Synthesis of thiol-containing amino acids through alkylation of glycinate ketimine

Article abstract of DOI:10.1080/00397911.2010.533803

A general synthetic route for the synthesis of thiol-containing amino acids through alkylation of glycinate ketimine followed by hydrolysis was developed in this work. The common problems associated with the instability of ketimines and thioesters were so

Full text of DOI:10.1080/00397911.2010.533803

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Synthesis of Thiol-Containing Amino
Acids Through Alkylation of Glycinate
Ketimine
Jian Zhi a , Yuli Xiao a & Aiguo Hu a
a Key Laboratory for Ultrafine Materials of Ministry of Education,
School of Materials Science and Engineering, East China University of
Science and Technology, Shanghai, China
Accepted author version posted online: 06 Sep 2011.Published
online: 11 Nov 2011.
To cite this article: Jian Zhi , Yuli Xiao & Aiguo Hu (2012) Synthesis of Thiol-Containing Amino
Acids Through Alkylation of Glycinate Ketimine, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:6, 914-920, DOI:
10.1080/00397911.2010.533803
To link to this article: http://dx.doi.org/10.1080/00397911.2010.533803
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Synthetic Communications1, 42: 914–920, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.533803
SYNTHESIS OF THIOL-CONTAINING AMINO ACIDS
THROUGH ALKYLATION OF GLYCINATE KETIMINE
Jian Zhi, Yuli Xiao, and Aiguo Hu
Key Laboratory for Ultrafine Materials of Ministry of Education, School of
Materials Science and Engineering, East China University of Science and
Technology, Shanghai, China
GRAPHICAL ABSTRACT
Abstract A general synthetic route for the synthesis of thiol-containing amino acids through
alkylation of glycinate ketimine followed by hydrolysis was developed in this work. The
common problems associated with the instability of ketimines and thioesters were solved
by optimization of both synthetic and purification conditions. A series of thiol-containing
amino acids were obtained in good yields. This method could be readily extended to the syn-
thesis of other thiol-containing amino acids, which are important intermediates in pharma-
ceutical research and medical applications.
Keywords Alkylation; ketimine; thiol-containing amino acids
INTRODUCTION
Thiol-containing amino acids and their derivatives have been regarded as versa-
tile tools that enable medicinal chemists and agrochemists to design new drugs and
peptides. As a reactive member of natural amino acids, cysteine, the simplest thiol-
containing amino acid, is commonly tapped as a nucleophile in enzyme active sites.
Homocysteine, which has an additional methylene group, is an excitatory amino acid
that markedly enhances the vulnerability of neuronal cells to excitotoxic and oxidative
injury in vitro and in vivo.[1] Elevated plasma homocysteine (Hcy) levels in human
blood are associated with great risk of venous and arterial thrombosis.[2] Thiotyrosine
Received August 19, 2010.
Address correspondence to Aiguo Hu, Key Laboratory for Ultrafine Materials of Ministry of
Education, School of Materials Science and Engineering, East China University of Science and
Technology, Shanghai 200237, China. E-mail: hagmhsn@ecust.edu.cn
914

THIOL-CONTAINING AMINO ACIDS
915
derivatives, (S)-40-mercaptophenylalanine (Tty) and 3-N-(40-mercaptophenyl)-(S)-
2,3-diaminoproprionate (Aty), have been prepared and incorporated into polyalanine
peptides.[3] Upon photocleavage of the S-S bond, the peptide can then commence to
fold into an a-helical conformation. Furthermore, thiol-containing amino acids
are employed to synthesize cyclic peptides, which are applied to build peptide
dendrimers.[4]
Several approaches have been reported for the synthesis of thiol-containing
amino acids. Sano et al. reported a microbial transformation method for L-cysteine
production using Pesudomonas thiazolinophilum (AJ3854).[5] Broxterman et al. suc-
cessfully synthesized sulfur-containing trisfunctional amino acids by radical addition
of thioacetic acid to unsaturated amino acids. The thioester moiety can be easily con-
verted to a free mercapto group by hydrolysis.[6] Escher et al. have successfully
obtained 40-mercaptophenylalanine by chlorosulfonation of L-phenylalanine fol-
lowed by tin–HCl reduction.[7] Most of these synthetic strategies were complex
and difficult to control. All these methods are developed for preparation of specific
thiol-containing amino acids, which limits their medical and biological application
beyond laboratory synthesis. Thus, a simple, effective, and universal synthesis of
thiol-containing amino acids with desired structure would meet the great demand
of clinical and biochemical usage and so is of great interest.
Herein, we report a simple, mild, and general method for preparation of thiol-
containing a-amino acids with diverse alkyl groups (Fig. 1). The procedure is based
on the alkylation of a single starting material, benzophenone glycine ketimine (Schiff
base) 1, which is commercially available, with various alkylation agents. The alky-
lation products (i.e., thioester ketimines) can be easily hydrolyzed to obtain the final
amino acids 4. A number of higher homologs of glycine have been successfully pre-
pared by this alkylation path,[8–10] however, synthesis of thiol-containing amino
acids is difficult because of the susceptibility of thiol or thioester groups to the alky-
lation conditions, and a general synthetic strategy for thiol-containing amino acids
through the alkylation route has not been reported yet. We employed x-bromo-a-
thioesters as the alkylation agents, and after incorporation of this moiety onto gly-
cine ketimine starting material, the acetyl group was successfully cleaved through
hydrolysis to give the desired amino acids.
x-Bromo-a-thioesters were synthesized in good yields through reaction of com-
mercially available a,x-dibromoalkanes with thioacetic acid under basic conditions
Figure 1. Structures of thiol-containing amino acids 4a–4c.

916
J. ZHI, Y. XIAO, AND A. HU
Table 1. Alkylation of ketimines 1 with different bromoalkyl thioestersa
Entry
Alkylbromide
Solvent
Base
Yieldc
1
2a
2b
2c
2c
2c
2b
DMF
DMF
DMF
NaH
NaH
NaH
NaH
DBUb
KOH
45
62
2
3
47
4
Toluene
Toluene
DCM=Toluene
Trace
Trace
Trace
5
6d
aReactions were carried out at 40 ꢀC (Entries 1–3), 110 ꢀC (entry 4), 90 ꢀC (entry 5) and 25 ꢀC (entry 6).
bDBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.
cIsolated yield.
dThe alkylation was run under phase-transfer conditions with 50% aqueous KOH as base, dichloro-
methane (DCM) and toluene (7:3) as solvent, and tetrabutylammonium bromide as catalyst.
and were isolated by fractional distillation. An initial trial on the synthesis of thiol-
containing amino acids involved generation of an anionic synthon from 1 either in
the presence of a strong base or under various phase-transfer conditions.[11,12] The
anion was allowed to react with x-bromo-a-thioesters to give a-substituted amino
acids. The main disadvantage of this route is the instability of the thioesters groups
toward aqueous basic conditions. A complex mixture was obtained after alkylation,
which was difficult to purify because of the lability of the ketimine group during
silica-gel chromatography.[13]
After screening several alkylation conditions (Table 1) to conquer these limita-
tions and extend the scope and generality of the method, one approach developed by
Ansari et al. was proven to be suitable for this purpose.[14] The ketimines 3 (benzophe-
none Schiff base) with an a-substituted alkyl thioester were obtained in good yields by
adding 1.2 equivalents bromoalkyl thioester derivatives 2 in N,N-dimethylformamide
(DMF) to a solution of 1 in DMF with sodium hydride (NaH) as base. The reaction
processed smoothly at 40 ꢀC. To avoid hydrolysis of ketimine intermediates on silica
gel, Florisil, as the neutral adsorbent, was used in the flash chromatography. After
these treatments, pure intermediates 3 were obtained and characterized with NMR
and high-resolution mass spectroscopy (HR-MS). The ketimine protecting group as
well as the thioester group at the end of the alkyl chain were successfully hydrolyzed
by refluxing with 6 N HCl under a nitrogen atmosphere, and the amino acids with a
thiol group were obtained in quantitative yields (Scheme 1).
1
The structures of 4a–4c were confirmed with H NMR, 13C NMR and MS
analysis. The free thiol groups (-SH) are visible in the 1.6–2.1 ppm region as triplets
or multiplets, which is consistent with literature data in similar structures.[15] 13
C
NMR spectra showed the resonance of carboxyl group at ca. d 170 ppm, that of
the a-carbon at 53 ppm, and the methylene group adjacent to the thiol group for
all the products. Other methylene groups appeared between 23 and 30 ppm. All
the spectra were clean, indicative of complete removal of both ketimine and thioester
protection groups. Molecular ion peaks were found in the MS for all these products,
and all were in good agreement with predicted patterns in MS, which further con-
firmed the structures of 4a-4c.
All the alkylation reactions were conducted with slight excess (1.2–1.5 eq.) of
2a–2c and monitored with thin-layer chromatography (TLC). It was found that even

THIOL-CONTAINING AMINO ACIDS
917
Scheme 1. Synthesis of a-substituted thiol-containing amino acids 4a–4c, wherein n ¼ 2 to 4.
after prolonged reaction time, no dialkylation product was observed. We speculated
that the second alkylation was hindered by the steric effect. Thus, to facilitate the
purification of thiol-containing ketimines on column chromatography, a large excess
of 2a–2c was used to guarantee full conversion of 1.
In conclusion, we have developed an effective and general synthesis of thiol-
containing amino acids through alkylation of a glycinate ketimine followed by
hydrolysis. The present method is a new route for the synthesis of amino acid deri-
vatives with thiol groups. This method could be readily extended to the synthesis of
other thiol-containing amino acids with desired structures, which have fascinating
applications in biology and gene chemistry.
EXPERIMENTAL
All reactions were carried out in oven-dried glassware under a nitrogen atmos-
phere. Tetrahydrofuran (THF) was distilled over Na under nitrogen prior to use.
˚
N,N-Dimethylformamide (DMF) was dried over 4 A molecular sieves and distilled
under vacuum. Column chromatography was performed with Florisil (200–300
1
mesh). TLC analysis was performed on 0.25 mm thick silica gel plates. H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Bruker AVANCE
400 FT-NMR spectrometer in CDCl3 or D2O. Mass spectra were generated with
Micromass LCT (ESI-TOF). FTIR was recorded from KBr pallets for solid samples
or neat for liquid samples on a Nicolet Magna 5700 FTIR spectrometer. Ethyl N-
(diphenylmethylene) glycinate (1) was prepared according to the literature
procedure.[13]
x-Bromo-a-thioesters 2a–2c
Thioacetic acid (3-bromopropyl) ester (2a). This compound was prepared
according to the literature procedure with minor modification.[16] Thioacetic acid
(8.28 g, 7.77 ml, 0.11 mol) was added to a solution of KOH (6.21 g, 0.11 mol) in

918
J. ZHI, Y. XIAO, AND A. HU
dry, degassed THF (60 ml) containing 1,3-dibromopropane (12.24 ml, 0.12 mol). The
mixture was stirred under nitrogen overnight at room temperature. The mixture was
then concentrated and 13.71 g of 2a was obtained after fraction distillation as a light
1
yellow oil (bp 110–120 ꢀC, 1.5 mmHg, 58% yield). H NMR (CDCl3, d): 2.05 (t,
J ¼ 6.8 Hz, 2H), 2.27 (s, 3H), 2.93 (t, J ¼ 6.9 Hz, 2H), 3.38 (t, J ¼ 6.5 Hz, 2H).
Thioacetic acid (4-bromobutyl) ester (2b)[17]. Following the same pro-
cedure, 2b was obtained after distillation as a light yellow oil (bp 80–90 ꢀC, 1.0
1
mmHg, 43% yield). H NMR (CDCl3, d): 1.66–1.73 (m, 2H), 1.84–1.92 (m, 2H),
2.29 (s, 3H), 2.86 (t, J ¼ 7.2 Hz, 2H), 3.37 (t, J ¼ 6.6 Hz, 2H).
Thioacetic acid (5-bromopentyl) ester (2c). Following the same procedure,
2c was obtained after distillation as a light yellow oil (bp 110–115 ꢀC, 1.0 mmHg,
1
62% yield). H NMR (CDCl3, d): 1.51–1.56 (m, 2H), 1.58–1.64 (m, 2H), 1.89 (t,
J ¼ 7.2 Hz, 2H), 2.34 (s, 3H), 2.89 (t, J ¼ 7.2 Hz, 2H), 3.41 (t, J ¼ 6.7 Hz, 2H). 13C
NMR (CDCl3, d): 27.29, 28.74, 28.83, 30.67, 32.19, 33.46, 196.86. IR (thin film):
2934.9, 2859.1, 1691.4, 1432.9, 1353.4, 1134.4 cmꢁ1. HRMS (ESI) calcd. for
C7H13BrOS (Mþ) 223.9870, found 223.9874.
Glycine Ketimine 1
A solution of 1 (1.0 g, 3.75 mmol) in dry DMF (5 ml) was added to a stirred
suspension of NaH (0.098 g, 4.1 mmol; 60% oil dispersion) in 15 ml dry DMF under
nitrogen. The mixture was stirred gently at 40 ꢀC for 30 min. The flask was removed
from the heating bath, and a solution of x-bromo-a-thioester (4.5 mmol, 1.2 eq) dis-
solved in a minimum amount of DMF was slowly added. After the addition, the
reaction mixture was gently stirred until the starting material disappeared (checked
by TLC). The reaction was stopped, and a small quantity of ethanol (2 mL) was
added to destroy unreacted NaH. The solution was concentrated, and the residue
was partitioned between water and ether. The ether fraction was dried (MgSO4), fil-
tered, and concentrated to yield a yellow liquid. Flash chromatography on Florisil
gave monoalkylated Schiff bases (3a–c).
Ethyl 5-(acetylthio)-2-((diphenylmethylene)amino)pentanoate (3a). Flash
chromatography (5% ethyl acetate–petroleum ether) gave a pale yellow oil 3a, 0.65 g,
45% yield. 1H NMR (CDCl3, d): 1.26–1.31 (m, 5H), 1.99 (q, J ¼ 7.4 Hz, 2H), 2.32 (s,
3H), 2.83 (t, J ¼ 7.2 Hz, 2H), 4.06 (t, J ¼ 6.49 Hz, 1H), 4.17–4.22 (m, 2H), 7.18–7.69
(m, 10H). 13C NMR (CDCl3, d): 14.23, 26.04, 28.89, 30.63, 32.74, 60.96, 64.88,
128.83, 131.03, 139.02, 170.75, 172.01, 192.21, 195.72. IR (thin film): 3058.6,
2932.8, 2858.1, 1738.0, 1690.8, 1623.7, 1445.4, 1353.4, 1278.8, 1184.6, 1135.9,
700.9, 629.0 cmꢁ1. HRMS (ESI) calcd. for C22H25NO3S (Mþ) 383.1555, found
383.1553.
Ethyl 6-(acetylthio)-2-((diphenylmethylene)amino)hexanoate (3b). Flash
chromatography (5% ethyl acetate–petroleum ether) gave a light yellow oil 3b, 0.92 g,
62% yield. 1H NMR (CDCl3, d): 1.26–1.30 (m, 5H), 1.52 (m, 2H), 1.94 (q, J ¼ 7.1 Hz,
2H), 2.21 (s, 3H), 2.84 (t, J ¼ 7.3 Hz, 2H), 4.05 (t, J ¼ 6.5 Hz, 1H), 4.15–4.24 (m, 2H),
7.17–7.72 (m, 10H). 13C NMR (CDCl3, d): 14.25, 25.21, 28.91, 29.29, 30.62, 33.11,
60.89, 65.25, 128.76, 131.22, 139.13, 170.54, 172.25, 192.54, 195.89. IR (thin

THIOL-CONTAINING AMINO ACIDS
919
film): 3061.5, 2925.0, 2854.4, 1736.9, 1691.0, 1448.0, 1361.4, 1277.5, 1184.6, 1135.3,
700.1, 628.8 cmꢁ1. HRMS (ESI) calcd. for C23H27NO3S (Mþ) 397.1712, found
397.1703.
Ethyl 7-(acetylthio)-2-((diphenylmethylene)amino)heptanoate (3c). Flash
chromatography (5% ethyl acetate–petroleum ether) gave light yellow oil 3c,
1
0.73 g, 47% yield. H NMR (CDCl3, d): 1.24–1.27 (m, 7H), 1.52 (m, 2H), 1.91 (q,
J ¼ 7.0 Hz, 2H), 2.29 (s, 3H), 2.81 (t, J ¼ 7.3 Hz, 2H), 4.02 (t, J ¼ 6.5 Hz, 1H),
4.15–4.20 (m, 2H), 7.17–7.70 (m, 10H). 13C NMR (CDCl3, d): 14.26, 25.53, 28.54,
29.04, 29.39, 30.64, 33.47, 60.82, 65.35, 128.73, 131.22, 139.09, 170.34, 172.36,
192.53, 195.89. IR (thin film): 3058.6, 2932.4, 2857.8, 1736.5, 1691.0, 1446.2,
1355.0, 1278.0, 1135.4, 701.2, 628.7 cmꢁ1. HRMS (ESI) calcd. for C24H29NO3S
(Mþ þ K) 450.1505, found 450.1501.
Hydrolysis
Schiff bases 3a–c (2 mmol) were suspended in 6 N HCl. The mixture
was refluxed under nitrogen overnight, cooled, and washed several times with
ether, and the layers were separated. The water fraction was concentrated to
yield 4a–c.
2-Amino-5-mercaptopentanoic acid hydrochloride (4a). White powder,
0.372 g, 100% yield. 1H NMR (D2O, d): 1.59–1.72 (m, 2H), 1.92–2.01 (m, 2H),
2.13 (m, 1H), 2.51 (t, J ¼ 6.9 Hz, 3H), 3.98 (t, J ¼ 6.3 Hz, 1H). 13C NMR (D2O, d):
23.01, 28.40, 40.03, 52.56, 169.86. IR (KBr): 3180.7, 2931.6, 2550.0, 1737.4,
1633.9, 1503.5, 1450.8, 1220.1, 1124.0, 1007.7 cmꢁ1. HRMS (ESI) calcd. for
C5H11NO2S (Mþ þ H) 150.0588, found 150.0560.
2-Amino-6-mercaptohexanoic acid hydrochloride (4b). White powder,
1
0.396 g, 100% yield. H NMR (D2O, d): 1.39–1.47 (m, 2H), 1.55–1.56 (m, CH2,
2H), 1.58 (m, 1H), 1.81–1.91 (m, 2H), 2.47 (t, J ¼ 6.7 Hz, 2H), 3.99 (t, J ¼ 5.9 Hz,
1H). 13C NMR (D2O, d): 22.81, 23.18, 29.12, 32.27, 52.77, 172.09. IR (KBr):
3000.3, 2958.8, 2536.6, 1737.6, 1581.7, 1495.6, 1461.3, 1206.6, 1129.8, 1018.5 cmꢁ1
HRMS (ESI) calcd. for C6H13NO2S (Mþ þ H) 164.0745, found 164.0688.
.
2-Amino-7-mercaptoheptanoic acid hydrochloride (4c). White powder,
1
0.428 g, 100% yield. H NMR (D2O, d): 1.31–1.36 (m, 4H), 1.53 (q, J ¼ 6.7 Hz,
2H), 1.62 (t, J ¼ 7.3 Hz, 1H), 1.87 (m, 2H), 2.46 (t, J ¼ 7.0 Hz, 2H), 3.99 (t,
J ¼ 6.2 Hz, 1H). 13C NMR (D2O, d): 23.50, 26.87, 29.56, 32.46, 52.85, 172.25. IR
(KBr): 3056.4, 2932.1, 2531.1, 1737.9, 1640.9, 1599.3, 1498.1, 1449.1, 1217.9,
1122.2, 1009.2 cmꢁ1. HRMS (ESI) calcd. for C7H15NO2S (Mþ þ H) 178.0901, found
178.0858.
ACKNOWLEDGMENT
This work was supported by the National Special Fund for State Key Labora-
tory of Bioreactor Engineering of China (2060204).

920
J. ZHI, Y. XIAO, AND A. HU
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