
6.39 (d, 1H, J = 8.0 Hz), 6.54 (d, 1H, J = 8.0 Hz), 6.59 (s,
1H). 13C{1H} NMR (100 MHz, DMSO): δ 21.1, 42.0, 66.0,
115.9, 118.8, 122.1, 127.9, 144.9, 145.7, 175.3; IR (ATR):
3528, 3105, 1626, 1370, 1122; LRMS (FAB): m/z 227 (M+H-
H2O)+; HRMS (FAB): Calcd for C10H15N2O4 227.1032, found
227.1040.
References and notes
1.
(a) Williams, R. M. in Synthesis of Optically Active α-Amino
Acids, Ed. Baldwin, J. E. Pergamon Press, Oxford, 1989. (b)
Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889–917.
(c) Duthaler, R. O. Tetrahedron 1994, 50, 1539–1650. (e)
Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013–3028. (f)
Nájera, C.; Sansano, J. C. Chem. Rev. 2007, 107, 4584–4671.
For reviews of asymmetric synthesis of α,α-disubstituted α-amino
acids, see: (a) Heimgartner, H. Angew. Chem. Int. Ed. Engl., 1991,
30, 238–264. (b) Cativiela, C.; Diaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 1998, 9, 3517–3599. (c) Ooi, T.;
Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am Chem. Soc. 2000,
122, 5228–5229. (d) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem.
2005, 5127–5143. (e) Cativiela, C.; Diaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 2007, 18, 569–623; (f) Tanaka, M.
Chem. Pharm. Bull. 2007, 55, 349–358. (g) Vogt, H.; Bräse, S.
Org. Biomol. Chem. 2007, 5, 406–430. (h) Metz, A. E.;
Kozlowski, M. C. J. Org. Chem. 2015, 80, 1–7. (i) Liu, Y.-L.,
Zhou, J. Synthesis 2015, 47, 1210–1226.
For representative reviews on asymmetric α-amination reaction,
see: (a) Genet, J.-P.; Creck, C.; Lavergne, D. In Modern
Amination Methods; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2000,
Chap. 3. (b) Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J.
Org. Chem., 2004, 1377–1385. (c) Erdik, E. Tetrahedron, 2004,
60, 8747–8782. (d) Janey, J. M. Angew. Chem., Int. Ed., 2005, 44,
4292–4300. (e) Guillena, G.; Ramón, D. J. Tetrahedron:
Asymmetry, 2006, 17, 1465–1492. (f) Nair, V.; Biju, A. T.;
Mathew, S. C.; Babu, B. P. Chem. Asian J. 2008, 3, 810–820. (g)
Vilaivan, T.; Bhanthumnavin, W. Molecules, 2010, 15, 917-958.
(h) Russo, A.; De Fusco, C.; Lattanzi, A. RSC Adv., 2012, 2, 385–
397. (i) Zhou, F.; Liao, F.-M.; Yu, J.-S.; Zhou, J. Synthesis, 2014,
2983–3003.
2.
4.4.1. (+)-2-[(1S)-1-(3,4-Dimethoxybenzyl)-2-
methoxy-1-methyl-2-oxoethyl] -1,2-
hydradinecarboxylic acid benzyl ester (7ec).
Colorless amorphous; 124.5 mg, 62% yield; TLC: Rf 0.36
(hexane/EtOAc = 1/1, stained orange with phosphomolybdic
acid); [α]D27 +14.5ꢀ(c 0.97, CHCl3) for 99% ee; 1H NMR (400
MHz, CDCl3): δ 1.40 (s, 3H), 2.90 (d, 1H, J = 13.7 Hz), 3.06
(d, 1H, J = 13.7 Hz), 3.71 (s, 3H), 3.85 (s, 3H), 3.88 (s, 3H),
4.19 (brs, 1H), 5.08-5.13 (m, 2H), 6.47 (brs, 1H), 6.68-6.78
(m, 3H), 7.30-7.38 (m, 5H). 13C{1H} NMR (100 MHz,
CDCl3): 21.2, 43.4, 52.1, 55.8, 66.0, 66.9, 111.0, 112.8, 121.9,
127.5, 128.2, 128.5, 136.1, 148.1, 148.7, 156.9, 175.5; IR
(ATR): 3312, 2950, 1721, 1514 cm–1; LRMS (FAB): m/z 425
(M+Na)+; HRMS (FAB): Calcd for C21H26N2NaO6 425.1683,
found 425.1680. The enantiomeric excess was determined to
be 99% ee by HPLC with Daicel Chiralpak OD-H column
[eluent: hexane/IPA = 4/1; flow rate: 1.0 mL/min; detection:
254 nm; tR: 18.7 min (minor, R), 24.5 min (major, S)].
3.
4.
5.
(a) Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2003, 42, 1367–1369. (b) Saaby, S.; Bella, M.; Jørgensen, K. A. J.
Am. Chem. Soc. 2004, 126, 8120–8121.ꢁ(c) Juhl, K.; Jørgensen,
K. A. J. Am. Chem. Soc. 2002, 123, 2420–2421.
For selected examples of metal-catalyzed asymmetric electrophilic
amination of α-alkyl-β-keto esters, see: (a) Ma, S.; Jiao, N.;
Zheng, Z.; Ma, Z.; Lu, Z.; Ye, L.; Deng, Y.; Chen, G. Org. Lett.
2004, 6, 2193–2196. (b) Foltz, C.; Stecker, B.; Marconi, G.;
Bellemin-Laponnaz, S.; Wadepohl, H.; Gade, L. H.; Chem.
Commun. 2005, 5115–5117. (c) Kang, Y. K.; Kim, D. Y.
Tetrahedron Lett. 2006, 47, 4565–4568. (d) Mang, J. Y.; Kwon D.
G.; Kim, D. Y. Bull. Korean Chem. Soc. 2009, 30, 249–252. (e)
Qian, Z.-Q.; Zhou, F.; Du, T.-P.; Wang, B.-L.; Ding, M.; Zhao,
X.-L.; Zhou, J. Chem. Commun. 2009, 6753–6755. (f) Mashiko,
T.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
14990–14999. (g) Nandakumar, M. V.; Ghosh, S.; Schneider, C.
Eur. J. Org. Chem. 2009, 6393–6398. (h) Ghosh, S.; Nandakumar,
M. V.; Krautscheid, H.; Schneider, C. Tetrahedron Lett. 2010, 51,
1860–1862. (i) Sandoval, D.; Charles, P. F.; Bugarin, A.; Read de
Alaniz, J. J. Am. Chem. Soc. 2012, 134, 18948–18951. (j) Zhou,
F.; Zeng, X.-P.; Wang, C.; Zhao, X.-L.; Zhou, J. Chem. Commun.
2013, 49, 2022–2024. (k) Xiao, X.; Lin, L.; Lian, X.; Liu, X.;
Feng, X. Org. Chem. Fact. 2016, 3, 809-812. (l) Kumar, A.;
Ghosh, S. K.; Gladysz, J. A. Org. Lett. 2016, 18, 760-763.
For selected examples of organocatalyst-catalyzed asymmetric
electrophilic amination of α-alkyl-β-keto esters, see: (a) Pihko, P.
M.; Pohjakallio, A. Synlett 2004, 2115–2118. (b) Terada, M.;
Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044–16045.
(c) Jung, S. H.; Kim, D. Y. Tetrahedron Lett. 2008, 49, 5527–
5530. (d) Zhang, Z.-H.; Dong, X.-Q.; Tao, H.-Y.; Wang, C.-J.
ARKIVOC 2011, (ii), 137ꢂ150. (e) Murai, K.; Fukushima, S.;
Nakamura, A.; Shimura, M.; Fujioka, H. Tetrahedron 2011, 67,
4862–4868. (f) Odagi, M.; Yamamoto, Y.; Nagasawa, K. Beilstein
J. Org. Chem. 2016, 12, 198-203.
4.5. Preparation of L
-carbidopa•monohydrate12
7ec (114.8 mg, 0.285 mmol) was dissolved in dichloromethane (3
mL) under argon atmosphere and to the mixture was added BBr3
(0.28 mL, 10 equiv) at –78 °C. The reaction mixture was warm to
23 °C and then stirred for 24 h. Addition of H2O (5 mL)
quenched the reaction, and the mixture was further stirred for 1
hour. The two-layers mixture was separated and water layer was
wash with dichloromethane (3 x 10 mL) and ethyl acetate (3 x 10
mL). Under reduced pressure, water was evaporated roughly, the
obtained residue was dissolved with methanol (5 mL), the
resulting solution was stirred for 16 h at 50 °C. Then, solvent was
evaporated to obtain L-carbidopa as the hydrobromide salt. The
residue was dissolved in isopropyl alcohol (0.5 mL), diethyl
amine (41.8 mg, 0.570 mmol) was added to give the solid, which
was corrected and dried under reduced pressure at 65 °C to
isolate L-carbidopa as monohydrate (66.1 mg, 95% yield). the
6.
Spectra of the synthesized
reported one.
L-carbidopa were identical to the
1 2
4.5.1.
L-Carbidopa•monohydrate
Colorless needle; 66.1 mg; 95% yield; m.p.; >195 °C
27
(decomposed); [α]D –12.8ꢁ(c 0.33, MeOH) for 99% ee [lit.
25
[α]D26 –11.8 (c 0.5, MeOH) for 97.5% ee; authentic sample [α]D
–16.6 (c 0.33, MeOH)]; 1H NMR (400 MHz, DMSO): δ 1.08

9
7.
8.
For selected examples of phase transfer catalyst-catalyzed
ACCEPTED MANUSCRIPT
asymmetric electrophilic amination of α-alkyl-β-keto esters, see:
(a) He, R.; Wang, X.; Hashimoto, T.; Maruoka, K. Angew. Chem.
Int. Ed. 2008, 47, 9466–9468. (b) Lan, Q.; Wang, X.; He, R.;
Ding, C.; Maruoka, K. Tetrahedron Lett. 2009, 50, 3280–3282. (c)
He, R.; Maruoka, K. Synthesis, 2009, 2289–2292.
For selected examples of hydrogen bonding catalyst-catalyzed
asymmetric electrophilic amination of α-alkyl-β-keto esters, see:
(a) Xu, X.; Yabuta, T.; Yuan, P.; Takemoto, Y. Synlett 2006, 137–
140. (b) Konishi, H.; Lam, T. Y.; Malerich, J. P.; Rawal, V. H.
Org. Lett. 2010, 12, 2028–2031. (c) Inokuma, T.; Furukawa, M.;
Uno, T.; Suzuki, Y.; Yoshida, K.; Yano, Y.; Matsuzaki, K.;
Takemoto, Y. Chem. Eur. J. 2011, 17, 10470–10477. (d) Azuma,
T.; Kobayashi, Y.; Sakata, K.; Sasamori, T.; Tokitoh N.;
Takemoto, Y. J. Org. Chem. 2014, 79, 1805-1817. (e) Trillo, P.
Synlett 2015, 26, 95-100.
9.
Kotani, S.; Moritani, M.; Nakajima, M. Asian J. Org. Chem. 2015,
4, 616–618.
10. Kotani, S.; Asano, T.; Moritani, M.; Nakajima, M. Tetrahedron
Lett. 2016, 57, 4217–4219.
11. Delea, T. E.; Thomas, S. K.; Hagiwara, M. CNS Drugs 2011, 25,
53–66.
12. Oericas, A.; Shafir, A.; Vallribera, A. Org. Lett. 2013, 15, 1448-
1451.
13. The yield of stepwise procedure was 25% in three steps.
14. (a) Wu, T. R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6, 2701-
2704. (b) Momiyama, N.; Nishimoto, H.; Terada, M. Org. Lett.
2011, 13, 2126-2129.
15. (a) Ravía, S. P.; Carrera, I.; Seoane, G. A.; Vero, S.; Gamenara, D.
Tetrahedron: Asymmetry 2009, 20, 1393–1397. (b) Iida, A.;
Nakazawa, S.; Nakatsuji, H.; Misaki, T.; Tanabe, Y. Chem. Lett.
2007,
36,
48-49.

ACCEPTED MANUSCRIPT
10
Tetrahedron