Derivatives and application to the asymmetric synthesis of unnatural α-amino acid derivative

Article abstract of DOI:10.1248/cpb.c17-00158

We describe herein a manganese(IV) oxide-mediated oxidation of N-p-methoxyphenyl (PMP)-protected glycine derivatives for the synthesis of a-imino carboxylic acid derivatives. Using this methodology, utilization of unstable glyoxic acid derivatives was avoided. Furthermore, using this methodology we synthesized novel a-imino carboxylic acid derivatives such as a-imino phenyl ester, perfluoroalkyl etsers, imides, and thioester. The asymmetric Mannich reaction of those novel imine derivatives with 1,3-dicarbonyl compound is also described, and the novel a-imino imide gave improved chemical yield and stereoselectivity compared with those obtained by the use of the conventional a-imino ester-type substrate.

Full text of DOI:10.1248/cpb.c17-00158

Vol. 65, No. 6
Chem. Pharm. Bull. 65, 573–581 (2017)
573
Regular Article
Highlighted Paper selected by Editor-in-Chief
A Convenient Method for Preparation of α-Imino Carboxylic Acid
Derivatives and Application to the Asymmetric Synthesis of Unnatural
α-Amino Acid Derivative
Tsubasa Inokuma, Takahisa Jichu, Kodai Nishida, Akira Shigenaga, and Akira Otaka*
Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University; Tokushima
770–8505, Japan.
Received February 19, 2017; accepted March 21, 2017
We describe herein a manganese(IV) oxide-mediated oxidation of N-p-methoxyphenyl (PMP)-protected
glycine derivatives for the synthesis of α-imino carboxylic acid derivatives. Using this methodology, utiliza-
tion of unstable glyoxic acid derivatives was avoided. Furthermore, using this methodology we synthesized
novel α-imino carboxylic acid derivatives such as α-imino phenyl ester, perfluoroalkyl etsers, imides, and
thioester. The asymmetric Mannich reaction of those novel imine derivatives with 1,3-dicarbonyl compound
is also described, and the novel α-imino imide gave improved chemical yield and stereoselectivity compared
with those obtained by the use of the conventional α-imino ester-type substrate.
Key words α-imino carboxylic acid derivative; heterogeneous oxidant; asymmetric organocatalysis; thiourea;
unnatural α-amino acid
Unnatural α-amino acids are often seen in varieties of bio-
Among a wide variety of oxidants, manganese(IV)
logically active compounds,1–4) including pharmaceutics, and oxide is potential choice of heterogeneous oxidant.24,25) The
have been used as indispensable chiral building blocks for the mild oxidative potential and easily separable nature allow
synthesis of such active compounds.5,6) Additionally, increas- manganese(IV) oxide to be favorably utilized in the oxidative
ing utilities of unnatural amino acids as a key structural ele- transformation at the near final step of complex molecules
ment have also been shown in fields of chemical biology and such as natural products. Although manganese(IV) oxide-
asymmetric transformation.7–11) These contexts evoke much mediated conversion of aliphatic amines to the corresponding
interest of synthetic chemists in asymmetric synthesis of the imines mainly consisting of N-heteroaromatization of cyclic
structural unit.12,13) Enabling easy access to diverse α-amino amines has been reported,26,27) application to the synthesis
acids only by changing nucleophiles employed, Mannich-type of α-imino ester remains to be reported.28) Being potentially
reaction of α-imino ester has been widely utilized for the applied to N-protected glycine derivatives possessing re-
asymmetric synthesis.14–20) Generally, condensation of glyoxa- placement of the ester function with other carboxylic acid
lates and primary amines affords α-imino esters as the requi- equivalents such as amide or imide, the envisioned oxidative
site substrate for Mannich-type reaction (Chart 1a); however, protocol could expand its substrate scope to barely accessible
the glyoxalates are unstable, and suffer easy hydrolysis or po- molecules by addition-dehydration sequence for the imine
lymerization at room temperature. Additionally, high suscep- formation. Such amides or imides could provide an additional
tibility of the resulting α-imino ester to silica gel has forced site for formation of an intermediary complex (substrate–cata-
us to directly use the imino esters for the Mannich reaction lyst–nucleophile) involved in the following asymmetric Man-
without purification, thereby leading to difficulty in maintain- nich reaction.
ing the reaction outcome. In this context, cross-dehydrogena-
tive coupling (CDC) has been investigated for the synthesis
Results and Discussion
One critical issue involved in the oxidation using
of α-functionalized amino acids21–23) (Chart 1b). The CDC
protocol features oxidative preparation of α-imino ester from manganese(IV) oxide is quality of the reagent. Generally,
glycinates with the use of the oxidants such as 2,3-dichlo- activated manganese(IV) oxide has been reported to be suit-
ro-5,6-dicyanobenzoquinone (DDQ), CuOAc, Ru(bpy)3Cl2/ able for the MnO2-mediated oxidative conversion of various
light (or N-oxyl radical), or Cu(I)/molecular oxygen, followed substrates. Thus, we initially subjected N-p-methoxyphenyl
by in situ Mannich reaction. Although the CDC protocol is (PMP) glycine ethylester 1a to oxidation in CH2Cl2 using
free from the use of unstable glyoxalates, the in situ Mannich 20eq of activated manganese(IV) oxide from commercial
reaction has to be performed in the presence of the employed source. The attempted reaction resulted in complete disap-
oxidant due to difficulty in achieving complete separation of pearance of 1a within 1h to give desired imine 2a only by
the imino ester and oxidant, by which the use of the CDC filtration through Celite; however, several byproducts derived
remains within application to the coupling of oxidant-tolerant from overoxidation were detected (see Supplementary materi-
functional units. Here, we envisioned that the heterogeneous als). On the other hand, the use of less expensive and non-
oxidation system enabling facile removal of insoluble oxidants activated powdered manganese oxide(IV) could afford better
by filtration allowed the imino ester to be readily obtained and result, in which desired imine 2a with satisfactory purity was
subsequently subjected to Mannich reaction under oxidant-free obtained in 92% isolated yield by simple filtration work-up on
conditions (Chart 1c).
Celite pad (Table 1, entry 1). Next, applicability of the oxida-
*To whom correspondence should be addressed. e-mail: aotaka@tokushima-u.ac.jp
© 2017 The Pharmaceutical Society of Japan

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Chart 1. Synthesis of α-Amino Acids via α-Imino Carboxylic Acids
Table 1. Synthesis of α-Imino Carboxylic Acid Derivativesa

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575
tion system to various carboxylic functionalities was exam- Takemoto et al. described that asymmetric Petasis reaction of
ined. Oxidation of methyl, t-butyl, benzyl, or allyl glycinate substrate such as 2g with vinyl boronate in the presence of a
with the non-activated manganese oxide(IV) in CH2Cl2 at hydroxyl thiourea-type organocatalyst furnished satisfactory
room temperature for 1h proceeded efficiently to give desired results.33) Next, we attempted the synthesis of novel imine
highly homogeneous imine in high chemical yield (Table 1, derivatives, never accessible by the conventional procedure,
entries 2–5). Resulting imino esters 2b–e are substrates of using the heterogeneous manganese(IV) oxide-meditated oxi-
great use for the following asymmetric Mannnich reaction, dation. The novel imines 2h–j, which possess highly-activated
because such ester functionalities can be generally cleaved ester moieties such as phenyl, trifluoroethyl, or hexafluoroiso-
without affecting enantiometric purity using acidic reagent,29) propyl esters could be prepared by our strategy (entries 8–10).
hydrogenation,30) and Pd-catalyzed reaction,31) respectively. Furthermore, attempted reactions led to almost quantitative
We next examined the synthesis of imino amides 2f and g, formation of desired imino imides 2k and l with high purity
of great value in Petasis reaction, using boric or boronate (entries 11, 12). Surprisingly, even thioester 2m, susceptible
reagent. Although laborious and time-consuming steps were to an oxidant, could be prepared without any problems (entry
required for the preparation of such imino amides using the 13). Although other protections except for PMP were also
conventional addition-dehydration sequence, dipeptide-type examined, we failed to find suitable protective groups (see
compound PMP-Gly-Gly-OEt 1f and glycyl N-ethyl anilide Supplementary materials). The derivative 1n, with electron
1g were successfully converted to the corresponding imino donating methoxy substituent both on the para- and ortho-
amides 2f and g by the action of manganese(IV) oxide. Petasis positions of the phenyl ring, suffered auto-oxidation by atmo-
reaction of the resulting imino amide 2f with aryl boric acids spheric oxygen during purification of 1n. Oxidation of ortho
was reported to afford aryl glycine derivatives.32) Furthermore, methoxy phenyl-protected derivative 1o proceeded more slow-
Table 2. Asymmetric Mannich Reaction of α-Imino Carboxylic Acid Derivativesa

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ly than that of PMP-protected substrate, probably due to steric a positive pressure of argon. Analytical TLC was performed
hindrance, and resulted in incomplete reaction. Increasing on Merck TLC silica gel 60F254 silica gel plates. Visual-
amount of the oxidant led to formation of a complex mixture. ization was accomplished with molibudenium phosphate,
Other protections including benzyl (Bn), tert-butyloxycarbonyl p-anisaldehyde, Hannessian’s cocktail or ninhydrin. For col-
(Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), and triphenyl- umn chromatography, silica gel (KANTO KAGAKU N-60)
methyl (Trt) also failed to afford the corresponding imines. was employed. NMR spectra were recorded using a Bruker
1
Thus, we decided to continue our investigation using N-PMP AV400N at 400MHz frequency or JEOL JNM-AL300 for H,
protection.
and JEOL JNM-AL300 at 75MHz frequency for 13C in the
Having several types of α-imino carbonyl derivatives 2h–m stated solvents using tetramethylsilane as an internal standard.
obtained in hand, we evaluated asymmetric Mannich reaction Chemical shifts were reported in parts per million (ppm) on
of the resulting imine in the presence of Takemoto’s chiral the δ scale from an internal standard (NMR descriptions:
bifunctional thiourea catalyst 334) compared with that of con- s, singlet; d, doublet; t, triplet; q, quartet; hept, heptet; m,
ventional α-imino ethyl ester 2a (Table 2). Initially, attempted multiplet; br, broad). Coupling constants, J, are reported in
asymmetric Mannich reaction of the ethyl α-imino carboxyl- Hertz. For chiral HPLC analysis, a chiralpak IA (DAICEL,
ate 2a with β-ketoester 4 gave the corresponding Mannich 4.6×250mm), a chiralcel IB-3 (DAICEL, 4.6×250mm) or a
adducts 5a as diastereomixture in low chemical yield. The chiralcel IC-3 (DAICEL, 4.6×250mm) were employed and
enantiomeric excess of one of the diastereomers was good eluting products were detected by UV at 254nm. A solvent
(entry 1). The reaction of phenyl ester-type substrate 2h also system consisting of HPLC grade of hexane and 2-propanol
produced the adduct 5b, albeit with diminished enantioselec- was used for HPLC analysis. Mass spectra were recorded on
tivities (entry 2). To our surprise, the perfluoroalkyl ester-type a Waters MICROMASS® LCT PREMIERTM (electrospray
substrates 2i and j did not give the desired products at all ionization-time-of-flight (ESI-TOF)). Optical rotations were
(entries 3, 4). Further exploration revealed that the reaction measured using a JASCO P-2200 polarimeter (concentra-
of the imino imide 2k proceeded smoothly to yield the corre- tion in gdL−1). IR was measured using a JEOL FT-IR 6200.
sponding Mannich adduct 5e in higher chemical yield and en- Melting point was determined on YANAGIMOTO micro
antioselectivities compared with those of the reaction using 2a melting point apparatus. Elemental combustion analyses were
(entry 5). On the other hand, the reaction of another type of performed using a J-SCIENCE LAB JM10. Unless other-
imide, benzimide-type substrate 2l did not proceed under the wise noted, materials were purchased from Tokyo Chemical
same condition (entry 6). Unfortunately, the chemical yield of Industry Co., Ltd. (Japan), Aldrich Inc. (U.S.A.), Wako Pure
the reaction using α-imino thioester 2m was moderate (entry Chemical Industries, Ltd. (Osaka, Japan), Nacalai Tesque
7). Although the reason the reaction rate of 2k was superior to Inc., Kanto Chemical Co., Inc. (Japan) commercial suppliers
that of 2a remains to be disclosed, we speculate that the inter- and were used as purchased. For manganese(IV) oxide, Wako
action of the carbonyl group in the five-membered ring with manganese(IV) oxide, powder (order number 138-09675) was
the thiourea catalysts contributes to the acceleration of the used. The substrates 1p,35) r36) and catalyst 334) were prepared
Mannich reaction leading to improvement of enatioselectivity. according to the literature procedure.
The two carbonyl groups of the other type of imide 2l might
have different orientation from those of 2k and this might
cause the difference of the reactivities of those substrates. We
Synthesis of the N-PMP Glycine Derivatives
Ethyl (4-Methoxyphenyl)glycinate (1a)
To a solution of ethyl bromoacetate (1.11mL, 10.0mmol) in
are currently performing further studies such as computation- CH3CN (25mL) were added NaOAc (1.23g, 15.0mmol), NaI
al analysis for elucidation of the reaction mechanism including (1.65g, 11.0mmol) and p-anisidine (1.19g, 9.66mmol) at room
origins of stereo selection. Being performed in the presence of temperature and stirred at the same temperature for 3h. After
manganese(IV) oxide, thiourea 4-catalyzed Mannich reaction that, the reaction mixture was extracted wih EtOAc, washed
of 2k and 3 did not proceed under the oxidative condition that with 5% KHSO4aq and brine, dried over Na2SO4, evaporated
the employed catalyst was decomposed (entry 8). This result in vacuo and purified by silica gel column chromatography
indicates that removal of the oxidant after the formation of (hexane–EtOAc=4:1) to afford 1a (1.47g, 73%) as a pale
1
imine is indispensable for the success of the present process.
brown plate crystal. mp 44–45°C (hexane–EtOAc); H-NMR
(400MHz, CDCl3) δ: 1.29 (t, J=7.0Hz, 3H), 3.75 (s, 3H), 3.86
(s, 2H), 4.02 (s, 1H), 4.23 (q, J=7.0Hz, 2H), 6.59 (d, J=9.0Hz,
Summary
We developed a novel and simple protocol for the synthe- 2H), 6.79 (d, J=9.0Hz, 2H); 13C-NMR (75.0MHz, CDCl3) δ:
sis of α-imino carboxylic acid derivatives by manganese(IV) 14.2, 46.8, 55.7, 61.2, 114.3, 114.9, 141.2, 152.6, 171.3; IR (neat)
oxide-mediated oxidation of glycine derivatives. This proto- 826, 1443, 1518, 1732, 2992, 3385cm−1; MS (ESI+) m/z 210
col enables the synthesis of α-iminocarboxylic acid deriva- (M+H+, 100); Anal. Calcd for C11H15NO3: C, 63.14; H, 7.23; N,
tives such as phenyl ester, perfluoroalkyl esters, imides, and 6.69. Found: C, 62.94; H, 7.20; N, 6.77.
thioester, which could not be prepared by conventional syn-
thetic procedure, and contributes an extension of the substrate
Methyl (4-Methoxyphenyl)glycinate (1b)
To a solution of p-anisidine (10.2g, 82.8mmol) in CH3CN
scopes for the synthesis of unnatural α-amino acid derivatives. (100mL) were added K2CO3 (12.3g, 89.0mmol) and methyl
Further examination of the reaction scope of the oxidation and bromoacetate (8.25mL, 89.0mmol) at room temperature
application of the resulting imines for asymmetric synthesis of and stirred at the same temperature for 10h. After that, the
unnatural α-amino acid derivatives are currently under way.
insolubilities were removed by filtration. Then the resulting
filtrate was evaporated in vacuo and purified by silica gel col-
umn chromatography (hexane–EtOAc=4:1 to 2:1) to afford
Experimental
General Methods All reactions were carried out under 1b (11.7g, 72%) as a pale brown plate crystal. mp 79–80°C

Vol. 65, No. 6 (2017)
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1
(hexane–EtOAc); H-NMR (400MHz, CDCl3) δ: 3.75 (s, 3H), 1H), 4.17 (q, J=7.3Hz, 2H), 6.59 (d, J=8.8Hz, 2H), 6.79 (d,
3.77 (s, 3H), 3.88 (s, 2H), 4.01 (s, 1H), 6.59 (d, J=9.0Hz, 2H), J=8.8Hz, 2H), 7.31 (t, J=5.5Hz, 1H); 13C-NMR (75.0MHz,
6.79 (d, J=9.0Hz, 2H); 13C-NMR (75.0MHz, CDCl3) δ: 46.4, CDCl3) δ: 14.0, 40.9, 49.5, 55.6, 61.4, 114.4, 114.9, 141.1,
52.0, 55.5, 114.2, 114.7, 141.1, 152.5, 171.8; IR (KBr) 1440, 153.1, 169.6, 171.3; IR (KBr) 1422, 1441, 1450, 1589, 1621,
1524, 1746, 3410cm−1; MS (ESI+) m/z 196 (M+H+, 100); Anal. 1655, 2969, 3363cm−1; MS (ESI+) m/z 267 (M+H+, 75), 289
Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.18. Found: C, (M+Na+, 100); Anal. Calcd for C13H18N2O4: C, 58.63; H, 6.81;
61.40; H, 6.69; N, 7.02.
N, 10.52. Found: C, 58.44; H, 6.81; N, 10.32.
tert-Butyl (4-Methoxyphenyl)glycinate (1c)
N-Ethyl-2-((4-methoxyphenyl)amino)-N-phenylacetamide
A procedure similar to that described for the preparation (1g)
1
of 1b afforded 1c in 92% yield as an yellow oil. H-NMR
A procedure similar to that described for the preparation
(500MHz, CDCl3) δ: 1.46 (s, 9H) 3.71 (s, 3H), 3.73 (s, 2H), of 1f afforded 1g in 42% yield as a white needle crystal. mp
4.02 (s, 1H), 6.55 (d, J=8.9Hz, 2H), 6.76 (d, J=8.9Hz, 2H); 118–119°C (hexane–EtOAc); 1H-NMR (400MHz, CDCl3)
13C-NMR (75.0MHz, CDCl3) δ: 27.9, 47.3, 55.5, 81.5, 114.1, δ: 1.15 (t, J=7.3Hz, 3H), 3.47 (s, 2H), 3.71, (s, 3H), 3.80 (q,
114.7, 141.4, 152.3, 170.4; IR (neat) 1462, 1506, 1731, 2980, J=7.3Hz, 2H), 4.48 (s, 1H), 6.41 (d, J=9.0Hz, 2H), 6.71
3381 cm−1; MS (ESI+) m/z 238 (M+H+, 100); high resolution (d, J=9.0Hz, 2H), 7.17–7.22 (m, 2H), 7.40–7.51 (m, 3H);
(HR)-MS (ESI+) m/z Calcd for C13H20NO3 ([M+H]+) 238.1438. 13C-NMR (75.0MHz, CDCl3) δ: 12.9, 44.3, 47.1, 55.7, 114.1,
Found 238.1444.
Benzyl (4-Methoxyphenyl)glycinate (1d)
114.7, 128.2, 128.4, 129.9, 140.6, 141.7, 152.1, 169.0; IR (KBr)
1423, 1461, 1518, 1535, 1653, 2980, 3394cm−1; MS (ESI+) m/z
A procedure similar to that described for the preparation 285 (M+H+, 100); Anal. Calcd for C17H20N2O2: C, 71.81; H,
of 1b afforded 1d in 92% yield as a white needle crystal. 7.09; N, 9.85. Found: C, 71.69; H, 7.13; N, 9.70.
mp 73–74°C (hexane–EtOAc); 1H-NMR (500MHz, CDCl3)
N-(tert-Butoxycarbonyl)-N-(4-methoxyphenyl)glycine
δ: 3.73 (s, 3H) 3.91 (s, 2H), 4.04 (s, 1H), 5.19 (s, 2H), 6.57
To a solution of 1a (5.04g, 25.8mmol) in EtOH (100mL)
(d, J=8.8Hz, 2H), 6.77 (d, J=8.8Hz, 2H), 7.31-7.38 (m, 5H); were added Na2CO3 (5.60g, 52.8mmol) and Boc2O (11.5g,
13C-NMR (75.0MHz, CDCl3) δ: 46.9, 55.7, 66.9, 114.4, 114.9, 52.7mmol) at room temperature and stirred at 80°C. After 2h,
128.3, 128.4, 128.6, 135.3, 141.1, 152.7, 171.3; IR (KBr) 757, Boc2O (5.13g, 23.5mmol) was added at room temperature and
797, 1451, 1464, 1518, 1728, 3388cm−1; MS (ESI+) m/z 272 stirred at 80°C for 1h. Then the reaction mixture was cooled
(M+H+, 100); Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; to 0°C, evaporated in vacuo, extracted with EtOAc, dried over
N, 5.16. Found: C, 70.72; H, 6.26; N, 5.07.
Na2SO4 and evaporated in vacuo to afford the crude Boc-
Allyl (4-Methoxyphenyl)glycinate (1e)
protected product as yellow oil. This crude intermediate was
A procedure similar to that described for the preparation directly used for the next transformation.
1
of 1b afforded 1e in 92% yield as an yellow oil. H-NMR
To a solution of crude Boc-protected intermediate in MeOH
(300MHz, CDCl3) δ: 3.72 (s, 3H), 3.88 (s, 2H), 4.04 (s, 1H), (25mL) was added 2M NaOHaq (25mL) at room temperature
4.64 (ddd, J1=4.6Hz, J2=1.5Hz, J3=1.3Hz, 2H), 5.24 (dt, and stirred at the same temperature for 90min. Then the
J1=10.4Hz, J2=1.3Hz, 1H), 5.31 (dt, J1=17.2Hz, J2=1.5Hz, reaction mixture was evaporated in vacuo, washed with
1H), 5.90 (ddt, J1=17.2Hz, J2=10.4Hz, J3=4.6Hz, 1H), CHCl3, acidified with 5% KHSO4aq, extracted with CHCl3,
6.57 (d, J=8.8Hz, 2H), 6.77 (d, J=8.8Hz, 2H); 13C-NMR dried over Na2SO4 and evaporated in vacuo to afford N-(tert-
(75.0MHz, CDCl3) δ: 46.6, 55.6, 65.6, 114.2, 114.8, 118.7, butoxycarbonyl)-N-(4-methoxyphenyl)glycine as a white pow-
1
131.6, 141.1, 152.5, 171.0; IR (neat) 937, 987, 1444, 1516, 1744, der. H-NMR (300MHz, DMSO-d6, 40°C) δ: 1.35 (s, 9H), 3.73
3031, 3389cm−1; MS (ESI+) m/z 222 (M+H+, 100); HR-MS (s, 3H), 4.13 (s, 2H), 6.87 (d, J=8.6Hz, 2H), 7.17 (d, J=8.6Hz,
(ESI+) m/z Calcd for C12H15NNaO3 ([M+Na]+) 244.0944. 2H), 12.6 (s, 1H); 13C-NMR (75.0MHz, DMSO-d6) δ: 27.7,
Found 244.0938.
51.9, 55.1, 79.5, 113.6, 127.4, 135.55, 135.59, 153.8, 157.0; IR
Ethyl (4-Methoxyphenyl)glycylglycinate (1f)
(KBr) 1415, 1513, 1668, 1769, 3142cm−1; MS (ESI+) m/z 304
To a suspension of ethylglycinate hydrochloride (3.58g, (M+Na+, 100); Anal. Calcd for C14H19NO5: C, 59.78; H, 6.81;
25.6mmol) in CH2Cl2 (50mL) were added Et3N (10.7mL, N, 4.98. Found: C, 59.62; H, 6.75; N, 4.90.
76.9mmol) and chloroacetyl chloride (3.05mL, 38.4mmol) at
0°C and stirred at room temperature for 20min. After that,
Phenyl (4-Methoxyphenyl)glycinate (1h)
To a solution of N-(tert-butoxycarbonyl)-N-(4-methoxy-
sat. NaHCO3aq was added at 0°C and the reaction mixture was phenyl)glycine (519mg, 1.84mmol) in CH2Cl2 (9.2mL) were
extracted with CH2Cl2, dried over Na2SO4 and evaporated in added DMAP (22.4mg, 0.18mmol), PhOH (324µL, 3.68mmol)
vacuo to afford the chloroacetamide intermediate as a dark and EDCI·HCl (936mg, 5.23mmol) at 0°C and stirred at room
black solid. This intermediate was directly used for the next temperature. After 0.5h, the reaction mixture was extracted
step without further purifications.
with CHCl3, dried over Na2SO4 and evaporated in vacuo to
To a solution of chloroacetamide in CH3CN (50mL) afford the crude phenyl ester as colorless oil. This product was
were added p-anisidine (4.90g, 39.8mmol), K2CO3 (4.04g, used for the next step without further purification.
29.2mmol) and KI (4.25g, 25.6mmol) at room temperature
To a solution of crude phenyl ester in CH2Cl2 (15.6mL) was
and stirred at the same temperature for 24h. After that, the added TFA (1.56mL) at 0°C and stirred at room temperature
reaction mixture was evaporated in vacuo, extracted with for 1h. Then, the reaction mixture was cooled to 0°C, basified
EtOAc, dried over Na2SO4, evaporated in vacuo and purified to pH 8 with sat.NaHCO3aq, extracted with CHCl3, dried over
by silica gel column chromatography (hexane–EtOAc=1:1 to Na2SO4, evaporated in vacuo and purified by silica gel column
1:2) to afford 1f (3.21g, 47% in two steps) as a pale brown chromatography (hexane–EtOAc=3:1) to afford 1h (284mg,
powder. 1H-NMR (400MHz, CDCl3) δ: 1.25 (t, J=7.3Hz, 60% over two steps) as a pale brown powder. mp 118–119°C
1
3H), 3.74 (s, 3H), 3.78 (s, 2H), 4.04 (d, J=5.5Hz, 2H), 4.12 (s, (hexane–EtOAc); H-NMR (400MHz, CDCl3) δ: 3.76 (s, 3H),

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4.09 (s, 1H), 4.14 (s, 2H), 6.66 (d, J=9.0Hz, 2H), 6.82 (d, the supernatant was discarded. This process was repeated six
J=9.0Hz, 2H), 7.08 (d, J=7.5Hz, 2H), 7.24 (dd, J1=J2=7.5Hz, times to afford the crude chloroacetimide. This intermediate
1H), 7.38 (dd, J1=J2=7.5Hz, 2H); 13C-NMR (75.0MHz, was directly used for the next step without further purifica-
CDCl3) δ: 47.0, 55.7, 114.5, 114.9, 121.3, 126.1, 129.5, 141.0, tions.
150.3, 152.8, 170.1; IR (KBr) 821, 1441, 1517, 1749, 3403cm−1;
To a solution of chloroacetimide in CH3CN (100mL)
MS (ESI+) m/z 258 (M+H+, 52), 280 (M+Na+, 100); Anal. were added p-anisidine (3.13g, 25.4mmol), K2CO3 (3.56g,
Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 25.8mmol) and KI (3.24g, 19.5mmol) at room temperature
69.93; H, 5.85; N, 5.67.
and stirred at the same temperature for 13h. After that, the
2,2,2-Trifluoroethyl (4-Methoxyphenyl)glycinate (1i)
reaction mixture was evaporated in vacuo, extracted with
A procedure similar to that described for the preparation EtOAc, dried over Na2SO4, evaporated in vacuo and the result-
1
of 1h afforded 1i in 82% yield as an yellow oil. H-NMR ing brown solid was purified by recrystallization from hexane
(300MHz, CDCl3) δ: 3.74 (s, 3H), 4.00 (s, 2H), 4.54 (q, and EtOAc to afford 1l (4.45g, 64% in two steps) as an yellow
1
J=8.3Hz, 2H), 6.58 (dd, J1=8.8Hz, J2=2.3Hz, 2H), 6.79 powder. H-NMR (300MHz, CDCl3) δ: 3.76 (s, 3H), 4.36 (s,
(dd, J1=8.8Hz, J2=2.3Hz, 2H); 13C-NMR (75.0MHz, 1H), 4.40 (s, 2H), 6.69 (d, J=8.8Hz, 2H), 6.82 (d, J=8.8Hz,
CDCl3) δ: 46.2, 55.5, 60.5 (q, J=36.5Hz),114.4, 114.8, 122.7 2H), 7.49 (dd, J1=J2=7.4Hz, 2H), 7.62 (dd, J1=J2=7.4Hz, 1H),
(q, J=275.0Hz), 140.7, 152.8, 170.1; IR (neat) 1423, 1445, 7.81 (d, J=7.4Hz, 2H), 9.13 (s, 1H); 13C-NMR (75.0MHz,
1517, 1766, 3393cm−1; MS (ESI+) m/z 264 (M+H+, 100), CDCl3) δ: 50.8, 55.7, 114.6, 115.0, 127.7, 128.9, 132.3, 133.3,
286 (M+Na+, 75); HR-MS (ESI+) m/z Calcd for C11H13F3NO3 141.0, 152.8, 165.4, 173.2; IR (KBr) 727, 1424, 1520, 1731,
([M+H]+) 264.0842. Found 264.0836.
3280, 3272 cm−1; MS (ESI+) m/z 285.3 (M+H+, 100); Anal.
1,1,1,3,3,3-Hexafluoropropan-2-yl (4-Methoxyphenyl)glyci- Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C,
nate (1j)
67.29; H, 5.64; N, 9.67.
A procedure similar to that described for the preparation
of 1h afforded 1j in 82% yield as an yellow oil. H-NMR
S-Benzyl 2-((4-Methoxyphenyl)amino)ethanethioate (1m)
1
A procedure similar to that described for the preparation
1
(400MHz, CDCl3) δ: 3.75 (s, 3H), 4.13 (s, 2H), 5.80 (hept, of 1h afforded 1m in 52% yield as a white powder. H-NMR
J=6.0Hz, 1H), 6.58 (dd, J1=9.0Hz, J2=2.2Hz, 2H), 6.80 (300MHz, CDCl3) δ: 3.74 (s, 3H), 4.02 (s, 2H), 4.11 (s, 2H),
(dd, J1=9.0Hz, J2=2.2Hz, 2H); 13C-NMR (75.0MHz, CDCl3) 6.56 (d, J=9.0Hz, 2H), 6.78 (d, J=9.0Hz, 2H), 7.19–7.32 (m,
δ: 46.2, 55.7, 66.9 (hept, J=34.6Hz), 114.5, 115.0, 120.2 5H); 13C-NMR (75.0MHz, CDCl3) δ: 32.8, 55.0, 55.7, 114.1,
(q, J=281.2Hz), 140.1, 153.2, 168.9; IR (KBr) 1386, 1519, 114.9, 127.3, 128.6, 128.8, 137.3, 140.7, 152.8, 200.6; IR (KBr)
1789, 3397cm−1; HR-MS (ESI+) m/z Calcd for C12H12F6NO3 823, 1436, 1459, 1515, 1682, 3399cm−1; MS (ESI+) m/z 288
([M+H]+) 332.0716. Found 332.0717.
1-((4-Methoxyphenyl)glycyl)pyrrolidin-2-one (1k)
To a solution of pyrrolidin-2-one (630mg, 7.40mmol) in
CH3CN (20mL) were added pyridine (1.19mL, 14.8mmol) and
(M+H+, 97), 310 (M+Na+, 100); Anal. Calcd for C16H17NO2S:
C, 66.87; H, 5.96; N, 4.87. Found: C, 66.57; H, 5.81; N, 4.81.
Methyl (2-Methoxyphenyl)glycinate (1o)
A procedure similar to that described for the preparation
bromoacetyl bromide (1.29mL, 14.8mmol) at 0°C and stirred of 1a afforded 1o in 32% yield as a colorless oil. The spectral
at room temperature for 52h. After that, the reaction mixture data were identical to that described in the literature.37)
was evaporated in vacuo, extracted with EtOAc, dried over
Na2SO4 and evaporated in vacuo to afford the bromoacetimide
Methyl Tritylglycinate (1s)
To a solution of methylglycinate hydrochloride (1.26g,
intermediate as a brown oil. This intermediate was directly 10.0mmol) in N,N-dimethylformamide (DMF) (20mL) were
used for the next step without further purifications. added Et3N (3.50mL, 25.1mmol) and chlorotriphenylmethane
To a solution of bromoacetimide in CH3CN (20mL) (2.90g, 10.4mmol) at 0°C. After stirring the resulting white
were added p-anisidine (1.12g, 9.09mmol), K2CO3 (1.54g, suspension at room temperature for 19h, the reaction was
11.1mmol) and KI (2.11g, 12.7mmol) at room temperature added H2O, extracted with EtOAc–hexane (2:1), dried over
and stirred at the same temperature for 18h. After that, Na2SO4, evaporated in vacuo and purified by silica gel column
the reaction mixture was extracted with EtOAc, dried over chromatography (hexane–EtOAc=4:1) to afford 1s (2.74g,
1
Na2SO4, evaporated in vacuo and purified by silica gel col- 83%) as a white solid. H-NMR (300MHz, CDCl3) δ: 3.21
umn chromatography (hexane–EtOAc=2:1 to 1:1) to afford (s, 2H), 3.65 (s, 3H), 7.23–7.26 (m, 3H), 7.32–7.35 (m, 6H),
1
1k (900mg, 49% in two steps) an yellow powder. H-NMR 7.53–7.55 (m, 6H); 13C-NMR (75.0MHz, CDCl3) δ: 45.7, 51.7,
(300MHz, CDCl3) δ: 2.11 (tt, J1=8.1Hz, J2=7.1Hz, 2H), 2.64 70.7, 126.5, 127.9, 128.6, 145.3, 172.6cm−1; IR (neat) 706, 1491,
(t, J=8.1Hz, 2H), 3.74 (s, 3H), 3.86 (t, J=7.1Hz, 2H), 4.42 (s, 1742, 3330 cm−1; HR-MS (ESI+) m/z Calcd for C22H21NO2
+
2H), 4.50 (s, 1H), 6.65 (d, J=8.8Hz, 2H), 6.79 (d, J=8.8Hz, ([M+Na] ) 354.1465. Found 354.1470.
2H); 13C-NMR (75.0MHz, CDCl3) δ: 17.6, 33.2, 45.2, 50.1,
55.7, 114.4, 114.9, 141.4, 152.4, 171.6, 175.4; IR (KBr) 1420,
1515, 1690, 1727, 3385cm−1; MS (ESI+) m/z 249 (M+H+,
MnO2-Mediated Oxidation of 1
Ethyl (E)-2-((4-Methoxyphenyl)imino)acetate (2a)
To a solution of 1a (209mg, 1.00mmol) in CH2Cl2 (100mL)
100); Anal. Calcd for C13H16N2O3: C, 62.89; H, 6.50; N, 11.28. was added MnO2 (740mg, 20.0mmol) at room temperature
Found: C, 62.23; H, 6.47; N, 11.16.
and stirred at room temperature for 1h. Then, the reac-
N-((4-Methoxyphenyl)glycyl)benzamide (1l)
tion mixture was passed through Celite and the filtrate was
A mixture of benzamide (2.94g, 24.3mmol) and chloro- evaporated in vacuo to afford the corresponding imine 2a
1
acetyl chloride (2.32mL, 29.1mmol) was stirred at 110°C (193mg, 93%) as a red oil. H-NMR (400MHz, CDCl3) δ:
for 45min. After that, the reaction mixture was evaporated 1.40 (t, J=7.3Hz, 3H), 3.84 (s, 3H), 4.42 (q, J=7.3Hz, 2H),
in vacuo to remove the volatile by-products. The resulting 6.94 (d, J=9.0Hz, 2H), 7.36 (d, J=9.0Hz, 2H), 7.94 (s, 1H);
residue was added Et2O and the precipitate was crashed. Then, 13C-NMR (75.0MHz, CDCl3) δ: 14.2, 55.5, 61.9, 114.5, 123.6,

Vol. 65, No. 6 (2017)
Chem. Pharm. Bull.
579
141.3, 147.9, 160.5, 163.6; IR (neat) 1506, 1585, 1713, 1741, CDCl3) δ: 12.7, 44.7, 55.3, 114.1, 122.8, 127.9, 128.2, 129.6,
2987cm−1; MS (ESI+) m/z 208 (M+H+, 13), 230 (M+Na+, 136.4, 140.5, 142.5, 150.7, 159.1, 162.6; IR (neat) 835, 1458,
100); HR-MS (ESI+) m/z Calcd for C11H14NO3 ([M+H]+) 1498, 1593, 1626, 1662, 2979cm−1; HR-MS (ESI+) m/z Calcd
208.0968. Found 208.0973.
Methyl (E)-2-((4-Methoxyphenyl)imino)acetate (2b)
for C17H19N2O2 ([M+H]+) 283.1441. Found 283.1455.
Phenyl (E)-2-((4-Methoxyphenyl)imino)acetate (2h)
A procedure similar to that described for the preparation of
A procedure similar to that described for the prepara-
1
1
2a afforded 2b in 92% yield as a red oil. H-NMR (300MHz, tion of 2a afforded 2h in 92% yield as a red solid. H-NMR
CDCl3) δ: 3.84 (s, 3H), 3.95 (s, 3H), 6.94 (d, J=8.8Hz, 2H), (400MHz, CDCl3) δ: 3.87 (s, 3H), 6.98 (d, J=9.0Hz, 2H),
7.37 (d, J=8.8Hz, 2H), 7.95 (s, 1H); 13C-NMR (75.0MHz, 7.23–7.31 (m, 3H), 7.40–7.46 (m, 4H), 8.14 (s, 1H); 13C-NMR
CDCl3) δ: 52.8, 55.5, 114.5, 123.6, 141.1, 147.3, 160.6, 164.1; (75.0MHz, CDCl3) δ: 55.5, 114.6, 121.4, 123.9, 126.2, 129.5,
IR (neat) 1507, 1585, 1715, 1743cm−1; MS (ESI+) m/z 194 141.0, 146.7, 150.5, 160.9, 162.0; IR (neat) 837, 1509, 1585,
(M+H+, 15), 216 (M+Na+, 100); HR-MS (ESI+) m/z Calcd for 1733, 1759 cm−1; HR-MS (ESI+) m/z Calcd for C15H14NO3
C10H12NO3 ([M+H]+) 194.0812. Found 194.0814.
tert-Butyl (E)-2-((4-Methoxyphenyl)imino)acetate (2c)
([M+H]+) 256.0968. Found 256.0963.
2,2,2-Trifluoroethyl (E)-2-((4-Methoxyphenyl)imino)acetate
A procedure similar to that described for the preparation of (2i)
1
2a afforded 2c in 98% yield as a red oil. H-NMR (400MHz,
A procedure similar to that described for the preparation of
CDCl3) δ: 1.59 (s, 9H), 3.83 (s, 3H), 6.92 (d, J=9.0Hz, 2H), 2a afforded 2i in 98% yield as a red solid. 1H-NMR (400MHz,
7.33 (d, J=9.0Hz, 2H), 7.86 (s, 1H); 13C-NMR (75.0MHz, CDCl3) δ: 3.85 (s, 3H), 4.72 (q, J=8.3Hz, 2H), 6.95 (d,
CDCl3) δ: 27.9, 55.4, 82.7, 114.3, 123.4, 136.4, 141.6, 149.4, J=9.0Hz, 2H), 7.42 (d, J=9.0Hz, 2H), 8.02 (s, 1H); 13C-NMR
160.2, 162.8; IR (neat) 1506, 1593, 1710, 1733, 2980cm−1; (75.0MHz, CDCl3) δ: 55.5, 61.0 (q, J=36.4Hz), 114.6, 122.7 (q,
HR-MS (ESI+) m/z Calcd for C13H18NO3 ([M+H]+) 236.1281. J=275.0Hz), 124.0, 136.5, 140.7, 145.0, 161.1, 161.6; IR (neat)
Found 236.1289.
Benzyl (E)-2-((4-Methoxyphenyl)imino)acetate (2d)
A procedure similar to that described for the preparation of
2a afforded 2d in 90% yield as a red oil. H-NMR (400MHz, imino)acetate (2j)
1443, 1507, 1585, 1738, 1763cm−1; HR-MS (ESI+) m/z Calcd
for C11H11F3NO3 ([M+H]+) 262.0686. Found 262.0698.
1,1,1,3,3,3-Hexafluoropropan-2-yl (E)-2-((4-Methoxyphenyl)-
1
CDCl3) δ: 3.84 (s, 3H), 5.38 (s, 2H), 6.93 (d, J=9.0Hz, 2H),
A procedure similar to that described for the prepara-
1
7.34–7.42 (m, 5H), 7.44–7.48 (m, 2H), 7.97 (s, 1H); 13C-NMR tion of 2a afforded 2j in 88% yield as a red solid. H-NMR
(75.0MHz, CDCl3) δ: 55.5, 67.4, 114.5, 123.6, 128.5, 128.59, (400MHz, CDCl3) δ: 3.86 (s, 3H), 5.98 (hept, J=6.0Hz, 1H),
128.62, 135.2, 141.3, 147.5, 160.6, 163.3; IR (neat) 836, 1459, 6.96 (d, J=9.0Hz, 2H), 7.46 (d, J=9.0Hz, 2H), 8.07 (s, 1H);
1510, 1585, 1715, 1741cm−1; HR-MS (ESI+) m/z Calcd for 13C-NMR (75.0MHz, CDCl3) δ: 55.5, 67.2 (hept, J=35.2Hz),
C16H16NO3 ([M+H]+) 270.1125. Found 270.1142.
Allyl (E)-2-((4-Methoxyphenyl)imino)acetate (2e)
114.7, 120.3 (q, J=280.0Hz), 124.4, 140.4, 142.9, 159.9, 161.7;
IR (neat) 1512, 1579, 1748, 1783cm−1; HR-MS (ESI+) m/z
A procedure similar to that described for the preparation of Calcd for C12H10F6NO3 ([M+H]+): 330.0559. Found 330.0556.
1
2a afforded 2e in 87% yield as a red oil. H-NMR (400MHz,
CDCl3) δ: 3.84 (s, 3H), 4.84 (ddd, J1=6.0Hz, J2=J3=1.2Hz, (2k)
2H), 5.32 (ddd, J1=10.3Hz, J2=J3=1.2Hz, 1H), 5.43 (ddd,
(E)-1-(2-((4-Methoxyphenyl)imino)acetyl)pyrrolidin-2-one
A procedure similar to that described for the preparation
1
J1=16.0Hz, J2=J3=1.2Hz, 1H), 6.03 (ddd, J1=16.0Hz, of 2a afforded 2k in 96% yield as a brown solid. H-NMR
J2=10.3Hz, J3=6.0Hz, 1H), 6.89 (d, J=9.0Hz, 2H), 7.37 (d, (400MHz, CDCl3) δ: 2.18 (tt, J1=8.3Hz, J2=7.3Hz, 2H),
J=9.0Hz, 2H), 7.97 (s, 1H); 13C-NMR (75.0MHz, CDCl3) 2.68 (t, J=8.3Hz, 2H), 3.97 (t, J=7.3Hz, 2H), 3.84 (s, 3H),
δ: 55.4, 66.3, 114.5, 119.4, 123.6, 131.4, 136.5, 141.2, 147.4, 6.93 (d, J=9.0Hz, 2H), 7.42 (d, J=9.0Hz, 2H), 8.86 (s, 1H);
160.6, 163.2; IR (neat) 935, 990, 1463, 1506, 1585, 1727, 1743, 13C-NMR (75.0MHz, CDCl3) δ: 17.7, 32.9, 45.1, 55.4, 114.3,
3367 cm−1; HR-MS (ESI+) m/z Calcd for C12H14NO3 ([M+H]+) 123.6, 142.2, 150.6, 160.1, 163.7, 176.0; IR (neat) 1508, 1580,
220.0968. Found 220.0976.
1691, 1741cm−1; HR-MS (ESI+) m/z Calcd for C13H14N2NaO3
([M+Na]+) 269.0897. Found 269.0892.
Ethyl (E)-(2-((4-Methoxyphenyl)imino)acetyl)glycinate (2f)
A procedure similar to that described for the preparation of
2a afforded 2f in 95% yield as a red solid. 1H-NMR (300MHz,
(E)-N-(2-((4-Methoxyphenyl)imino)acetyl)benzamide (2l)
A procedure similar to that described for the prepara-
1
CDCl3) δ: 1.31 (t, J=7.1Hz, 3H), 4.18 (d, J=5.5Hz, 2H), 3.64 tion of 2a afforded 2l in 91% yield as a red solid. H-NMR
(s, 3H), 4.26 (q, J=7.1Hz, 2H), 6.94 (d, J=8.8Hz, 2H), 7.30 (d, (300MHz, CDCl3) δ: 3.85 (s, 3H), 6.96 (dd, J1=2.0, J2=2.2Hz
J=8.8Hz, 2H), 7.70 (s, 1H), 7.89 (s, 1H); 13C-NMR (75.0MHz, 2H), 7.39 (dd, J1=2.2, J2=2.0Hz, 2H), 7.60–7.63 (m, 1H),
CDCl3) δ: 14.0, 40.9, 55.3, 61.4, 114.4, 123.4, 140.2, 149.4, 7.92 (d, J=1.5Hz, 1H), 7.93 (br, 2H), 10.59 (s, 1H); 13C-NMR
160.1, 163.8, 169.4; IR (neat) 1464, 1506, 1593, 1680, 1752, (75.0MHz, CDCl3) δ: 55.5, 114.7, 127.7, 128.9, 133.1, 138.8,
2982, 3382cm−1; HR-MS (ESI+) m/z Calcd for C13H17N2O4 148.3, 161.2, 161.4, 164.3; IR (neat) 837, 1504, 1579, 1682,
([M+H]+): 265.1183. Found 265.1188.
(E)-N-Ethyl-2-((4-methoxyphenyl)imino)-N-phenylacetamide ([M+H]+): 283.1077. Found 283.1085.
(2g) S-Benzyl (E)-2-((4-Methoxyphenyl)imino)ethanethioate (2m)
A procedure similar to that described for the prepara- A procedure similar to that described for the preparation
1743, 3354cm−1; HR-MS (ESI+) m/z Calcd for C16H15N2O3
1
tion of 2a afforded 2g in 99% yield as a red solid. H-NMR of 2a afforded 2m in quantitative yield as a brown solid.
(400MHz, CDCl3) δ: 1.22 (t, J=7.3Hz, 3H), 3.77 (s, 3H), 3.95 1H-NMR (400MHz, CDCl3) δ: 3.84 (s, 3H), 4.23 (s, 2H),
(q, J=7.3Hz, 2H), 6.81 (d, J=8.8Hz, 2H), 7.00 (d, J=8.8Hz, 6.93 (d, J=9.0Hz, 2H), 7.22–7.38 (m, 7H), 8.02 (s, 1H);
2H), 7.24 (d, J=7.3Hz, 2H), 7.38 (dd, J1=J2=7.3Hz, 1H), 7.44 13C-NMR (75.0MHz, CDCl3) δ: 32.6, 55.5, 114.6, 124.1, 127.3,
(dd, J1=J2=7.3Hz, 2H), 7.73 (s, 1H); 13C-NMR (75.0MHz, 128.6, 129.0, 137.2, 140.3, 151.0, 160.8, 191.9; IR (neat) 838,

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1457, 1505, 1583, 1659cm−1; HR-MS (ESI+) m/z Calcd for CDCl3) (mixture of diastereomers) δ: 14.0, 19.4, 19.9, 30.2,
C16H16NO2S ([M+H]+) 286.0896. Found 286.0903.
31.6, 37.5, 38.6, 55.6, 55.7, 61.4, 62.09, 62.12, 62.5, 62.6, 65.0,
Asymmetric Mannich Reaction of α-Imino Carboxylic 114.7, 114.8, 116.2, 117.3, 121.2, 121.3, 126.1, 126.2, 129.4,
Acid Derivatives 140.3, 150.2, 150.4, 153.7, 153.9, 169.1, 169.9, 170.3, 170.4,
Ethyl 1-(1-((4-Methoxyphenyl)amino)-2-oxo-2-(2-oxopyr- 212.3, 212.6; IR (neat) 825, 1463, 1514, 1724, 1753, 2980,
rolidin-1-yl)ethyl)-2-oxocyclopentane-1-carboxylate (5e)
3368 cm−1; HR-MS (ESI+) m/z Calcd for C23H26NO6 ([M+H]+)
A mixture of 2k (18.4mg, 0.0747mmol), thiourea 3 (3.0mg, 412.1755. Found 412.1749.
0.00726mmol) and cyclopentanone-2-carboxylic acid ethyl
Ethyl 1-(2-(Benzylthio)-1-((4-methoxyphenyl)amino)-2-oxo-
ester 4 (21.6 µL, 0.149mmol) in toluene (0.75mL) was stirred ethyl)-2-oxocyclopentane-1-carboxylate (5g)
at room temperature for 24h. Then, the reaction mixture was
A procedure similar to that described for the preparation of
directly purified by silica gel column chromatography (hex- 5e afforded 5g in 40% yield as pale yellow oil. (dr=51:49).
ane–EtOAc=2:1 to 1:1) to afford the desired Mannich adduct HPLC [Chiralpak IC-3, hexane–2-propanol=97/3, 1.0mL/min,
5e (23.1mg, 77%, dr=61:39) as a brown oil. HPLC [Chiral- λ=254nm, retention times: (major) 75.3min, (minor) 85.5min,
pak IA, hexane–2-propanol=90:10, 1.0mL/min, λ=254nm, 82% ee and (major) 93.9min, (minor) 57.9min, 56% ee];
1
retention times: (major) 57.5min (minor) 53.4min, 92% en- [α]D23 −66.4 (c=0.45 in CHCl3); H-NMR (400MHz, CDCl3)
antiomeric excess (ee) and (major) 63.4min (minor) 43.5min, (mixture of diastereomers, with signals corresponding to the
1
52% ee]; [α]D23 +9.2 (c=0.94 in CHCl3); H-NMR (300MHz, one of them indicated by) δ: 1.00 (t, J=7.0Hz, 3H), 1.84–1.94
CDCl3) (mixture of diastereomers, with signals correspond- (m, 3H), 2.12–2.54 (m, 4H), 3.66 (s, 3H), 3.89–4.06 (m, 4H),
ing to the one of them indicated by) δ: 1.24 (t, J=9.5Hz, 3H), 4.79 (s, 1H), 6.59–6.70 (m, 4H), 7.11–7.21 (m, 5H); 13C-NMR
1.89–2.10 (m, 4H), 2.23–2.48 (m, 3H), 2.51–2.71 (m, 3H), (75.0MHz, CDCl3) (mixture of diastereomers) δ: 13.7, 13.9
3.70–3.84 (m, 5H), 4.07–4.20 (m, 3H), 6.35 (s, 1H), 6.71–6.74 19.4, 19.8, 29.4, 30.4, 33.5, 33.8, 37.7, 38.7, 55.57, 55.61, 62.0,
(m, 2H), 6.77–6.82 (m, 2H); 13C-NMR (75.0MHz, CDCl3) 62.1, 62.7, 65.0, 67.8, 67.9, 114.7, 114.8, 115.1, 115.7, 127.2,
(mixture of diastereomers) δ: 13.9, 14.0, 17.0, 17.1, 19.6, 19.8, 127.3, 128.5, 128.8, 128.9, 136.9, 137.1, 139.8, 140.0, 153.2,
30.0, 33.0, 33.6, 33.7, 38.2, 38.4, 45.77, 45.82, 55.6, 55.8, 58.9, 153.3, 168.3, 169.0, 199.9, 202.0, 210.6, 213.4; IR (neat) 824,
59.2, 61.8, 62.1, 62.5, 64.7, 114.6, 114.8, 116.7, 117.0, 139.9, 1460, 1514, 1679, 1724, 1752, 2980, 3382cm−1; HR-MS
140.3, 153.2, 153.4, 168.5, 170.9, 172.7, 173.2, 175.3, 175.8, (ESI+) m/z Calcd for C24H28NO5S ([M+H]+) 442.1683. Found
212.1, 212.3; IR (neat) 1463, 1513, 1690, 1745, 2982, 3363cm−1; 442.1676.
HR-MS (ESI+) m/z Calcd for C21H27N2O6 ([M+H]+) 403.1864.
Found 403.1862.
Ethyl 1-(2-Ethoxy-1-((4-methoxyphenyl)amino)-2-oxoethyl)- by a Grant-in-Aid for Young Scientist (B) (JP16K18845) from
2-oxocyclopentane-1-carboxylate (5a) the Japan Society for the Promotion of Science (JSPS). The
Acknowledgments This research was supported in part
A procedure similar to that described for the preparation of Takeda Science Foundation is also acknowledged. TJ is grate-
5e afforded 5a in 25% yield as pale yellow oil. (dr=57:43). ful for a SUNBOR Scholarship.
HPLC [Chiralpak IC-3, hexane–2-propanol=95:5, 1.0mL/min,
λ=254nm, retention times: (major) 63.6min, (minor) 54.7min,
Conflict of Interest The authors declare no conflict of
84% ee and (major) 47.1min, (minor) 35.4min, 36% ee]; [α]D20 interest.
1
+0.15 (c=0.58 in CHCl3); H-NMR (300MHz, CDCl3) (mix-
ture of diastereomers, with signals corresponding to the one
Supplementary Materials The online version of this ar-
of them indicated by) δ: 1.15–1.27 (m, 6H), 1.97–1.98 (m, 2H), ticle contains supplementary materials.
2.12–2.33 (m, 2H), 2.38–2.55 (m, 2H), 3.72 (s, 3H), 4.10–4.20
(m, 4H), 4.66–4.73 (m, 1H), 6.59–6.81 (m, 4H); 13C-NMR
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