New approach to oligotriazoles using a cobalt complex of propargyl azides as a synthetic component

Article abstract of DOI:10.1016/j.tetlet.2011.04.082

We have developed an efficient method for preparation of triazolamers using a dicobalt hexacarbonyl complex of propargyl azides (CPA) as a synthetic component. Several types of CPAs possessing the side chains found in the natural amino acids were prepared

Full text of DOI:10.1016/j.tetlet.2011.04.082

Tetrahedron Letters 52 (2011) 3358–3360
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Tetrahedron Letters
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New approach to oligotriazoles using a cobalt complex of propargyl
azides as a synthetic component
⇑
Yuichi Tsukada, Kohei Yamada, Munetaka Kunishima
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an efficient method for preparation of triazolamers using a dicobalt hexacarbonyl
complex of propargyl azides (CPA) as a synthetic component. Several types of CPAs possessing the side
chains found in the natural amino acids were prepared by Nicholas reaction as well as by a reaction of
propargyl azides with dicobalt octacarbonyl. Triazolamers with both amino and carboxyl termini were
readily synthesized by repetitive reaction sequence involving a copper-catalyzed 1,3-dipolar cycloaddi-
tion followed by an oxidative deprotection.
Received 25 March 2011
Revised 15 April 2011
Accepted 20 April 2011
Available online 27 April 2011
Keywords:
Oligotriazole
Ó 2011 Elsevier Ltd. All rights reserved.
Peptidomimetic
Click chemistry
Cobalt alkyne complex
Nicholas reaction
According to the recent developments of Cu(I)-catalyzed azide-
alkyne 1,3-dipolar cycloaddition (CuAAC) as the most useful liga-
tion process in click chemistry,1,2 a variety of compounds with
1,4-disubstituted 1,2,3-triazole backbone have been synthesized.3
The 1,2,3-triazole linkage has been revealed to be a promising
amide bond surrogate, particularly with respect to its structure
and hydrogen-bonding ability, while it shows a higher chemical
and biological stability in comparison with the amide bonds.4 Thus,
it is now of great interest to elucidate the effects of replacement of
an amide bond with a 1,2,3-triazole ring on the secondary struc-
ture as well as on the bioactivities in a wide range of amides.
Recently, Angelo and Arora introduced a new class of oligotriazole
as a peptidomimetic, named tirazolamer, in which the triazole
rings and the sp3-hybridized carbons possessing amino acid side
chains are alternately connected. They indicated that optically
active trimeric and tetrameric triazolamers adopt zigzag confor-
the silyl group prevents the propargyl azides from self-polymeriza-
tion by CuAAC reaction, extension of a triazolic chain can be at-
tained by a two-step iterative reaction sequence involving CuAAC
reaction and desilylation. In this Letter, we wish to report a new
approach to the synthesis of triazolamers utilizing a dicobalt hexa-
carbonyl complex of propargyl azides (CPA) as
component.
a
synthetic
R
R
H
N
CO2H
R n
peptide
H2N
N
CO2H
R n
H2N
N N
O
triazolamer
Alkynes are known to readily react with dicobalt octacarbonyl
by simple mixing to the formation of alkyne–dicobalt hexacar-
bonyl complex, which can undergo oxidative degradation to liber-
ate the alkynes.7 Thus, if the alkyne–cobalt complexes are inert to
CuAAC, chain extension of triazolamers can be accomplished by
only a repetition of CuAAC and oxidative deprotection of alkynes.
Variety of CPAs can be readily prepared from not only propargyl
azide with dicobalt octacarbonyl, but also propargyl alcohols or
alk-3-en-1-yne compounds by Nicholas reaction via the alkyne–
cobalt complexes.7,8
mations and show
a potential inhibitory activity of HIV-1
protease.5
Their synthetic method for preparation of triazolamer employs
N-Boc propargylamines derived from amino acids as a synthetic
component and involves a three-step iterative reaction sequence;
diazotransfer to amines, CuAAC reaction of the resulting azides
with N-Boc propargylamines, followed by deprotection of the ami-
nes.5a On the other hand, Hughes and co-workers described a more
convenient synthesis of triazolamers employing propargyl azide
possessing a trialkylsilyl group at the acetylenic terminal.6 Since
We employed several types of CPA possessing a substituent (R)
corresponding to the side chain of the natural amino acids. As we
had expected, CPAs (2a–f) were readily prepared from the corre-
sponding propargyl alcohols (1a–f) by Nicholas reaction using
⇑
Corresponding author. Tel./fax: +81 76 264 6201.
E-mail address: kunisima@p.kanazawa-u.ac.jp (M. Kunishima).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.082

Y. Tsukada et al. / Tetrahedron Letters 52 (2011) 3358–3360
3359
ole 4a in 76% yield.11 The second reaction cycle was carried out
on the resulting 4a using various types of CPA 2a–g under the same
conditions, and bis(triazoles) 5 with various substituents were ob-
tained in reasonable yields. The final elongation of 5 with methyl
azidoacetate 6 gave tris(triazoles) 7 in good yields.
Table 1
Preparation of CPA 2 by Nicholas reaction
1) CO2(CO)8 (1.2 eq)
CH2Cl2, rt, 2 h
R
R
Co2(CO)6
N3
HO
Epimerization at the asymmetric
a-carbon of the carbonyl
2) BF3-OEt2 (1.1 eq),
TMSN3 (2.0 eq)
CH2Cl2, 0°C
groups of peptide bonds has been a major challenge in peptide syn-
thesis, as seen in its history. Thus, it is essential to employ syn-
CPA: 2a
–
f
1a–
f
thetic methods free form racemization at the
a-carbon in
preparation of peptides. Since the same thing holds true for prep-
aration of chiral triazolamers, we examined the possibility that our
synthetic method is accompanied by epimerization at the asym-
CPA (2)
R
Reaction timea (h)
Yieldb (%)
2a
2b
2c
2d
2e
2f
H
Me
i-Bu
Bn
CH2OAc
CH2CH2COOMe
10
6
3
16
8
5
81
78
88
79
71
86
metric a-carbon between two triazoles and/or at the propargyl car-
bon of CPA. As shown in Scheme 2, by using (S)-2d,12,13 whose
enantiomeric purity was 92% ee, we synthesized triazole 4d and
bis(triazole) 8 in 79% and 75% yield, respectively. Both of them
a
The reaction time of the second step.
Yields from 1.
b
1) TFA, CH2Cl2
2) Co2(CO)8, CH2Cl2
3) TfN3, CuSO4, K2CO3
TMSN3 and BF3-Et2O (Table 1).9 Since 2g (R = CH2CH2SMe) possess-
ing the side chain of methionine was found to be difficult to syn-
thesize by the same method presumably due to the high
nucleophilicity of sulfide group, it was prepared in a stepwise fash-
ion from 1g in 61%; mesylation of the hydroxyl group 1g, nucule-
ophilic substitution with sodium azide, followed by complexation
with Co2(CO)8. (Eq. 1)
CH2Cl2/MeOH/H2O
Co2(CO)6
BocHN
92% ee
N3
(S)-2d
89% yield (3 steps)
92% ee
1) (S)-2d
CuSO4-5H2O
SMe
1) MsCl, Et3N, CH2Cl2
SMe
Sodium L-ascorbate
CH2Cl2/H2O (1 : 1)
O
O
2) NaN3, DMSO
N
H
N
H
N
Co2(CO)6
ð1Þ
3) Co2(CO)8, CH2Cl2
N3
N N
4d
HO
2) CAN, MeOH
3
1g
2g
61% yield (3 steps)
79% yield
92% ee
We designed triazolamers possessing both amino and carboxyl
groups on their termini to mimic the structure of peptide chains
(Scheme 1). The CuAAC reaction between 2a and N-benzoylpropar-
gylamine 3 was attempted under several conditions according to
literatures,2b,10 and the best yield of 4a was obtained by using
1) 2a
CuSO4-5H2O
Sodium L-ascorbate
CH2Cl2/H2O (1 : 1)
O
N
H
N
N
N N
N N
2) CAN, MeOH
CuSO4 and sodium L-ascorbate in a heterogeneous mixed solvent
8
of dichloromethane and water (1:1).10a The crude reaction mixture
obtained by CuAAC was directly treated with ceric ammonium ni-
trate (CAN) for deprotection of the alkyne followed by purification
by column chromatography to give the corresponding monotriaz-
75% yield
92% ee
Scheme 2.
_
1) 2a (1.1 equiv)
CuSO4-5H2O
1) 2a g (1.1 equiv)
CuSO4-5H2O
Sodium L-ascorbate
Sodium L-ascorbate
CH2Cl2/H2O (1 : 1)
O
O
O
N
R
CH2Cl2/H2O (1 : 1)
2) CAN, MeOH
N
H
N
H
N
N
N
H
N N
N N
N N
2) CAN, MeOH
3
4a (76%)
5a: R = H (67%)
5b: R = Me (68%)
5c: R = i-Bu (76%)
5d: R = Bn (75%)
N3 CO2Me
6 (1.1 equiv)
5e: R = CH2OAc (66%)
O
N
R
5f: R = CH2CH2COOMe (70%)
5g: R = CH2CH2SMe (72%)
N
N
N
CO2Me
H
N N
N N
N N
CuSO4-5H2O
Sodium L-ascorbate
CH2Cl2/H2O (1 : 1)
7a: R = H (72%)
7b: R = Me (78%)
7c: R = i-Bu (86%)
7d: R = Bn (90%)
7e: R = CH2OAc (69%)
7f: R = CH2CH2COOMe (82%)
7g: R = CH2CH2SMe (83%)
Scheme 1.

3360
Y. Tsukada et al. / Tetrahedron Letters 52 (2011) 3358–3360
6. Montagnat, O. D.; Lessene, G.; Hughes, A. B. Tetrahedron Lett. 2006, 47, 6971–
6974.
7. Nicholas, K. M.; Pettit, R. Tetrahedron Lett. 1971, 12, 3475–3478.
8. Teobald, B. J. Tetrahedron 2002, 58, 4133–4170.
9. Gómez, A. M.; Uriel, C.; Valverde, S.; López, J. C. Org. Lett. 2006, 8, 3187–3190.
10. (a) Lee, B.-Y.; Park, S. R.; Jeon, H. B.; Kim, K. S. Tetrahedron Lett. 2006, 47, 5105–
5109; (b) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.; Voit, B.;
Pyun, J.; Fréchet, J. M. J.; Sharpless, K. B.; Folkin, V. V. Angew. Chem., Int. Ed.
2004, 43, 3928–3932; (c) Li, Y.; Huffman, J. C.; Flood, A. H. Chem. Commun.
2007, 26, 2692–2694; (d) Lee, J. W.; Kim, B.-K.; Kim, J. H.; Shin, W. S.; Jin, S.-H. J.
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8376–8382.
exhibited exactly the same enantiomeric purity as 2d (92% ee),
indicating that no epimerization took place during a series of reac-
tions for preparing triazolamers in the present procedure.
In conclusion, we have demonstrated a new strategy for the
synthesis of triazolamer using CPAs 2 as a monomeric synthetic
component. The cobalt complex has two different roles in our
method; one is the protection of alkynes, and the other is the
essential activating group for Nicholas reaction to prepare CPAs,
in part. The chain extension of triazolamer is conveniently attained
without racemization by iteration of reaction sequence of CuAAC
and oxidative deprotection. Further applications of our method
for preparation of various oligotriazoles are currently under
investigation.
11. General procedure for chain extension by use of CPA. Preparation of 5d as a typical
example. To
0.550 mmol) in CH2Cl2 (1.00 mL) were added an aqueous solution of
CuSO4ꢀ5H2O (0.200 M, 0.50 mL) and an aqueous solution of sodium
a solution of 4a (120 mg, 0.500 mmol) and 2d (251 mg,
L
-
ascorbate (1.3 M, 0.50 mL). The resulting solution was stirred for 1.5 h at
room temperature, and was diluted with CH2Cl2 and H2O. The organic layer
was separated and washed with brine, dried over Na2SO4, and concentrated
under vacuum. The crude mixture was dissolved in MeOH (5.0 mL) followed by
addition of CAN (1.51 g, 2.75 mmol), and then stirred for 5 min at room
temperature. The reaction mixture was extracted with CH2Cl2, and the
combined organic layers were washed with water, brine, dried over Na2SO4,
and concentrated under vacuum. The residue was purified by flash column
chromatography (hexane/EtOAc, 2:8) to give 5d (155 mg, 75% yield) as a white
solid. mp 168–170 °C. 1H NMR (400 MHz, CDCl3) d 7.81–7.76 (m, 2H), 7.67 (s,
1H), 7.56 (s, 1H), 7.54–7.39 (m, 3H), 7.25–7.19 (m, 3H), 7.04–6.98 (m, 2H), 6.85
(br s, 1H), 5.66 (ddd, J = 2.3, 5.5, 7.1 Hz, 1H), 5.60 (s, 2H), 4.72 (d, J = 5.5 Hz, 2H),
3.38 (dd, J = 5.5, 13.7 Hz, 1H), 3.34 (dd, J = 7.1, 13.7 Hz, 1H), 2.64 (d, J = 2.3 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 167.3, 144.9, 141.0, 134.0, 133.9, 131.7,
129.5, 128.6, 128.5, 127.7, 127.0, 122.6, 122.3, 77.8, 77.2, 54.1, 45.4, 42.8, 35.4;
HR-MS m/z for C23H22N7O (M+H)+, calcd 412.1886, found 412.1876; IR (CHCl3)
References and notes
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