An efficient enantioselective synthesis of (S)-α-methyl-serine methyl ester hydrochloride via asymmetrically catalyzed amination

Article abstract of DOI:10.1080/10286020.2019.1634058

We present the synthesis of enantiomerically pure (S)-α-methyl-serine methyl ester hydrochloride from 2-methyl-3-((4-(trifluoromethyl)benzyl)oxy)propanal and di-p-chlorobenzyl azodicarboxylate via asymmetrically catalyzed amination with naphthylalanine de

Full text of DOI:10.1080/10286020.2019.1634058

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: https://www.tandfonline.com/loi/ganp20
An efficient enantioselective synthesis of (S)-α-
methyl-serine methyl ester hydrochloride via
asymmetrically catalyzed amination
Qiong Xiao, Yi-Fan Tang & Ping Xie
To cite this article: Qiong Xiao, Yi-Fan Tang & Ping Xie (2019): An efficient enantioselective
synthesis of (S)-α-methyl-serine methyl ester hydrochloride via asymmetrically catalyzed amination,
Journal of Asian Natural Products Research, DOI: 10.1080/10286020.2019.1634058
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JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
https://doi.org/10.1080/10286020.2019.1634058
An efficient enantioselective synthesis of (S)-a-methyl-
serine methyl ester hydrochloride via asymmetrically
catalyzed amination
Qiong Xiaoa, Yi-Fan Tangb and Ping Xiea
aDepartment of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and
Druggability Evaluation & State Key Laboratory of Bioactive Substance and Function of Natural
Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of
b
Medical Sciences, Beijing 100050, China; Department of Synthetic Medicinal Chemistry, Beijing
Union Pharmaceutical Factory, Beijing 102600, China
ABSTRACT
ARTICLE HISTORY
Received 17 March 2019
Accepted 17 June 2019
We present the synthesis of enantiomerically pure (S)-a-methyl-
serine methyl ester hydrochloride from 2-methyl-3-((4-(trifluoro-
methyl)benzyl)oxy)propanal and di-p-chlorobenzyl azodicarboxy-
late via asymmetrically catalyzed amination with naphthylalanine
derivative catalyst. The application of the organocatalyst of D-3-
(1-Naphthyl)-alanine is the key step in the synthesis and ensures
the product is obtained with high levels of stereocontrol.
KEYWORDS
Asymmetric Michael
a-amination; a-methyl-
a-protected hydroxymethyl
aldehydes; one-pot
protocol; (S)-
a-methyl-serine
1. Introduction
Non-natural amino acids are important nitrogen-containing compounds with signifi-
cant biological relevance [1]. They are typically derived from secondary metabolism
[2] and have been found the use as modified peptides for enzyme inhibitors and pep-
tidomimetics [3]. Among the non-natural amino acids, quaternary amino acids have
attracted particular interest [4]. Peptides containing this type of amino acid have
higher conformational rigidity and hydrolytic stability [4–6].
(S)- or (R)-a-methyl-serine is a non-natural amino acid, with uses ranging from
potential C-terminal a-helix stabilising building blocks [7] to being used in the
synthesis of natural products [8] or pharmaceutical molecules [9]. To date, several
CONTACT Ping Xie
xp@imm.ac.cn
Department of Medicinal Chemistry, Beijing Key Laboratory of Active
Substances Discovery and Druggability Evaluation & State Key Laboratory of Bioactive Substance and Function of
Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical
Sciences, Beijing 100050, China
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
Q. XIAO ET AL.
synthetic methods of this important amino acid have been reported. These include
kinetic resolution [10], asymmetric synthesis via chiral induced asymmetric alkyl-
ation [11], Sharpless asymmetric aminohydroxylation (AA) [12] and dihydroxyla-
tion (AD) [13] methods. However, it is very desirable to develop an economical,
safe, and convenient catalytic method for the synthesis of quaternary amino acids.
Herein, we present an efficient synthesis of (S)-a-methyl-serine methyl ester
hydrochloride.
2. Results and discussion
Proline and proline derived organocatalysts often struggle to induce chirality in asym-
metric Michael a-aminations of a-branched aldehydes, producing compounds with
low to moderate enantioselectivites [14]. In 2005, Barbas et al. reported the higher
stereoselectivity obtained with proline derived tetrazole catalyst for amination of
a-alkyl-a-benzyl disubsitituted aldehydes with 80% ee [15]. But for a-alkyl-a-alkyl dis-
ubsitituted aldehydes only 4–28% ee could be achieved [14]. Herein, we report
the efficient enantioselective synthesis of (S)-a-methyl-serine methyl ester hydrochlor-
ide via asymmetrically catalyzed amination of a-methyl-a-protected hydroxy-
methyl aldehydes.
Initially, we chose 3-(benzyloxy)-2-methylpropanal as model substrate and dibenzyl
azodicarboxylate (DBAD) as the nitrogen source to provide the quaternary amino
aldehyde. However, the two catalysts, D-proline and its tetrazole derivative [15], did
not show good enantioselectivity with only 7% ee and 19% ee, respectively. After
screening a series of amine catalysts, we discovered that the simple chiral primary
amino acid D-3-(1-Naphthyl)-alanine was the best organo catalyst with 61% ee. Also,
we found that enantioselectivity could not be improved by increasing the amount of
catalyst or lowering the temperature. After optimization of other reaction conditions,
we observed that when coupled with 2-methyl-3-((4-(trifluoromethyl)benzyl)oxy)
propanal as starting material and di-p-chlorobenzyl azodicarboxylate (DCAD) as the
nitrogen source, a,a-disubstituted amino aldehyde 1d-p-ClBn was obtained in 90%
yield with 73% ee (Table 1, entry 7). After recrystallization from 90% aqueous etha-
nol, the enantiomerically pure aldehyde (S)-1d-p-ClBn was obtained in 63% yield
with > 99% ee.
Oxidation of the amino aldehyde (S)-1d-p-ClBn using NaClO2 at room tempera-
ture gave the corresponding carboxylic acid (S)-2. Subsequent coupling of (S)-2 with
(trimethylsilyl) diazomethane [15, 16] afforded ester (S)-3. Following Barbas’s one-pot
protocol [15], we prepared (S)-4 via a trifluoroacetylation/selective benzyloxycarbonyl
deprotection strategy. Thus, (S)-3 was treated with pyridine at 40 ꢀC for 18 h followed
by addition of trifluoroacetic anhydride (TFAA) to give (S)-4. Selective N-N bond
cleavage of (S)-4 with SmI2 afforded the protected quaternary amino acid methyl
ester (S)-5. Hydrogenation using 10% Pd/C in methanol and then acidification with
1M HCl in Et2O produced the desired a-methyl-L-serine methyl ester hydrochloride
(Scheme 1).
In the light of the absolute configuration of the amino aldehyde (S)-1d-p-ClBn,
we propose the following transition state model shown in Figure 1. Aldehyde was

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Table 1. Asymmetric amination reaction for the synthesis of a,a-disubsitituted amino aldehyde.a
Entry
R1
R2
Product
Yieldb (%)b
ee (%)c
1
2
3
4
5
6
7
Bn
Bn
Bn
Et
i-Pr
Bn
p-ClBn
p-ClBn
p-ClBn
p-ClBn
1a-Et
1a-i-Pr
1a-Bn
1a-p-ClBn
1b-p-ClBn
1c-p-ClBn
1d-p-ClBn
80
83
82
86
84
86
90
62
44
61
71
51
Bn
p-CH3Bn
p-FBn
p-CF3Bn
61
73/>99d
aReaction conditions: The azodicarboxylate (1 equiv) was added to the aldehyde (1.5 equiv), with catalyst (15 mol %)
in THF at rt for the stated period of time under argon.
bIsolated yield.
cIsolated by silica gel column chromatography and ee determined by HPLC with a Chiralpak AD-H column.
dee determined by chiral HPLC after recrystallization.
Scheme 1. Synthesis of a-methyl-L-serine methyl ester hydrochloride from (S)-1d-p-ClBn.
Reagents and conditions: (a) NaClO2, NaH2PO4, 2-methyl-2-butene, isopropyl alcohol/H2O (3:1), 0 ꢀC-rt, 10h, 89%; (b)
TMSCHN2, toluene-MeOH (2:1), rt, 30min, 90%; (c) (i) pyridine, 40ꢀC, 18h; (ii) TFAA, rt, 48h, 92%; (d) SmI2, MeOH, rt,
30min, 91%; (e) (i) H2,10% Pd-C, MeOH/AcOH,12h, rt; (ii)1M HCl/Et2O, rt, 86%.
activated by the amine group via the formation of enamine transition state and
azodicarboxylate might be activated by hydrogen binding interaction with nitrogen
atom.

4
Q. XIAO ET AL.
Figure 1. Proposed transition state model.
In conclusion, a highly efficient synthesis of enantiopure (S)-a-methyl-serine is
described, obtaining the product in 32.7% yield over six steps. To the best of our
knowledge, this represents the first asymmetric synthesis of (S)-a-methyl-serine
methyl ester hydrochloride via catalytic amination. This methodology allows the syn-
thesis of either R or S-enantiomer of a-methyl-serine methyl ester hydrochloride by
selecting the corresponding catalyst. The catalytic reaction and the following trans-
formation conditions are mild and suitable for large practical synthesis.
3. Experimental
3.1. Materials and methods
Melting points were determined on Yanaco MP-J3 (Japan) microscope melting point
1
apparatus. H and 13C NMR spectra were recorded on an NMR spectrometer (400
(100) MHz, Varian Mercury-400, America). ESI-MS were determined on a mass spec-
trometer (Exactive Plus, Thermo, Germany). Reactions were monitored by TLC (silica
gel GF254). The enantiomeric excess (ee) of the products was determined by HPLC
on Agilent 1100 Series (America) using Diacel Chiracel AD-H (250 ꢁ 4.6 mm).
Rotational values were determined on a Rudolph Polarimeter (America) at
k ¼ 589 nm (sodium D-line). Solvents were purified according to standard procedures.
Analytical TLC was performed using Polychrom SI F254 plates. Products were puri-
fied by column chromatography on silica gel (300–400 mesh) by using the solvent
system indicated.
3.2. General procedure for the synthesis of the a, a-disubsitituted
amino aldehyde
Catalyst (15 mol% in respect to the azodicarboxylate) was added to a suspension of
aldehydes (1.5 eq. in respect to the azodicarboxylate) and azodicarboxylate in THF.
The mixture was stirred 24h at rt under argon, then quenched by addition of H2O,
and extracted three times with Et2O (20 ml ꢁ 3). The combined organic layers were
dried over Na2SO4, filtered, and concentrated. The resulting crude was purified by

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
flash chromatography on silica gel, eluted with light petroleum ether–ethyl acetate
mixture (4:1 v/v) to afford 1 as a solid or oil.
3.2.1. Compound 1a-Et
Oil, in 80% yield with 62% ee. H NMR (400 MHz, CDCl3): d 1.24-1.30 (m, 6 H,
1
2 ꢁ CH3), 1.35 (s, 3 H, CH3), 3.63-3.76 (m, 2 H, CH2), 4.15-4.24 (m, 4 H, 2 ꢁ CH2),
4.47 (s, 2 H, CH2), 6.57 (s, 1 H, NH), 7.24-7.36 (m, 5 H, Har), 9.57 (s, 1 H, CHO).
HRESIMS: m/z 353.1700 [M þ H]þ (calcd for C17H25N2O6, 353.1707). HPLC (Daicel
Chirapak AD-H, hexane/isopropanol ¼ 95: 5, flow rate 1.0 ml/min, k ¼ 213 nm): tR ¼
18.21 min (major), tR ¼ 20.59 min (minor).
3.2.2. Compound 1a-i-P
Oil, in 83% yield wtih 44% ee. H NMR (400 MHz, CDCl3): d 1.12-1.28 (m, 12 H,
1
4 ꢁ CH3), 1.34 (s, 3 H, CH3), 3.63-3.76 (m, 2 H, CH2), 4.47 (s, 2 H, CH2), 4.93-4.94
(m, 2 H, CH2), 6.47 (s, 1 H, NH), 7.23-7.36 (m, 5 H, Har), 9.58 (s, 1 H, CHO).
HRESIMS: m/z 381.2016 [M þ H]þ (calcd for C19H29N2O6, 381.2020). HPLC (Daicel
Chirapak AD-H, hexane/isopropanol ¼ 95: 5, flow rate 1.0 ml/min, k ¼ 213 nm): tR ¼
14.05 min (major), tR ¼ 17.97 min (minor).
3.2.3. Compound 1a-Bn
Oil, in 82% yield wtih 61% ee. H NMR (400 MHz, CDCl3): d 1.36 (s, 3 H, CH3),
1
3.61-3.77 (m, 2 H, CH2), 4.42 (s, 2 H, CH2), 5.07-5.19 (m, 4 H, 2 ꢁ CH2), 6.71 (s, 1 H,
NH), 7.19-7.36 (m, 15 H, Har), 9.58 (s, 1 H, CHO). HRESIMS: m/z 477.2004
[M þ H]þ (calcd for C27H28N2O6, 477.2020). HRMS for C27H28N2O6 (MHþ): calcd
477.2020, obsd 477.2004, HPLC (Daicel Chirapak AD-H, hexane/isopropanol ¼ 90:
10, flow rate 1.0 ml/min, k ¼ 213 nm): tR
¼
22.65 min (major), tR
¼
26.35 min (minor).
3.2.4. Compound 1a-p-ClBn
1
White solid, in 86% yield wtih 71% ee. H NMR (400 MHz, CDCl3): d 1.36 (s, 3 H,
CH3), 3.60-3.77 (m, 2 H, CH2), 4.42 (s, 2 H, CH2), 5.01-5.15 (m, 4 H, 2 ꢁ CH2), 6.70
(s, 1 H, NH), 7.16-7.30 (m, 13 H, Har), 9.55 (s, 1 H, CHO). HRESIMS: m/z 545.1235
[M þ H]þ (calcd for C27H27N2O6Cl2, 545.1241). HPLC (Daicel Chirapak AD-H, hex-
ane/isopropanol ¼ 85: 15, flow rate 1.0 ml/min, k ¼ 213 nm): tR ¼ 19.38 min (minor),
tR ¼ 21.25 min (major).
3.2.5. Compound 1b-p-ClBn
White solid, in 85% yield wtih 51% ee. H NMR (400 MHz, CDCl3): d 1.33 (s, 3 H,
1
CH3), 2.31 (s, 3 H, CH3), 3.58-3.75 (m, 2 H, CH2), 4.42 (s, 2 H, CH2), 5.01-5.15 (m,
4 H, 2 ꢁ CH2), 6.69 (s, 1 H, NH), 7.07-7.31 (m, 12 H, Har), 9.55 (s, 1 H, CHO).
HRESIMS: m/z 559.1385 [M þ H]þ (calcd for C28H29N2O6Cl2, 559.1397). HPLC
(Daicel Chirapak AD-H, hexane/isopropanol ¼ 90: 10, flow rate 1.0 ml/min,
k ¼ 213 nm): tR ¼ 25.17 min (minor), tR ¼ 28.42 min (major).

6
Q. XIAO ET AL.
3.2.6. Compound 1c-p-ClBn
1
White solid, in 86% yield wtih 61% ee. H NMR (400 MHz, CDCl3): d 1.33 (s, 3 H,
CH3), 3.58-3.75 (m, 2 H, CH2), 4.37 (s, 2 H, CH2), 5.03-5.16 (m, 4 H, 2 ꢁ CH2), 6.67
(s, 1 H, NH), 6.98-7.00 (m, 2 H, Har), 7.15-7.29 (m, 10 H, Har), 9.55 (s, 1 H, CHO).
HRESIMS: m/z 563.1145 [M þ H]þ (calcd for C27H26N2O6Cl2F, 563.1147). HPLC
(Daicel Chirapak AD-H, hexane/isopropanol ¼ 90: 10, flow rate 1.0 ml/min,
k ¼ 213 nm): tR ¼ 32.59 min (minor), tR ¼36.22 min (major).
3.3. (S)-bis(4-chlorobenzyl)-1-(2-methyl-1-oxo-3-((4-(trifluoromethyl) benzyl)oxy)
propan-2-yl)hydrazine-1,2-dicarboxylate (S)-1d-p-ClBn
Catalyst D-3-(1-Naphthyl)-alanine (191mg, 15 mol% in respect to the azodicarboxy-
late) was added to a suspension of 2-methyl-3-((4-(trifluoromethyl)benzyl)oxy)propa-
nal (2.2 g, 8.93 mmol) and di-p-chlorobenzyl azodicarboxylate (2.17 g, 5.93 mmol) in
THF (50 ml). The mixture was stirred at r.t. under argon until the colour of the azo-
dicarboxylate disappeared, and the reaction was quenched by addition of H2O, then
extracted three times with Et2O (50 ml ꢁ 3). The combined organic layers were dried
over Na2SO4, filtered, and concentrated. The resulting crude was purified by flash
chromatography on silica gel, eluted with light petroleum ether–ethyl acetate mixture
(4:1 v/v) to afford (S)-1d-p-ClBn (3.27g) as solid in 90% yield with 73% ee. Upon
recrystallization from 90% ethanol, the aldehyde (S)-1d-p-ClBn (2.04g) was obtained
1
in >99% ee (63% yield). [a]20
-8.1 (c 0.3, CHCl3). mp: 145–149 ꢀC. H NMR
D
(400 MHz, CDCl3): d 1.32 (s, 3 H, CH3), 3.71-3.87 (m, 2 H, CH2), 4.54 (s, 2 H, CH2),
5.10-5.20 (m, 4 H, 2 ꢁ CH2), 6.71 (s, 1 H, NH), 7.22-7.38 (m, 10 H, Har), 7.62 (d, 2 H,
J ¼ 4.0 Hz, Har), 9.62 (s, 1 H, CHO). HRESIMS: m/z 613.110 [M þ H]þ (calcd for
C28H26N2O6Cl2F3, 613.1115). HPLC (Daicel Chirapak AD-H, hexane/isopropanol ¼
85: 15, flow rate 1.0 ml/min, k ¼ 213 nm): tR ¼ 18.00 min (minor), tR
¼
20.29 min (major).
3.4. (S)-2-(1,2-Bis(((4-chlorobenzyl)oxy)carbonyl)hydrazinyl)-2-methyl-3-((4
(trifluromethyl)benzyl)oxy) propanoic acid (S)-2
To a solution of (S)-1d-p-ClBn (2 g, 3.26 mmol) in isopropyl alcohol-H2O (3:1,
40 ml), NaClO2 (1.18g, 13.0 mmol), NaH2PO4.H2O (1.25 g, 6.5 mmol) and 2-methtl-2-
butene (2.18 ml, 26 mmol) was added and stirred for 10 h. Then the solvent was
removed under vacuum. The crude material was extracted with ethyl acetate and
washed with brine. The organic phase was dried (Na2SO4), and the solvent was
evaporated under reduced pressure. The crude product was chromatographed
(dichloromethane/methanol, 10:1) to afford the corresponding acid (S)-2 as an oil
1
(1.86 g, 89% yield). [a]20 -2.46 (c 0.3, CH3OH). H NMR (400 MHz, CDCl3): d 1.51
D
(s, 3 H, CH3), 3.56-3.73 (m, 2 H, CH2), 4.46-4.51 (m, 2 H, CH2), 5.05-5.21 (m, 4 H,
2 ꢁ CH2), 7.15-7.33 (m, 10 H, Har), 7.55 (d, 2 H, J ¼ 8.0 Hz, Har). HRESIMS: m/z
629.1048 [M þ H]þ (calcd for C28H26N2O7Cl2F3, 629.1064).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
3.5. Bis (4-chlorobenzyl) (S)-1-(1-methoxy-2-methyl-1-oxo-3-((4-(trifluoromethyl)
benzyl)oxy) propan-2-yl)hydrazine-1, 2-dicarboxylate (S)-3
A solution of (S)-2 (1.85 g, 2.94 mmol) in toluene-MeOH (2:1, 20 ml), (trimethylsilyl)-
diazomethane (2.94 ml of 2 M solution in hexanes, 5.88 mmol) was added and stirred
at room temperature for 30 min. Then excess trimethyl silyl diazomethane was
quenched by drop wise addition of acetic acid. The reaction was concentrated, and
the residue was purified by flash column chromatography (silica gel, light petroleum
ether/ethyl acetate ¼ 80:20) to afford product (S)-3 (1.70 g, 90% yield). [a]20 -12.64
D
1
(c 1.1, CHCl3). H NMR (400 MHz, CDCl3): d 1.67 (s, 3 H, CH3), 3.61-3.64 (m, 4 H,
2 ꢁ CH2), 4.48 (s, 3 H, CH3), 5.02-5.16 (m, 4 H, 2 ꢁ CH2), 6.69 (s, 1 H, NH), 7.13-
7.32 (m, 10 H, Har), 7.55 (d, 2 H, J ¼ 8.0 Hz, Har). HRESIMS: m/z 643.1195 [M þ H]þ
(calcd for C29H28N2O7Cl2F3, 643.1220).
3.6. 4-Chlorobenzyl (S)-1-(1-methoxy-2-methyl-1-oxo-3-((4-(trifluoromethyl)
benzyl)oxy)propan-2-yl)-2-(2, 2, 2-trifluoroacetyl)hydrazine-1-carboxylate (S)-4
A solution of amino acid ester (S)-3 (1.6 g, 2.49 mmol) in pyridine (10 ml) was heated
at 40 ꢀC for 18 h. Then the reaction was cooled to room temperature and trifluoroace-
tic anhydride (1.81 ml, 13.0 mmol) was added and stirred at room temperature for
further 48 h. The reaction was concentrated, and the residue was purified by flash col-
umn chromatography (silica gel, light petroleum ether/ethyl acetate ¼ 80:20) to afford
the product (S)-4 (1.31 g, 92% yield). [a]20
-0.35 (c 1.1, CHCl3). 1H NMR
D
(400 MHz, CDCl3): d 1.59 (s, 3 H, CH3), 3.68-3.73 (m, 4 H, CH and CH3), 3.94 (m,
1 H, CH), 4.52 (s, 2 H, CH2), 5.09 (s, 2 H, CH2), 7.21 (d, 2 H, J ¼ 8.0 Hz, Har), 7.27-
7.33 (m, 4 H, Har), 7.59 (d, 2 H, J ¼ 8.0 Hz, Har), 8.10 (s, 1 H, NH). 13C NMR
(100 MHz, CDCl3): d 20.0, 31.2, 52.8, 68.0, 72.9, 77.2, 125.6, 125.6, 127.6, 127.6,
127.6, 127.6, 128.8, 128.8, 128.8, 128.8, 129.4, 129.4, 130.2, 133.5, 134.5, 154.0170.97.
HRESIMS: m/z 571.1059 [M þ H]þ (calcd for C23H22N2O6ClF6, 571.1065).
3.7. (S)-Methyl-2-((((4-chlorobenzyl)oxy)carbonyl)amino)-2-methyl-3-((4-
(trifluoromethyl)benzyl)oxy) propanoate (S)-5
To a solution of amino acid ester (S)-4 (1.0 g, 1.75 mmol) in MeOH (3 ml) 0.1 M
solution of samarium iodide in THF (100 ml) was added in an atmosphere of argon
and stirred at room temperature for 30 min. The volatiles were removed under vac-
uum and the residue was purified by flash column chromatography (silica gel, light
petroleum ether/ethyl acetate ¼ 80:20) to afford the product (S)-5 (1.15 g, 91% yield).
1
mp: 98–100 ꢀC. [a]20 -4.2 (c 0.6, CHCl3). H NMR (400 MHz, CDCl3): d 1.54 (s,
D
3 H, CH3), 3.68-3.78 (m, 4 H, CH and CH3), 3.88-3.90 (m, 1 H, CH), 5.02 (s, 2 H,
CH2), 5.79 (s, 1 H, NH), 7.26-7.34 (m, 6 H, Har), 7.66-7.67 (m, 2 H, Har). 13C NMR
(100 MHz, CDCl3): d 20.2, 29.7, 52.9, 60.5, 65.7, 72.5, 125.4, 127.4, 127.4, 127.7,
128.7, 128.7, 128.8, 129.4, 129.4, 130.1, 134.0, 135.0, 141.8, 154.7, 173.0. HRESIMS:
m/z 460.1133 [M þ H]þ (calcd for C21H22NO5ClF3, 460.1133).

8
Q. XIAO ET AL.
3.8. (S)-a-Methyl-serine methyl ester hydrochloride
To a solution of (S)-5 (784 mg, 1.70 mmol) in 8 ml of methanol and 4 mlml acetic
acid, 360 mg of 10% palladium on charcoal was added. The mixture was hydrogen-
ated with at ambient pressure for 12 h and filtered. 1M HCl/Et2O (2 ml) was added
into the filtrate. After removal of the solvent, diethyl ether was added. Then, a
white solid appeared. After filtration and removal of solvent, (S)-a-methyl-serine
methyl ester hydrochloride was obtained (250 mg, 86% yield). [a]20
-3.16 (c 0.5,
D
1
CH3OH). H NMR (400 MHz, CD3OD): d 1.48 (s, 3 H, CH3), 3.64 (d, 1 H, J ¼ 8.0 Hz,
CH), 3.85 (s, 3 H, CH3), 3.95 (d, 1 H, J ¼ 8.0 Hz, CH). 13C NMR (100 MHz, CDCl3): d
22.7, 52.5, 68.9, 72.9, 159.4. HRESIMS: m/z 134.0811 [M þ H]þ (calcd for
C5H12NO3, 134.0812).
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was financially supported by the Drug Innovation Major Project (No.
2018ZX09711001-005-012), National Key R&D Program of China (No. 2018YFC1706403) and
CAMS Innovation Fund for Medical Sciences (No. 2016-I2M-2-002).
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