Synthesis of thioureido-linked peptidomimetics, glycosylated amino acids, and neoglycoconjugates using bis(benzotriazolyl)methanethione as thioacylating agent

Article abstract of DOI:10.1055/s-0029-1219393

A practical synthesis of thiourea-linked peptidomimetics, glycosylated amino acids, and neoglycoconjugates is described employing bis(benzotriazolyl) methanethione as thiocarbonylating reagent. The entire protocol is mild, efficient, high-yielding, and free from hazardous reagents. All the intermediates and products have been isolated and fully characterized by ¹H NMR, ¹³C NMR, and mass spectrometry. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0029-1219393

LETTER
715
Synthesis of Thioureido-Linked Peptidomimetics, Glycosylated Amino Acids,
and Neoglycoconjugates Using Bis(benzotriazolyl)methanethione as
Thioacylating Agent
S
ynthesis of Thiou
o
reido-Linked
m
Peptidomimetics mina V. Sureshbabu,* Gundala Chennakrishnareddy, Hosahalli P. Hemantha
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi,
Bangalore University, Bangalore 560001, India
E-mail: sureshbabuvommina@rediffmail.com; E-mail: hariccb@hotmail.com; E-mail: hariccb@gmail.com
Received 15 June 2009
phosphate binders in water18 and in the design of mimics
Abstract: A practical synthesis of thiourea-linked peptidomimet-
of natural oligosaccharides.19
ics, glycosylated amino acids, and neoglycoconjugates is described
employing bis(benzotriazolyl)methanethione as thiocarbonylating
reagent. The entire protocol is mild, efficient, high-yielding, and
free from hazardous reagents. All the intermediates and products
have been isolated and fully characterized by 1H NMR, 13C NMR,
and mass spectrometry.
Among several strategies available for the synthesis of
thioureas, coupling of isothiocyanates with amines is the
most widely employed.20 Though the nucleophilic dis-
placement of a substituted halide with isothiocyanate ion
is another option, this suffers from the ambidentate nature
of the ion itself.21 Other methods such as the reaction of
CS2 with amines,22 H2S with substituted guanidines,23
treatment of an amine with triphenylphosphine thiocya-
nogen,24 and catalyst-driven decomposition of dithicarb-
amic salts have also been reported.25 Many of them
involve the use of the toxic reagents, generate unstable in-
termediates, and result in isolation and handling prob-
lems. On the other hand the use of several thiocarbonyl
transfer reagents such as 1-(methyldithiocarbonyl)imida-
zole,26 di-2-pyridyl thionocarbonate (DTP),27 1,1¢-(thio-
Key words: peptidomimetics, isothiocyanates, thioureidopeptides,
pseudoglycoconjugates
Peptidomimetics and glycomics are known to exhibit im-
proved therapeutical and biological properties.1 Their
ability to sustain enzymatic hydrolysis due to the presence
of unnatural linkages provides them with a longer shelf
life while the better solubility in the biological system
helps to deliver the desired drug action effectively.
Among various backbone modifications used, several
classes of pseudopeptides and neoglycoconjugates have
been reported by inserting urea,2 sulfonamide,3 phospora-
mide,4 carbamate5 functionalities and also several hetero-
cycles as native bond surrogates.6 Among them, the
ureidopeptides and oligoureas have received special inter-
est due to their significance in medicinal chemistry.7 Sim-
ilarly, the thioureido linkage has also received attention
because of its interesting biological as well as structural
aspects. The ability to provide hydrogen-bond donor and
acceptor points makes it an efficient anion receptor8 and it
serves as a building block in the construction of supramo-
lecular structures.9 A number of thioureido derivatives has
been reported to exhibit marked antiarrhythmic,10 antivi-
ral,11 and anticancer12 activities. Their utility as non-nu-
cleoside inhibitors of HIV-1, HIV-2 RT,13 antagonists for
the human NK1 tachykinin receptor,14 influenza virus,
and potential anti-TB therapeutic agents15 has also been
documented. The –NHCSNH– moiety has been widely
employed to bridge carbohydrates and related glycocon-
jugates,16 which are used in tailoring oligonucleoside an-
alogues. The thiourea moiety is the key structural element
in many organic catalysts being exploited in the asymmet-
ric synthesis in a wide variety of reactions.17 Furthermore,
thiourea-linked glycooligomers have been employed as
carbonyldioxy)dibenzotriazole,28
1,1¢-thiocarbonyldi-
2,2¢-pyridone,29 1,1¢-thiocarbonyldiimidazole30 are known.
Among them, bis(benzotriazolyl)methanethione (Bt-CS-
Bt, 1) stands out as the preferred reagent due to its ease of
preparation, stability, and efficient reaction with the nu-
cleophiles.31 Katritzky and co-workers have demonstrated
its applications in the preparation of diverse array of alkyl
and aryl thiocarbonyl benzotriazoles.31 These intermedi-
ates have been employed as isothiocyanate equivalents in
organic synthesis. However, to the best of our knowledge,
the application of this reagent in peptide and glycochem-
istry for the synthesis of thioureido derivatives has yet to
be demonstrated. In this letter, we report a simple and con-
venient protocol for the synthesis of thioureidopeptides,
thiourea-tethered glycosylated amino acids and neoglyco-
conjugates. The protocol employs a stepwise replacement
of each benzotriazolyl unit of 1 with a suitably protected
amino acid or carbohydrate derived amine.
The reagent 1 (Figure 1) was prepared by the reaction of
trimethylsilyl benzotriazole with thiophosgene employing
the reported procedure.30 The required trimethylsilyl de-
S
N
N
N
N
N
N
SYNLETT 2010, No. 5, pp 0715–0720
1
6.
3
.2
0
1
0
1
Advanced online publication: 18.02.2010
DOI: 10.1055/s-0029-1219393; Art ID: D16009ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Bt-CS-Bt

716
V. V. Sureshbabu et al.
LETTER
R2
R1
NH2
H2N
CO2Me
4
S
R2
PG-HN
R1
2
H
1
N
Bt
CH2Cl2, r.t.
12 h
Bt
N
H
CO2Me
PG-HN
S
3
5
3a: Nβ-Fmoc-Ile-ψ[NHCSBt], 112–114 °C, 89%
3b: Nβ-Fmoc-Leu-ψ[NHCSBt], 72–74 °C, 92%
5a: Bt-CS-Phe-OMe, 83–85 °C, 89%
5b: Bt-CS-Ala-OMe, 77–79 °C, 89%
3c: Nβ-Fmoc-Asp(Ot-Bu)-ψ[NHCSBt], 110–112 °C, 87%
3d: Nβ-Z-Leu-ψ[NHCSBt], 98–100 °C, 90%
3e: Nβ-Z-Cys(OBzl)-ψ[NHCSBt], 108–110 °C, 82%
3f: Nβ-Boc-Phe-ψ[NHCSBt], 126–128 °C, 91%
Scheme 1 Preparation of monosubstituted thiocarbonyl benzotrazoles
rivative was synthesized according to the Birkofer proce- solids and were fully characterized. They were found to be
dure.32 We initiated our studies on the synthesis of stable and storable at ambient temperature for long peri-
dipeptidomimetics 6 possessing both N- and C-terminals ods with out any decomposition.
as such peptidomimetics with N- and C-termini, similar to
the natural peptides, will enable further chain extensions/
modifications. For such molecular assembly, one of the
contributing amines has to be derived from an N-protected
In the next stage, isothiocyanate equivalents 3a–f and
5a,b were further substituted; accordingly, reaction of 3a
with b-alanine methyl ester in the presence of diisopropy-
lethyl amine (DIPEA) afforded the desired thiouredo
dipeptidomimetic 6a (Scheme 2). The N-Fmoc thioureido
peptides 6a–c were obtained as low melting solids; where-
amino acid through suitable carboxyl modification, and
the amino acid ester is an obvious choice as another part-
ner. Initially, for the synthesis of the required Nb-protect-
as the Boc- and Z-protected thioureoido peptides 6d–f
ed alkyl amine 2, the Na-Fmoc-amino acid was converted
were gummy compounds; all were fully characterized
to the corresponding alcohol by reduction of its mixed an-
spectroscopically.
hydride using NaBH4.33 The hydroxyl group was trans-
In the same manner, the reaction of valine methyl ester
ferred to azide moiety via the iodo intermediate under
with 5a and alanine methyl ester with 5b in the presence
Mitsunobu conditions employing Ph3P, imidazole, and
of DIPEA afforded unsymmetrical and symmetrical thio-
ureidopeptides 6g and 6h, respectively; while reaction of
2,3,4,6-tetra-O-acetyl-b-D-glucosyl-1-amine with Nb-
Boc-Phe-y[NH-CS-Bt] (3f) yielded thiourea-linked glyc-
osylated amino acid 6i in good yield and purity (Table 1).
Importantly, the above protocol was found to cause no ra-
cemization as confirmed through NMR studies.38
I2.34 On subjecting the Nb-Fmoc-alkyl azide to catalytic
hydrogenation employing Pd/C, the corresponding amine
2 was obtained in good yield and purity.35 In the case of Z-
chemistry, Nb-Z-protected amino acid derived alkyl azides
were reduced using Ph3P in refluxing THF.36 In a different
approach, the Boc counterparts were prepared by reducing
the Na-Boc-amino nitriles using LiAlH4.37
Sugar isothiocyanates constitute an important class of in-
termediates but the synthetic difficulties involved in the
preparation of glycosyl isothiocyanates are a major con-
cern in assembling a diverse array of thiourea-linked car-
bohydrate derivatives.39 Hence, we prepared sugar
isothiocyanate equivalent 8 by replacing one Bt group of
1 with amino sugar 7 (Scheme 3). O-Protected sugar-1-
amines 7 were prepared from glucose, galactose, and lac-
tose through established protocols using acetyl or benzoyl
groups for hydroxyl protection.40 The masked sugar
isothiocyanates 8a–d from both monosaccharides and dis-
accharides were isolated in good yield after a simple
workup and were characterized spectroscopically
(Scheme 3). Subsequent reaction of these derivatives 8
with amino sugars in the presence of DIPEA yielded sym-
metrical and unsymmetrical thioureido neoglycoconju-
In the following step towards 6, we undertook tandem nu-
cleophillic replacement of the Bt groups of 1 with the
amines in hand. Thus, a reaction of Nb-Fmoc/Boc/Z-ami-
no alkyl amine 2 with Bt-CS-Bt at room temperature
yielded the corresponding monosubstituted thiocarbonyl
benzotriazoles 3 in yields greater than 80% (Scheme 1).
Employing a similar approach, an amino acid ester 4 was
reacted with 1 to afford monosubstituted thiocarbonyl
benzotriazoles 5. Isolating monosubstituted compounds 3
and 5, which can be further utilized in the synthesis of un-
symmetrical thioureas, is possible because replacement of
the first Bt moiety by a nucleophile takes place readily at
room temperature whereas the second Bt group gets re-
placed by another nucleophile only in the presence of a
base. All derivatives 3 and 5 were isolated as crystalline
R1
R3
H
H
DIPEA, CH2Cl2
r.t.
N
N
CO2Me
+
PG-HN
CO2Me
3
H2N
S
R3
6
PG = Fmoc, Boc, Z
3 = H, Me, i-Pr, t-Bu
R
Scheme 2 Nb-Fmoc/Boc/Z-protected thioureido peptides
Synlett 2010, No. 5, 715–720 © Thieme Stuttgart · New York

LETTER
Synthesis of Thioureido-Linked Peptidomimetics
717
Table 1 Characteristic Data for Thiourea-Linked Peptidomimetics
S
X
Y
Compd 6
X
Y
Mass (Calcd, Found)a
506.2089, 506.2079
Yield (%)
H
N
6a
87
H
N
CO2Me
FmocHN
H
N
6b
6c
6d
520.2246, 520.2241
606.2614, 606.2618
418.1776, 418.1781
92
85
90
CO2Me
CO2Me
H
N
FmocHN
FmocHN
CO2t-Bu
H
N
H
N
H
N
H
N
CO2Me
CO2Me
ZHN
ZHN
H
N
S
Bzl
6e
6f
554.2123, 554.2119
418.1776, 418.1776
86
85
H
N
H
N
CO2Me
H
N
BocHN
O
H
N
O
O
H
MeO
N
6g
6h
375.1354, 375.1351
271.0728, 271.0720
662.2359, 662.2355
83
87
79
OMe
O
H
N
H
N
MeO
OMe
NHBoc
OAc
N
H
6i
AcO
AcO
O
H
N
OAc
a Mass = HRMS.
gates 10a–c, which were isolated and recrystallized using corresponding thiourea-tethered glycosylated amino acid
CH2Cl2–hexane before being fully characterized conjugates 11a–d as solids in 85–90% yields (Scheme 3,
(Table 2).
Table 2).43
It is known from the literature that the molecules bearing In summary, we report the synthesis of thioureido-linked
b-amino-L-alanine unit have acquired profound biological peptidomimetics, neoglycosylated amino acids, and
and synthetic interest and are present in several natural pseudoglycoconjugates by employing bis(benzotriaz-
products of therapeutic significance.41 Na-Cbz-b-amino- ole)methanethione as the thiocarbonyl transfer reagent.
L-alanine methyl ester (9) was synthesized through The stepwise replacement of each Bt group of the reagent
Hoffmann rearrangement of L-Asn using iodosobenzene 1 with an appropriate amine has resulted in thiourea-
diacetate (PIDA) as reported by Zhang et al.42 The result- linked products. The method obviates the use of hazard-
ing free g-amine was reacted with various O-protected ous reagents and handling problems. All the monosubsti-
glycosylamino thiocarbonyl benzotriazoles 8 to afford the tuted thiocarbonyl benzotriazoles and thioureas have been
Synlett 2010, No. 5, 715–720 © Thieme Stuttgart · New York

718
V. V. Sureshbabu et al.
LETTER
OR
R2
H
H
O
R1
RO
N
N
Sugar
OR
OR
R2
R2
OR
DIEA
2
S
H
O
R1
RO
1
O
R1
RO
N
Bt
10
NH2
OR
R2
CH2Cl2
OR
OR
S
H2N
H
H
8
O
7
R1
RO
N
N
8a: R = Ac, R1 = OAc, R2 = H; mp = 116–118 °C; Yield = 79%
8b: R = Ac, R1 = Gal, R2 = H; mp = 82–84 °C; Yield = 67%
8c: R = Bz, R1 = H, R2 = OBz; mp = 72–74 °C; Yield = 75%
8d: R = Bz, R1 = Gal, R2 = H; mp = 84–86 °C; Yield = 72%
OR
ZHN
CO2Me
S
ZHN
9
CO2Me
11
Scheme 3 Preparation of pseudoglycoconjugates and neoglycosylated amino acids
Table 2 Characterization Data of Pseudoglycoconjugates and Neoglycosylated Amino Acids
Compd 10 and 11 Pseudoglycoconjugates/neoglycosylated amino acids
Mp (°C)
Mass (Calcd, Found)a
759.1895, 759.1891
Yield (%)
OAc
OAc
H
N
H
N
10a
10b
113
81
89
O
AcO
BzO
AcO
AcO
OAc
OAc
O
OAc
S
OAc
OBz
BzO
H
N
H
N
115
116
1007.2521, 1007.2518
1047.2740, 1047.2735
O
AcO
AcO
O
OBz
OAc
S
OAc
OAc
AcO
AcO
OAc
10c
O
80
H
N
H
N
O
AcO
OAc
OAc
O
O
AcO
OAc
OAc
S
OAc
NHCbz
CO2Me
H
N
H
11a
11b
68
96
664.1788, 664.1785
912.2414, 912.2409
88
79
O
AcO
N
AcO
OAc
S
OBz
OAc
BzO
BzO
NHCbz
CO2Me
H
N
H
O
N
OBz
S
OAc
AcO
AcO
NHCbz
CO2Me
11c
90
94
952.2633, 952.2638
81
76
O
H
N
H
O
O
N
AcO
OAc
OAc
S
S
OBz
OBz
BzO
BzO
NHCbz
CO2Me
11d
O
1386.3729, 1386.3719
H
N
H
O
O
N
BzO
OBz
OBz
a Mass = HRMS.
isolated and well characterized. The protocol is simple
and efficient giving quantitative yields in all the steps.
References and Notes
(1) (a) Synthesis of Peptides and Peptidomimetics (Houben-
Weyl), Vol. E22c; Goodman, M.; Felix, A.; Moroder, L.;
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J. Org. Chem. 2006, 71, 7697; and references cited therein.
Acknowledgment
We thank the Department of Science and Technology, New Delhi,
for financial assistance (grant No. SR/S1/OC-26/2008). GC thanks
Council of Scientific and Industrial Research, New Delhi for awar-
ding SRF.
Synlett 2010, No. 5, 715–720 © Thieme Stuttgart · New York

LETTER
Synthesis of Thioureido-Linked Peptidomimetics
719
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(43) General Procedure for the Preparation of 3, 5, or 8
To a solution Nb-Fmoc/Boc/Z-amino alkyl amine 2 (1.0
mmol), amino acid ester 4, and O-protected b-glycosyl
amine 7 (1.0 mmol) in CH2Cl2 (10 mL), Bt-CS-Bt 1 (1.0
mmol) was added at r.t., and the reaction mixture was stirred
overnight. After the completion of reaction (as monitored by
TLC), it was diluted with CH2Cl2, the organic layer was
washed with 10% NaHCO3 (to remove benzotriazole
byproduct), brine, and dried over anhyd Na2SO4. The solvent
was removed under reduced pressure to afford 3, 5, or 8
which were recrystallized from CH2Cl2–n-hexane.
General Procedure for the Preparation of 6a–i, 10a–c,
and 11a–d
To a stirring solution of 3, 5, or 8 (1.0 mmol) in CH2Cl2 (10
mL) was added amino-free amino acid ester (1.0 mmol), or
O-protected b-glycosyl amine (1.0 mmol), or Na-Cbz-b-
amino-L-alanine methyl ester (1.0 mmol) followed by the
addition of DIPEA (1.0 mmol) at r.t. The mixtrue was stirred
for about 5–6 h until completion (TLC analysis). The solvent
was removed in vacuo, and the residue was taken into
EtOAc. The organic layer was washed with 10% citric acid
solution, NaHCO3 (10%) solution, brine, and dried over
anhyd Na2SO4. The solvent was removed under reduced
pressure and the residue recrystallized from CH2Cl2–
n-hexane to afford the title compounds.
(23) Dogadkin, B. A.; Pavlov, N. N. Dokl. Akad. Nauk. SSSR
1961, 138, 1111.
(24) Tamura, Y.; Adachi, M.; Kawasaki, T.; Kita, Y. Tetrahedron
Lett. 1978, 19, 1753.
(25) Wong, R.; Dolman, S. J. J. Org. Chem. 2007, 72, 3969.
(26) Mohanta, P. K.; Dhar, S.; Samal, S. K.; Ila, H.; Junjappa, H.
Tetrahedron 2000, 56, 629.
(27) Kim, S.; Yi, K. Y. Tetrahedron Lett. 1985, 26, 1661.
(28) Chang, H.; Kim, S. Bull. Korean Chem. Soc. 1986, 7, 407.
(29) Kim, S.; Yi, K. Y. J. Org. Chem. 1986, 51, 2613.
Fmoc-b-Ile-y[NH-CS-NH]-b-Ala-OMe (6a)
1H NMR (400 MHz, CDCl3): d = 0.83–0.96 (m, 6 H), 1.25
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V. V. Sureshbabu et al.
LETTER
(m, 2 H), 2.00 (m, 2 H), 2.35 (t, J = 8.0 Hz, 2 H), 3.37 (t,
J = 8.0 Hz, 2 H), 3.56 (s, 3 H), 3.67 (m, 2 H), 3.81 (m, 1 H),
4.18 (m, 1 H), 4.37 (m, 2 H), 5.35 (br, 1 H), 6.84 (br, 1 H),
7.31–7.76 (m, 8 H). 13C NMR (100 MHz, CDCl3): d = 12.1,
15.9, 25.8, 30.9, 33.9, 37.8, 40.1, 47.6, 52.3, 56.4, 67.5,
125.6, 125.7, 127.6, 128.2, 141.7, 144.2, 158.0, 173.5, 183.1
HRMS: m/z calcd for C26H33N3O4S: 506.2089 [M + Na];
found: 506.2079 [M + Na].
[M + Na]; found: 375.1351 [M + Na].
Compound (11b)
1H NMR (300 MHz, CDCl3): d = 2.05 (br, 1 H), 3.64 (s, 3
H), 3.93 (m, 1 H), 4.18 (m, 1 H), 4.41 (m, 2 H), 4.51 (m, 2
H), 5.06 (m, 3 H), 5.64 (s, 2 H), 5.96 (br, 1 H), 7.14–8.01 (m,
25 H). 13C NMR (100 MHz, CDCl3): d = 53.6, 53.8, 62.7,
68.0, 69.7, 69.9, 71.9, 72.3, 77.8, 83.3, 128.2, 128.8, 128.9,
129.0, 129.2, 129.4, 130.4, 130.5, 131.1, 133.6, 133.9,
134.2, 134.4, 136.1, 157.2, 165.9, 166.5, 168.2, 168.9.
171.2, 183.2. HRMS: m/z calcd for C47H43N3O13S: 912.2414
[M + Na]; found: 912.2409 [M + Na].
Z-b-Cys(BzI)-y[NH-CS-NH]-b-Leu-OMe (6e)
1H NMR (400 MHz, CDCl3): d = 0.98 (d, J = 6.8 Hz, 6 H),
1.23 (m, 2 H), 1.76 (m, 1 H), 2.40 (m, 2 H), 2.53–2.67 (m, 2
H), 3.35 (m, 1 H), 3.47 (m, 1 H), 3.77 (m, 3 H), 3.89–3.99
(m, 4 H), 5.04 (s, 2 H), 5.04 (s, 2 H), 5.30 (br, 1 H), 7.23–
7.33 (m, 10 H). 13C NMR (100 MHz, CDCl3): d = 21.9, 22.6,
23.0, 25.2, 34.1, 36.9, 44.5, 44.6, 49.6, 55.4, 55.6, 67.3,
127.7, 128.4, 128.6, 128.9, 129.6, 136.9, 137.1, 138.1,
156.7, 175.1, 183.8: HRMS: m/z calcd for C27H37N3O4S2Na:
554.2123 [M + Na]; found: 554.2119 [M + Na]
Compound (11d)
1H NMR (300 MHz, CDCl3): d = 2.06 (br, 1 H), 3.64 (s, 3
H), 3.87 (m, 1 H), 4.42–4.49 (m, 3 H), 4.62–4.66 (m, 5 H),
4.82 (m, 1 H), 5.00–5.04 (m, 3 H), 5.17 (m, 1 H), 5.41 (m, 3
H), 5.61 (m, 1 H), 5.70 (m, 1 H), 5.93–5.98 (m, 2 H), 7.20–
8.08 (m, 40 H). 13C NMR (100 MHz, CDCl3): d = 50.1, 53.5,
56.1, 63.2, 67.8, 68.5, 69.9, 70.5, 71.5, 71.9, 72.1, 73.0, 73.1,
75.2, 82.6, 102.1, 119.0, 119.1, 119.6, 120.1, 120.4, 120.7,
121.1, 121.4, 127.7, 127.8, 127.9, 128.2, 128.3, 128.4,
128.8, 129.1, 129.5, 130.3, 130.4, 130.5, 131.1, 131.3,
132.0, 132.3, 133.9, 134.4, 136.5, 137.1, 137.2: 157.6,
170.1, 170.2, 170.4, 170.9, 171.0, 171.3, 171.7, 171.9,
183.1. HRMS: m/z calcd for C74H65N3O21S: 1386.3729 [M +
Na]; found: 1386.3719 [M + Na].
OMe-Phe-[NH-CS-NH]-Val-OMe (6g)
1H NMR (400 MHz, CDCl3): d = 0.95 (d, J = 7.6 Hz, 6 H),
2.23 (m, 1 H), 3.12 (m, 2 H), 3.34 (m, 1 H), 3.67 (s, 3 H),
3.76 (s, 3 H), 3.83 (m, 1 H), 6.80 (br, 1 H), 7.10–7.32 (m, 5
H). 13C NMR (100 MHz, CDCl3): d = 18.4, 18.5, 30.5, 37.1,
52.2, 52.6, 60.1, 64.2, 126.8, 127.5, 129.4, 136.3, 168.8,
173.1, 183.4. HRMS: m/z calcd for C17H24N2O4S: 375.1354
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