Novel N,S-phenacyl protecting group and its application for peptide synthesis

Article abstract of DOI:10.1055/s-2008-1077887

The phenacyl group can be introduced onto amino and thio groups by N,S-alkylation reactions. Conversely, these groups are removed rapidly by employing magnesium in acetic acid. This protecting group was successfully applied to a short peptide synthesis of Boc-L-Cys-Gly-OMe. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1077887

LETTER
1907
Novel N,S-Phenacyl Protecting Group and Its Application for Peptide
Synthesis
Novel
N
,
S
-Phenac
u
yl Protecting
o
G
roup Tang,* Tao Ji, An-Fu Hu, Yu-Fen Zhao
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, P. R. of China
Fax +86(592)2185780; E-mail: t12g21@xmu.edu.cn
Received 17 March 2008
O
O
R1
R2
Abstract: The phenacyl group can be introduced onto amino and
thio groups by N,S-alkylation reactions. Conversely, these groups
are removed rapidly by employing magnesium in acetic acid. This
protecting group was successfully applied to a short peptide synthe-
sis of Boc-L-Cys-Gly-OMe.
R1
R2
X
Br
base
r.t.
XH
+
84–93%
X = N, S R1, R2 = alkyl, aromatic groups, hydrogen
Key words: protecting groups, alkyl halides, magnesium, peptides,
thiols
Scheme 1
Secondly, Pac can be cleaved by reduction with Zn or Mg
in acetic acid at room temperature (Table 1). However,
the magnesium/acetic acid method is better that the zinc/
acetic acid method because the latter proceeded sluggish-
ly and several byproducts were also produced. Addition-
ally, the removal of the remained zinc was also a
troublesome procedure. In contrast, using magnesium af-
ford the desired products in high yields.
Although currently there are a lot of methods available for
protection of amino and mercapto groups, the alkylation
reaction is a simple yet challenging method of accom-
plishing this. Very often this has involved protection of
the amine followed by alkylation and subsequent depro-
tection. To the best of our knowledge, only limited studies
have been done related to the protection of amino and thio
groups using phenacyl as a protecting group.
To demonstrate the generality of this method, a series of
nitrogen and thio compounds were used (Table 2). We
found that these reactions took place rapidly and the
deprotection was usually complete within 60 minutes to
give 88–94% yield of the products.
Phenacyl esters have been used for many years as deriva-
tives of carboxylic acids for identification purposes and
more recently as temporary protecting groups for organic
synthesis. Phenacyl group (Pac) is stable in 50% trifluoro-
acetic acid in dichloromethane, hydrogen fluoride (0 °C,
1 h),1 and even in high concentrations of hydrogen chlo-
ride or hydrogen bromide in acetic acid.2 A few methods
have been developed for the cleavage of phenacyl ester
over the past years.3–8
Using substrate 4 as a model reaction, we studied the ef-
fect of solvent on this magnesium/acetic acid deprotection
process using THF, acetone, ethyl acetate, and methanol.
We found that the above-mentioned solvents were all ef-
ficient. More time was needed for full deprotection (150
min) when the solvent contains 5% H2O.
The photolysis of phenacyl derivatives of primary and
secondary amines yields the carbonyl compound, not the
desired primary and secondary amines.9 The removal of
protecting groups by treating a compound with a metal10–14
prompted an investigation of the utility of metal reduction
in effecting the conversion of phenacyl N,S-protected de-
rivatives to amino and thiol compounds. We report here
that phenacyl is an efficient N,S-protecting group for pep-
tide synthesis under mild conditions.
Having successfully established a protocol for the depro-
tection of the substrates in Table 2, we set out to examine
this process on derivatives 4, 5, and 12 (Table 3) contain-
ing other sensitive groups (such as halide and carbonyl).
It has been proved that the phenacyl group is an important
reagent for protecting amino and thio functions during or-
thogonal organic synthesis in the presence of other func-
tions. On the other hand, the deprotection products from
substrate 12 (Table 3) by magnesium turnings have the
same specific rotation as the original L-cysteine. This fact
indicates that no racemization took place during derivati-
zation with phenacyl protected and subsequent deprotec-
tion.
Firstly, phenacyl group (Pac) is an efficient and economic
protecting group for amino and thio compounds. As
shown in Scheme 1, Pac was easily introduced to amines
and thiols to produce the corresponding compounds in
high yields. The products were of high purity (>95%) and
were characterized by 1H NMR, 13C NMR, and ESI-MS.
Finally, the deprotection method using magnesium/acetic
acid can be used in the syntheis of Boc-L-Cys-Gly-OMe
(Scheme 2) was prepared in four steps from l-cysteine.
The above deprotection methodology was successfully in-
SYNLETT 2008, No. 12, pp 1907–1909
x
x
.x
x
.2
0
0
8
Advanced online publication: 19.06.2008
DOI: 10.1055/s-2008-1077887; Art ID: W04508ST
© Georg Thieme Verlag Stuttgart · New York

1908
G. Tang et al.
LETTER
Table 1 Removal of Protecting Groupa
Table 2 Removal of Protecting Group with Mg15
O
Substrate
Product
Yield
(%)
O
R1
R1
R2
M, AcOH
X
+
XH
R2
O
solvent
O
6
88
NH2
N
M = Zn, Mg
X = N, S R1, R2 = alkyl, aromatic groups, hydrogen
Starting material
Zn/AcOH,
yield (%)
Mg/AcOH,
yield (%)
1
7
8
92
91
90
O
O
O
O
NH
O
O
O
N
N
1
2
60
89
O
N
NH
40
87
H
N
NH2
H
N
3
4
65
55
90
92
N
O
O
N
N
2
91
93
90
92
O
O
O
O
H
NH2
N
N
O
9
H
N
N
5
58
91
N
O
S
N
3
N
N
N
Cl
N
N
a Reaction time = 45 min.
N
H
10
SH
O
O
Table 3 Removal of Protecting Group with Mg in the Presence of
Sensitive Groups15
S
Substrate
Product
Yield (%)
91
O
O
11
94
5
Cl
SH
SH
S
S
N
N
Cl
4
89
90
O
O
deprotection method can be performed in various organic
solvents, showing that this method is widely applicable to
the orthogonal organic synthesis bearing other kinds of
functional groups.
NH
N
O
O
12
HO
SH
NH2
HO
S
O
NH2
O
H
O
H
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
corporated into a short synthesis of Boc-L-Cys-Gly-OMe
in high yield (93%).
The authors would like to acknowledge the financial supports from
Major Program of National Natural Science Foundation of China
(20732004) and Projects of International Cooperation of the Mini-
stry of Science and Technology of the People’s Republic of China
(2006DFA43030).
In summary, this work describes a new protecting group,
the phenacyl residue, for which the deprotecting step in-
volves magnesium tunings in acetic acid. Finally, this
Synlett 2008, No. 12, 1907–1909 © Thieme Stuttgart · New York

LETTER
Novel N,S-Phenacyl Protecting Group
1909
O
O
NH2
H2N
OH
Br
S
OH
C
C
a
+
HS
O
O
13
NHBoc
O
NHBoc
O
O
H
S
OH
S
N
C
b
C
O
c
C
O
OMe
14
15
NHBoc
O
d
H
HS
N
C
C
O
OMe
16
Scheme 2 Reagents and conditions: (a) KOH, EtOH–H2O, 80%; (b) (Boc)2O, NaHCO3, NaOH, dioxane–H2O, 92%; (c) L-Gly-OMe·HCl,
DCC, HOBt, THF, 94%; (d) Mg, AcOH, MeOH, r.t., 93%.
Typical Deprotection Procedure
To a solution of the protected substrate (2 mmol) in MeOH
(15 mL) was added AcOH (1.5 mL, 24 mmol) and Mg
turnings (288 mg, 12 mmol). The solution was stirred for
50–70 min (followed by TLC) at r.t. The reaction mixture
was filtered, and the filtrate was concentrated in vacuo. The
residue was diluted with 5% NaHCO3 (10 mL), EtOAc
(2 × 10 mL), and combined organic solution. The organic
References and Notes
(1) Yang, C. C.; Merrifield, R. B. J. Org. Chem. 1976, 41, 1032.
(2) Stelakatos, G. C.; Zervas, L. J. Chem. Soc. C. 1966, 1191.
(3) Fletcher, A. R.; Jones, J. H.; Ramage, W. I.; Stachulski, A.
V. J. Chem. Soc., Perkin Trans. 1 1979, 2261.
(4) Sheehan, J. C.; Daves, G. D. J. Org. Chem. 1964, 29, 2006.
(5) Tam, J. P.; Cunningham-Rundles, W. F.; Erickson, B. W.;
Merrifield, R. B. Tetrahedron Lett. 1977, 4001.
layer was washed with brine (2 × 10 mL), dried with
(6) (a) Ueki, M.; Kai, K.; Amemiya, M.; Horino, H.; Oyamada,
Na2SO4, and filtered. The filtrate was evaporated in vacuo.
H. J. Chem. Soc., Chem. Commun. 1988, 414.
(b) Namikoshi, M.; Kundu, B.; Rinehart, K. L. J. Org. Chem.
1991, 56, 5464.
The crude product was purified by silica gel chromatography
using a mixture of PE–EtOAc.
N-[N-(tert-Butoxycarbonyl)-S-(phenacylthio)cyste-
inyl]glycine Methyl Ester (15)
(7) Sheehan, J. C.; Umezawa, K. J. Org. Chem. 1973, 21, 3771.
Brown solid. 1H NMR (400 MHz, CDCl3): d = 1.44 (s, 9 H),
2.89–2.99 (m, 2 H), 3.73 (s, 3 H), 3.97–4.08 (m, 4 H), 4.49
(s, 1 H), 5.64 (d, J = 8.0 Hz), 7.30 (s, 1 H), 7.30–7.49 (m, 2
H), 7.57–7.61 (m, 1 H), 7.96–7.98 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): d = 195.2, 170.8, 169.8, 155.6, 135.2,
133.6, 128.7, 128.6, 80.3, 53.3, 52.3, 41.2, 38.3, 34.9, 28.2
(8) Ram, R. N.; Singh, L. Tetrahedron Lett. 1995, 36, 5401.
(9) Hyat, J. A. J. Org. Chem. 1972, 37, 1255.
(10) Kakinaki, S.; Leondiadis, L.; Ferderigos, N. Org. Lett. 2005,
7, 1723.
(11) Hendrickson, J. B.; Kandall, C. Tetrahedron Lett. 1970, 343.
(12) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1970,
345.
(13) Eckert, H.; Listl, M.; Ugi, I. Angew. Chem., Int. Ed. Engl.
1978, 17, 361.
(14) Kende, A. S.; Mendoza, J. S. Tetrahedron Lett. 1990, 31,
7105.
ppm. ESI-MS: m/z = 411.2 [M + H]+, 433.1 [M + Na]+; [a]D
–19.3 (c 1, MeOH). ESI-HRMS: m/z calcd for [C19H26N2O6S
+ Na]+: 433.1409; found: 433.1411; for [C19H26N2O6S +
H]+: 411.1590; found: 411.163.
N-[N-(tert-Butoxycarbonyl)cysteinyl]glycine Methyl
Ester (16)
20
(15) Synthesis of Substrate Materials 1–12; Typical
Clear oil. 1H NMR (400 MHz, CDCl3): d = 1.46 (s, 9 H),
1,69 (dd, J = 7.6, 2.8 Hz), 2.73–2.75 (m, 1 H), 3.11–3.15 (m,
1 H), 3.76 (s, 3 H), 3.99–4.13 (m, 2 H), 4.42 (s, 1 H), 5.54 (d,
J = 7.6 Hz, 1 H), 6.96 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): d = 170.5, 169.9, 155.4, 128.1 125.6, 80.9, 55.4,
52.4, 41.2, 28.2, 28.1, 26.9 ppm. ESI-MS: m/z = 293.1 [M +
H]+, 315.1 [M + Na]+.
Protection Procedure
To an ice-cooled solution of amino or thio compound (5
mmol) in EtOAc (20 mL) was added Et3N (0.55 g, 5.5 mmol)
and phenacyl bromide (1.1 g, 5.5mmol). After stirring at r.t.
for 4 h, the reaction mixture was diluted with EtOAc (25
mL). The organic layer was washed with brine (10 mL), sat.
NaHCO3 (10 mL), brine (2 × 10 mL), dried over Na2SO4,
and filtered. The filtrate was evaporated in vacuo and the
crude product was purified by silica gel chromatography
using a mixture of PE–EtOAc.
Synlett 2008, No. 12, 1907–1909 © Thieme Stuttgart · New York

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