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Carbohydrate-based Cu(I) stabilizing ligands and their use in the synthesis of carbohydrate–ferrocene conjugates
Accepted Manuscript Note Carbohydrate-based Cu(I) stabilizing ligands and their use in the synthesis of carbohydrate-ferrocene conjugates Magnus S. Schmidt, Kim Leitner, Moritz Welter, Markus Ringwald PII: DOI: Reference:
S0008-6215(14)00020-2 http://dx.doi.org/10.1016/j.carres.2014.01.005 CAR 6645
To appear in:
Carbohydrate Research
Received Date: Revised Date: Accepted Date:
31 October 2013 10 December 2013 8 January 2014
Please cite this article as: Schmidt, M.S., Leitner, K., Welter, M., Ringwald, M., Carbohydrate-based Cu(I) stabilizing ligands and their use in the synthesis of carbohydrate-ferrocene conjugates, Carbohydrate Research (2014), doi: http://dx.doi.org/10.1016/j.carres.2014.01.005
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Carbohydrate-based Cu(I) stabilizing ligands and their use in the synthesis of carbohydrate-ferrocene conjugates. Magnus S. Schmidt,*[a] Kim Leitner,[b] Moritz Welter,[b] and Markus Ringwald[c] *[a]
Corresponding author, Head of R&D, MCAT GmbH, Hermann-von-Vicari-Str. 23, 78464 Konstanz, Germany; Tel.: (+49) 174-2465904; Fax: (+49) 7531-939098; Email: [email protected]; Homepage: http://www.mcat.de
[b]
Department of Chemistry, University of Konstanz E-mail: [email protected] E-mail: [email protected]
[c]
CEO, MCAT GmbH, Hermann-von-Vicari-Str. 23, 78464 Konstanz E-mail: [email protected]
1
Abstract: A series of carbohydrate-ferrocene conjugates have been synthesized by copper(I)-catalyzed cycloaddition of carbohydrate-azides and ethynylferrocene (CuAAC). Newly carbohydratebased tris-triazoles have been used as Cu(I) stabilizing ligands and showed at least comparable, in some cases even better results compared to the use of tris(benzyltriazolylmethyl)amine (TBTA).
Keywords: click chemistry; carbohydrates; ferrocene; glycoconjugates; Cu(I) stabilizing ligands
2
1 Introduction By now the regiospecific copper(I)-catalyzed cycloaddition of azides and alkynes (CuAAC)[1,2] is a widely used synthetic tool and finds application in a wide range of scientific fields.[3-7] In this context, tris-triazoles such as tris(benzyltriazolylmethyl)amine (TBTA) 1 have been shown to be powerful additives, which stabilize copper(I) and increase its catalytic activity. [8,9] In the meantime a series of different tris-triazoles and other Cu(I) stabilizing ligands have been reported, such as different derivatives of TBTA 1a[10] and 1b[11], watersoluble ethylene glycol-based analogues 2 and 3 [11] and the bathophenanthroline 4,[12] (Scheme 1)
R
N N N
H
N
O
N 4N N
3 1 R = H (TBTA) 1a R = COOH 1b R = CH2(OCH2CH2)4OCH3
H
O
N 4N N
N 3
2
2 N
NH
3 N
4 HO3S AcO AcO AcO
SO3H
OAc O
N
N
O
O
N
AcO AcO
N N
3
5
OAc O
O NHAc
O
N
N N 3
6
Scheme 1: copper(I)-stabilizing ligands. Carbohydrate-ferrocene conjugates have been shown to be interesting compounds; the combined chemical properties of the conjugated partners result in possible uses, which are not amenable to carbohydrates or ferrocenes by themselves. Orvig et.al., for example, reported a series of carbohydrate-ferrocene conjugates which displayed high antimalarial activity.[13] 3
Other recent studies concern electrochemical,[14-17] biological and bioorganic[15,16] properties of carbohydrate-ferrocene conjugates. 2 Results and Discussion In order to investigate alternative copper(I)-stabilizing ligands based on carbohydrate-azides, we have explored the use of two carbohydrate-based tris-triazoles, TManTA 5 and TGlcNAcTA 6, as ligands in the synthesis of a series of carbohydrate-ferrocene conjugates. To evaluate the catalytic activity of compounds 5 and 6, we chose the reaction of five different azido-sugars with ethynylferrocene (Scheme 2) and compared the results with the activity of TBTA 1 and with the reaction without any tris-triazole. AcO AcO AcO
N3 O 7
AcO AcO AcO
AcO AcO AcO
OAc
O 8
N3
OAc O O
OAc
AcO AcO O
N3 O
AcO AcO 9
OAc
OAc Fe
OAc O
O NHAc
N3
12 N3
11
10
Scheme 2: used starting materials. All reactions were performed in DCM/MeOH/H2 O 10:10:3, 0.04 equiv. CuSO4, 0.2 equiv. sodium ascorbate and 0.01 equiv. of the respective tris-triazole were added to the azide/alkyne solution. The reaction mixture was stirred at 60°C for one hour; in some cases we investigated also longer reaction times. Table 1 shows the results of the experiments. The CuAAC reaction of 7-11 with ethynylferrocene (12) resulted in the formation of 13-17 (Scheme 3). All carbohydrate-ferrocene conjugates were monitored by TLC and the isolated products were analyzed by NMR, mass spectrometry and elemental analysis. In their 1HNMR spectra all triazole products showed singlets around δ = 7.9-7.5 ppm (triazole proton) as well as the characteristic doublet of the anomeric proton around δ = 6.33-6.55 ppm (2-, or 6triazolesugars 13-15) or at δ = 4.5-4.9 (glycosides 16 and 17). The protons of the
4
unsubstituted Cp ring appears for all compounds between δ = 4.0 and 4.1 ppm. In 13C-NMR spectra the characteristic triazole carbons appear between δ = 146 and 148 ppm and δ = 118 and 121 ppm. As expected, addition of tris-triazoles in catalytic amounts leads to much higher yields. While the reactions of 7 and 8 with ethynylferrocene (12) in the presence of all tris-triazoles studied lead to comparable yields of 90 % or higher, we observed significantly higher yields for the use of carbohydrate-based tris-triazoles in the reactions of 9, 10 and 11 with ethynylferrocene 12 compared to the use of TBTA 1. The most significant differences were observed in the reaction of 9 with 12, which showed the lowest yields after 1h at 60°C in the presence of TBTA 1. The use of TGlcNAcTA 6 leads to a yield higher by 50 %; use of TManTA 5 even leads nearly to a doubling of the yield compared to the use of TBTA 1.
O
Fe
N3 7-11
12
CuSO4, Na-ascorbate tris-triazole (1,5,6,-) DCM/MeOH/H2O 60°C, 1h
N AcO
N N O
AcO AcO 13 AcO AcO AcO
N
Fe
OAc
N 14
N 2
N
N N ON
AcO AcO Fe
OAc
OAc O O
O
13-17
N
OAc
N N
Fe
OAc O
AcO AcO
Fe
N
OAc O
AcO AcO
O
N
N N
HNAc
N
17
16
Fe Fe
Scheme 3: carbohydrate-ferrocene conjugates.
5
OAc
15
Table 1: reactions and results.
Azide 7
8
9
10
11
Cu(I)-ligand none 5 TBTA 6 none 5 TBTA 6 none 5 TBTA 6 none 5 TBTA 6 none 5 TBTA 6
conditions 60°C for 1h
60°C for 1h
60°C for 1h 60°C for 1h 60°C for 2h 60°C for 1h 60°C for 1h 60°C for 1h
60°C for 1h
Yield (%) 26 95 93 93 36 92 89 94 9 42 79 23 35 29 94 81 91 33 89 78 91
product 13
14
15
16
17
In summary, we have shown that the use of commercially available carbohydrate-based tristriazoles 5 and 6 leads at least to comparable or to higher yields than the use of TBTA 1 in the synthesis of different carbohydrate-ferrocene conjugates. Interestingly, the use of TManTA 5 leads to the highest yields in reactions with mannose-based azides, whereas the use of TGlcNAc 6 leads to somewhat higher yields in reactions with GlcNAc/glucosamine-based azides.
3 Experimental Section 3.1 General Methods TLC was carried out on Silica Gel 60 F254 (Merck, layer thickness 0.2 mm) with detection by UV light (254 nm) and/or by charring with 15% sulfuric acid in ethanol. Flash column chromatography (FC) was performed on Merck Silica Gel 60 (0.040–0.063 mm). 1H NMR and 13C NMR spectra were recorded on Bruker Avance II 400. Chemical shifts are reported in ppm relative to solvent signals (CDCl3: δH = 7.26 ppm, δC = 77.0 ppm; DMSO-d6: δH =
6
2.49 ppm, δC = 39.7 ppm; CD3OD: δH = 4.78 ppm, δC = 49.3 ppm). Signals were assigned by first-order analysis andassignments were supported, where feasible, by two-dimensional 1H, 1H and 1H, 13C correlation spectroscopy. 3JH–H and 1JH–C coupling constants are reported in Hz. Mass spectra were recorded on a Finnigan MAT8200 spectrometer. Elemental analysis was performed on an elementar CHNS vario EL instrument. All azido-compounds and tris-triazoles are commercially available (from MCAT www.mcat.de order numbers tris-triazoles: MC 9292 (TManTA) and MC 9293 (TGlcNAcTA)); all other chemicals and reagents were purchased from Acros, Sigma-Aldrich or ABCR and were used as received.
3.2 General procedure for the synthesis of ferrocenyl-sugars Azido-sugar compound (0.67 mmol) and ethynylferrocene (0.67 mmol) were dissolved in 9ml of a 10:10:3 mixture of DCM/MeOH/H2O. CuSO4 (4.7 mg, 29 µmol), sodiumascorbate (30 mg, 0.15 mmol) and the corresponding tris-triazole (7 umol) were added. The mixture was stirred at 60 °C. After a defined time (see table) the mixture was diluted with 50 ml H2O and extracted with DCM (2 x 40 ml). The organic layer was dried (Na2SO4) and the solvent was evaporated. Purification by flash chromatography (petroleum ether-EtOAc 2:1) yielded an orange to red solid (yields see table).
2-Deoxy-2-(4-Ferrocenyl-1H-1,2,3-triazol-1-yl)-1,3,4,6-tetra-Oacetyl-α-D-mannopyranose 13 Rf 0.62 (petroleum ether/EtOAc 3:1); 1H-NMR (400.1 MHz, CDCl3): δ = 7.90 (s, 1 H, triazole-H), 6.44 (s, 1 H, H-1), 5.51 (dd, J = 10.0, 5.0, 1 H, H-3), 5.42 (d, J = 5.0, 1 H, H-2), 5.39 (‘t’, J = 10.0 1 H, H-4), 4,79 (s, 1 H, Cp-H), 4.70 (s, 1 H, Cp-H), 4.39 (dd, J = 12.2, 2.8, 1 H, H-6a), 4.33 (s, 2 H, Cp-H), 4.25-4.18 (m, 2 H, H-5, H-6b), 4.09 (s, 5 H, Cp-H), 2.25 (s, 3H, C(O)CH3), 2.20 (s, 3H, C(O)CH3), 2.04 (s, 3H, C(O)CH3), 1.98 (s, 3H, C(O)CH3); 13C7
NMR (100.6 MHz, CDCl3): δ = 170.3 (C(O)CH3), 170.1 (C(O)CH3), 169.0 (C(O)CH3), 167.9 (C(O)CH3), 147.6 (quaternary triazole C), 118.1 (triazole CH), 90.6 (C-1), 70.6 (C-5), 69.6 (Cp-Cs), 68.8 (Cp-Cs), 68.4 (C-3), 66.8 (Cp-C), 66.4 (Cp-C), 64.1 (C-4), 61.6 (C-6), 59.2 (C2), 20.8 (CH3), 20.7 (CH3), 20.5 (CH3), 20.4 (CH3); (FAB-MS): m/z [M+H]+: 584.0; Anal. Calcd for C26H29FeN3O9: C, 53.53; H, 5.01; N, 7.20; Found: C, 53.08; H, 5.13; N, 7.12;
2-Deoxy-2-(4-Ferrocenyl-1H-1,2,3-triazol-1-yl)-1,3,4,6-tetra-O-acetyl-D-glucopyranose 14 (anomeric mixture, α:β = 4:1) Rf 0.16 (petroleum ether/EtOAc 2:1); 1H-NMR (400.1 MHz, CDCl3) alpha-compound: δ = 7.52 (s, 1 H, triazole-H), 6.44 (d, J = 3.6, 1 H, H-1), 5.99 (dd, J = 11.3, 9.3, 1 H, H-3), 5.29 (‘t’, J = 9.9 1 H, H-4),5.42 (dd, J = 11.4, 3.6, 1 H, H-2), 4,75 (s, 1 H, Cp-H), 4.66 (s, 1 H, CpH), 4.36 (dd, J = 12.5, 4.1, 1 H, H-6a), 4.30 (s, 2 H, Cp-H), 4.24 (ddd, J = 10.2, 3.8, 2.2, 1 H, H-5), 4.15 (dd, J = 12.5, 2.2, 1 H, H-6b), 4.03 (s, 5 H, Cp-H), 2.15 (s, 3H, C(O)CH3), 2.12 (s, 3H, C(O)CH3), 2.07 (s, 3H, C(O)CH3), 1.89 (s, 3H, C(O)CH3);
13
C-NMR (100.6 MHz,
CDCl3): δ = 170.5 (C(O)CH3), 169.9 (C(O)CH3), 169.3 (C(O)CH3), 167.5 (C(O)CH3), 147.3 (quaternary triazole C), 117.3 (triazole CH), 90.6 (C-1), 70.0 (C-5), 69.6 (Cp-Cs), 68.9 (C-3), 68.8 (Cp-Cs), 68.2 (C-4) 66.7 (Cp-C), 66.3 (Cp-C), 61.4 (C-6), 61.0 (C-2), 20.7 (CH3), 20.6 (CH3), 20.5 (CH3), 20.3 (CH3); 1
H-NMR (400.1 MHz, CDCl3) beta-compound: δ = 7.48 (s, 1 H, triazole-H), 6.20 (d, J = 8.9,
1 H, H-1), 5.77 (dd, J = 10.7, 9.4, 1 H, H-3); 13C-NMR (100.6 MHz, CDCl3): δ = 91.59 (C-1); (FAB-MS): m/z [M+H]+: 583.9; Anal. Calcd for C26H29FeN3O9: C, 53.53; H, 5.01; N, 7.20; Found: C, 53.62; H, 5.05; N, 7.06;
8
6-Deoxy-6-(4-Ferrocenyl-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetra-O-acetyl-α-D-glucopyranose 15 Rf 0.60 (petroleum ether/EtOAc 2:1); 1H-NMR (400.1 MHz, CDCl3) alpha-compound: δ = 7.56 (s, 1 H, triazole-H), 6.33 (d, J = 3.6, 1 H, H-1), 5.48 (‘t’, J = 9.7, 1 H, H-3), 5.05 (dd, J = 10.0, 3.7, 1 H, H-2), 4.88 (‘t’, J = 9.7, 1 H, H-4), 4,76 (s, 1 H, Cp-H), 4.71 (s, 1 H, Cp-H), 4.60 (dd, J = 14.4, 1.7, 1 H, H-6a), 4.40-4.27 (m, 4 H, Cp-H, H-5, H-6b), 4.06 (s, 5 H, Cp-H), 2.12 (s, 3H, C(O)CH3), 2.09 (s, 3H, C(O)CH3), 2.01 (s, 3H, C(O)CH3), 2.00 (s, 3H, C(O)CH3);
13
C-NMR (100.6 MHz, CDCl3): δ = 170.0 (C(O)CH3), 169.6 (C(O)CH3), 169.6
(C(O)CH3), 168.6 (C(O)CH3), 147.3 (quaternary triazole C), 120.2 (triazole CH), 88.6 (C-1), 70.5 (C-5), 70.3 (Cp-Cs), 69.5 (C-3), 69.3 (Cp-Cs), 69.2 (C-2), 69.1 (C-4), 67.2 (Cp-C), 67.1 (Cp-C), 50.5 (C-6), 20.7 (CH3), 20.6 (CH3), 20.5 (CH3), 20.4 (CH3); (FAB-MS): m/z [M+H]+: 583.8; Anal. Calcd for C26H29FeN3O9: C, 53.53; H, 5.01; N, 7.20; Found: C, 53.62; H, 5.24; N, 7.03;
2-(2-(4-Ferrocenyl-1H-1,2,3-triazol-1-yl)ethoxy)ethyl-2,3,4,6-tetra-O-acetyl-α-Dmannopyranosid 16 Rf 0.15 (petroleum ether/EtOAc 1:4); 1H-NMR (400.1 MHz, CDCl3): δ = 7.60 (s, 1 H, triazole-H), 5.36 (dd, J = 9.9, 3.5, 1 H, H-3), 5.31-5.26 (m, 2H, H-2, H-4), 4.87 (d, J = 1.6, 1 H, H-1), 4,73 (s, 2 H, Cp-H), 4.55 (t, J = 5.2, 2 H, CH2), 4.28 (s, 2 H, Cp-H), 4.26 (dd, J = 12.1, 5.4, 1 H, H-6a), 4.09 (dd, J = 12.3, 2.5, 1 H, H-6b), 4.06 (s, 5 H, Cp-H), 4.00 (ddd, J = 9.8, 5.3, 2.5, 1 H, H-5), 3.91 (t, J = 5.3, 2 H, CH2), 3.80-3.53 (m, 4 H, CH2), 2.15 (s, 3H, C(O)CH3), 2.07 (s, 3H, C(O)CH3), 2.03 (s, 3H, C(O)CH3), 2.00 (s, 3H, C(O)CH3); 13C-NMR (100.6 MHz, CDCl3): δ = 170.5 (C(O)CH3), 170.1 (C(O)CH3), 169.9 (C(O)CH3), 169.7 (C(O)CH3), 146.6 (quaternary triazole C), 120.0 (triazole CH), 97.7 (C-1), 70.2 (CH2), 69.8 (CH2), 69.6 (Cp-Cs), 69.6 (C-4), 69.0 (Cp-C), 68.7 (C-3), 68.6 (C-5), 67.3 (CH2), 66.7 (CpC), 66.1 (C-2), 62.5 (C-6), 50.2 (CH2), 20.9 (CH3), 20.7 (CH3), 20.7 (CH3), 20.6 (CH3); 9
(FAB-MS): m/z [M+H]+: 672.6; Anal. Calcd for C26H29FeN3O9: C, 53.66; H, 5.55; N, 6.26; Found: C, 53.51; H, 5.79; N, 6.16;
2-(4-Ferrocenyl-1H-1,2,3-triazol-1-yl)ethyl-2-deoxy-2-acetamido-3,4,6-tri-O-acetyl-β-Dglucopyranosid 16 Rf 0.22 (DCM/MeOH 9:1); 1H-NMR (400.1 MHz, CDCl3): δ = 7.61 (s, 1 H, triazole-H), 5.45, (d, J = 9.1, 1 H, NH), 5.10 (‘t’, J = 9.3, 1 H, H-3), 5.07 (‘t’, J = 9.3, 1 H, H-4), 4,82 (s, 1 H, Cp-H), 4.71 (s, 1 H, Cp-H), 4.61 (m, 1H, CH2), 4.51 (m, 1H, CH2), 4.50 (d, J = 8.4, 1 H, H-1), 4.30-4.22 (m, 4 H, Cp-Hs, CH2, H-6a), 4.14 (dd, J = 12.4, 2.4, 1 H, H-6b), 4.08 (s, 5 H, CpH), 4.04 (m, 1 H, H-2), 3.90 (m, 1H, CH2), 3.66 (ddd, J = 9.3, 4.8, 2.5, 1 H, H-5), 2.08 (s, 3H, C(O)CH3), 2.02 (s, 3H, C(O)CH3), 2.01 (s, 3H, C(O)CH3), 1.76 (s, 3H, C(O)CH3); 13C-NMR (100.6 MHz, CDCl3): δ = 171.0 (C(O)CH3), 170.6 (C(O)CH3), 170.3 (C(O)CH3), 169.3 (C(O)CH3), 146.8 (quaternary triazole C), 120.6 (triazole CH), 101.0 (C-1), 72.4 (C-3), 72.1 (C-5), 69.2 (Cp-Cs), 68.3 (Cp-C), 67.5 (C-4), 67.1 (CH2), 61.9 (C-6), 54.1 (C-2), 49.9 (CH2), 23.3 (CH3), 20.7 (CH3), 20.6 (CH3), 20.6 (CH3); (FAB-MS): m/z [M-H]- : 627.7; Anal. Calcd for C26H29FeN3O9: C, 53.68; H, 5.47; N, 8.94; Found: C, 53.54; H, 5.58; N, 8.85;
Analytical data of TManTA 5 1
H-NMR (400.1 MHz, CDCl3): δ = 7.86 (s, 3 H, triazole-Hs), 5.34-5.22 (m, 9 H, 3 x H-2, 3 x
H-3, 3 x H-4), 4.86 (s, 3 H, 3 x H-1), 4,54 (m, 6 H, 3 x CH2), 4.26 (dd, J = 12.4, 5.0, 3 H, 3 x H-6a), 4.09 (dd, J = 12.8, 2.6, 3 H, 3 x H-6b), 4.00 (ddd, J = 8.5, 4.9, 2.5, 3 H, 3 x H-5), 3.90 (t, J = 5.2, 6 H, 3 x CH2), 3.83-359 (m, 18 H, 9 x CH2), 2.14 (s, 9 H, C(O)CH3), 2.08 (s, 9 H, C(O)CH3), 2.04 (s, 9 H, C(O)CH3), 1.98 (s, 9 H, C(O)CH3); 13C-NMR (100.6 MHz, CDCl3):
δ = 170.6 (C(O)CH3), 170.0 (C(O)CH3), 169.9 (C(O)CH3), 169.7 (C(O)CH3), 124.7 (triazole CH), 97.7 (C-1), 70.1 (CH2), 69.7 (CH2), 69.5 (C-4), 69.0 (C-2), 68.5 (C-5), 67.3 (CH2), 66.1 (C-4), 62.5 (C-6), 50.1 (CH2), 47.11 (CH2), 20.9 (CH3), 20.7 (CH3), 20.7 (CH3), 20.6 (CH3); 10
Analytical data of TGlcNAcTA 6 1
H-NMR (400.1 MHz, CDCl3): δ = 8.14 (s, 3 H, triazole-Hs), 7.35, (d, J = 8.7, 3 H, NHs),
5.42 (‘t’, J = 9.7, 3 H, 3 x H-3), 5.03 (‘t’, J = 9.7, 3 H, 3 x H-4), 4.96 (d, J = 8.4, 3 H, 3 x H1), 4.61 (m, 6 H, 3 x CH2), 4.21 (dd, J = 12.3, 4.4, 3 H, 3 x H-6a), 4.12 (dd, J = 12.1, 2.2, 3 H, 3 x H-6b), 4.00-3.62 (m, 30 H, 3 x H-2, 3 x H-5, 12 x CH2), 2.03 (s, 9 H, C(O)CH3), 2.00 (s, 9 H, C(O)CH3), 1.96 (s, 9 H, C(O)CH3), 1.90 (s, 9 H, C(O)CH3);
13
C-NMR (100.6 MHz,
CDCl3): δ = 170.6 (C(O)CH3), 170.6 (C(O)CH3), 170.5 (C(O)CH3), 169.5 (C(O)CH3), 142.3 (quaternary triazole C), 125.7 (triazole CH), 100.6 (C-1), 72.6 (C-3), 71.8 (C-5), 70.3 (CH2), 69.2 (C-4), 69.1 (CH2), 68.6 (CH2), 62.3 (C-6), 54.4 (C-2), 50.4 (CH2), 46.6 (CH2), 23.2 (CH3), 20.7 (CH3), 20.6 (CH3), 20.6 (CH3);
References:
[1] Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.; Angew. Chem., Int. Ed. 2002, 41, 2596-2599. [2] Tornoe, C. W.; Christensen, C.; Meldal, M., J. Org. Chem. 2002, 67, 3057-3064. [3] Laughlin, S. T.; Baskin, J. M.; Amacher, S. L.; Bertozzi, C. R.; Science 2008, 320, 664667. [4] Lin, P.-C.; Ueng, S.-H.; Yu, S.-C.; Jan, M.-D.; Adak, A. K.; Yu, C.-C.; Lin, C.-C.; Org. Lett. 2007, 9, 2131-2134. [5] Geng, J.; Lindqvist, J.; Mantovani, G. D.; Haddleton, M.; Angew. Chem., Int. Ed. 2008, 47, 4180-4183. [6] Beckmann, H. S. G.; Wittmann, V.; Org. Lett. 2007, 9, 1-4. [7] Ortega-Munoz, M.; Morales-Sanfrutos, J.; Perez-Balderas, F.; Hernandez-Mateo, F.; Giron-Gonzalez, M.; Sevillano-Tripero, D. N.; Salto-Gonzalez, R.; Santoyo-Gonzalez, F.; Org. Biomol. Chem. 2007, 5, 2291-2301. 11
[8] Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V.; Org. Lett. 2004, 6, 2853-2855 [9] Donnelly, P. S.; Zanatta, S. D.; Zammit, S. C.; White, J. M.; Williams, S. J.; Chem. Commun., 2008, 2459–2461. [10] Hong, V.; Udit, A. K.; Evans R. A.; Finn, M. G.; ChemBioChem, 2008, 9, 1481-1486. [11] Kumar, A.; Li, K.; Cai, C.; Chem. Commun., 2011, 47, 3186-3188. [12] Lewis, W. G.; Magallon, F. G.; Fokin, V. V.; Finn, M. G.; J. Am. Chem. Soc., 2004, 126, 9152-9153. [13] Herrmann, C.; Salas P. F.; Patrick B.O.; de Kock C.; Smith P. J.; Adam M.J.; Orvig C.; Dalton Trans. 2012 41(21), 6431-42. [14] Casas-Solvas, J. M.; Vargas-Berenguel, A.; Capitan-Vallvey, L. F.; Santoyo-Gonzalez, F.; Org. Lett. 2004, 6, 3687-3690. [15] Casas-Solvas, J. M.; Ortiz-Salmeron, E., Garcia-Fuentes, L.;Vargas-Berenguel, A.; Org. Biomol. Chem. 2008, 6, 4230-4235. [16] Trivedi, R.; Deepthi, S. B.; Giribabu, L.; Sridhar, B.; Sujitha, P.; Kumar, C. G.; Ramakrishna, K. V. S.; Eur. J. Inorg. Chem. 2012, 2267-2277. [17] Casas-Solvas, J. M.; Ortiz-Salmeron, E., Gimenez-Martinez, J. J.; Garcia-Fuentes, Capitan-Vallvey, L. F.; Santoyo-Gonzalez, F.; Vargas-Berenguel, A.; Chem. Eur. J 2009, 15, 710-725.
12
azide 7
8
9
10
11
copper(I)-ligand none 5 TBTA 6 none 5 TBTA 6 none 5
TBTA 6 none 5 TBTA 6 none 5 TBTA 6
conditions 60°C for 1h
60°C for 1h
60°C for 1h 60°C for 1h 60°C for 2h 60°C for 1h 60°C for 1h 60°C for 1h
60°C for 1h
13
Yield (%) 26 95 93 93 36 92 89 94 9 42 79 23 35 29 94 81 91 33 89 78 91
product 13
14
15
16
17
Highlights
New carbohydrate-based Cu(I) stabilizing ligands are used in CuAAC. The ligands evaluated in some cases proved to be more efficient than TBTA. The synthesis of carbohydrate-ferrocene conjugates is shown with high yields.
14
Graphical abstract
15
S0008-6215(14)00020-2 http://dx.doi.org/10.1016/j.carres.2014.01.005 CAR 6645
To appear in:
Carbohydrate Research
Received Date: Revised Date: Accepted Date:
31 October 2013 10 December 2013 8 January 2014
Please cite this article as: Schmidt, M.S., Leitner, K., Welter, M., Ringwald, M., Carbohydrate-based Cu(I) stabilizing ligands and their use in the synthesis of carbohydrate-ferrocene conjugates, Carbohydrate Research (2014), doi: http://dx.doi.org/10.1016/j.carres.2014.01.005
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Carbohydrate-based Cu(I) stabilizing ligands and their use in the synthesis of carbohydrate-ferrocene conjugates. Magnus S. Schmidt,*[a] Kim Leitner,[b] Moritz Welter,[b] and Markus Ringwald[c] *[a]
Corresponding author, Head of R&D, MCAT GmbH, Hermann-von-Vicari-Str. 23, 78464 Konstanz, Germany; Tel.: (+49) 174-2465904; Fax: (+49) 7531-939098; Email: [email protected]; Homepage: http://www.mcat.de
[b]
Department of Chemistry, University of Konstanz E-mail: [email protected] E-mail: [email protected]
[c]
CEO, MCAT GmbH, Hermann-von-Vicari-Str. 23, 78464 Konstanz E-mail: [email protected]
1
Abstract: A series of carbohydrate-ferrocene conjugates have been synthesized by copper(I)-catalyzed cycloaddition of carbohydrate-azides and ethynylferrocene (CuAAC). Newly carbohydratebased tris-triazoles have been used as Cu(I) stabilizing ligands and showed at least comparable, in some cases even better results compared to the use of tris(benzyltriazolylmethyl)amine (TBTA).
Keywords: click chemistry; carbohydrates; ferrocene; glycoconjugates; Cu(I) stabilizing ligands
2
1 Introduction By now the regiospecific copper(I)-catalyzed cycloaddition of azides and alkynes (CuAAC)[1,2] is a widely used synthetic tool and finds application in a wide range of scientific fields.[3-7] In this context, tris-triazoles such as tris(benzyltriazolylmethyl)amine (TBTA) 1 have been shown to be powerful additives, which stabilize copper(I) and increase its catalytic activity. [8,9] In the meantime a series of different tris-triazoles and other Cu(I) stabilizing ligands have been reported, such as different derivatives of TBTA 1a[10] and 1b[11], watersoluble ethylene glycol-based analogues 2 and 3 [11] and the bathophenanthroline 4,[12] (Scheme 1)
R
N N N
H
N
O
N 4N N
3 1 R = H (TBTA) 1a R = COOH 1b R = CH2(OCH2CH2)4OCH3
H
O
N 4N N
N 3
2
2 N
NH
3 N
4 HO3S AcO AcO AcO
SO3H
OAc O
N
N
O
O
N
AcO AcO
N N
3
5
OAc O
O NHAc
O
N
N N 3
6
Scheme 1: copper(I)-stabilizing ligands. Carbohydrate-ferrocene conjugates have been shown to be interesting compounds; the combined chemical properties of the conjugated partners result in possible uses, which are not amenable to carbohydrates or ferrocenes by themselves. Orvig et.al., for example, reported a series of carbohydrate-ferrocene conjugates which displayed high antimalarial activity.[13] 3
Other recent studies concern electrochemical,[14-17] biological and bioorganic[15,16] properties of carbohydrate-ferrocene conjugates. 2 Results and Discussion In order to investigate alternative copper(I)-stabilizing ligands based on carbohydrate-azides, we have explored the use of two carbohydrate-based tris-triazoles, TManTA 5 and TGlcNAcTA 6, as ligands in the synthesis of a series of carbohydrate-ferrocene conjugates. To evaluate the catalytic activity of compounds 5 and 6, we chose the reaction of five different azido-sugars with ethynylferrocene (Scheme 2) and compared the results with the activity of TBTA 1 and with the reaction without any tris-triazole. AcO AcO AcO
N3 O 7
AcO AcO AcO
AcO AcO AcO
OAc
O 8
N3
OAc O O
OAc
AcO AcO O
N3 O
AcO AcO 9
OAc
OAc Fe
OAc O
O NHAc
N3
12 N3
11
10
Scheme 2: used starting materials. All reactions were performed in DCM/MeOH/H2 O 10:10:3, 0.04 equiv. CuSO4, 0.2 equiv. sodium ascorbate and 0.01 equiv. of the respective tris-triazole were added to the azide/alkyne solution. The reaction mixture was stirred at 60°C for one hour; in some cases we investigated also longer reaction times. Table 1 shows the results of the experiments. The CuAAC reaction of 7-11 with ethynylferrocene (12) resulted in the formation of 13-17 (Scheme 3). All carbohydrate-ferrocene conjugates were monitored by TLC and the isolated products were analyzed by NMR, mass spectrometry and elemental analysis. In their 1HNMR spectra all triazole products showed singlets around δ = 7.9-7.5 ppm (triazole proton) as well as the characteristic doublet of the anomeric proton around δ = 6.33-6.55 ppm (2-, or 6triazolesugars 13-15) or at δ = 4.5-4.9 (glycosides 16 and 17). The protons of the
4
unsubstituted Cp ring appears for all compounds between δ = 4.0 and 4.1 ppm. In 13C-NMR spectra the characteristic triazole carbons appear between δ = 146 and 148 ppm and δ = 118 and 121 ppm. As expected, addition of tris-triazoles in catalytic amounts leads to much higher yields. While the reactions of 7 and 8 with ethynylferrocene (12) in the presence of all tris-triazoles studied lead to comparable yields of 90 % or higher, we observed significantly higher yields for the use of carbohydrate-based tris-triazoles in the reactions of 9, 10 and 11 with ethynylferrocene 12 compared to the use of TBTA 1. The most significant differences were observed in the reaction of 9 with 12, which showed the lowest yields after 1h at 60°C in the presence of TBTA 1. The use of TGlcNAcTA 6 leads to a yield higher by 50 %; use of TManTA 5 even leads nearly to a doubling of the yield compared to the use of TBTA 1.
O
Fe
N3 7-11
12
CuSO4, Na-ascorbate tris-triazole (1,5,6,-) DCM/MeOH/H2O 60°C, 1h
N AcO
N N O
AcO AcO 13 AcO AcO AcO
N
Fe
OAc
N 14
N 2
N
N N ON
AcO AcO Fe
OAc
OAc O O
O
13-17
N
OAc
N N
Fe
OAc O
AcO AcO
Fe
N
OAc O
AcO AcO
O
N
N N
HNAc
N
17
16
Fe Fe
Scheme 3: carbohydrate-ferrocene conjugates.
5
OAc
15
Table 1: reactions and results.
Azide 7
8
9
10
11
Cu(I)-ligand none 5 TBTA 6 none 5 TBTA 6 none 5 TBTA 6 none 5 TBTA 6 none 5 TBTA 6
conditions 60°C for 1h
60°C for 1h
60°C for 1h 60°C for 1h 60°C for 2h 60°C for 1h 60°C for 1h 60°C for 1h
60°C for 1h
Yield (%) 26 95 93 93 36 92 89 94 9 42 79 23 35 29 94 81 91 33 89 78 91
product 13
14
15
16
17
In summary, we have shown that the use of commercially available carbohydrate-based tristriazoles 5 and 6 leads at least to comparable or to higher yields than the use of TBTA 1 in the synthesis of different carbohydrate-ferrocene conjugates. Interestingly, the use of TManTA 5 leads to the highest yields in reactions with mannose-based azides, whereas the use of TGlcNAc 6 leads to somewhat higher yields in reactions with GlcNAc/glucosamine-based azides.
3 Experimental Section 3.1 General Methods TLC was carried out on Silica Gel 60 F254 (Merck, layer thickness 0.2 mm) with detection by UV light (254 nm) and/or by charring with 15% sulfuric acid in ethanol. Flash column chromatography (FC) was performed on Merck Silica Gel 60 (0.040–0.063 mm). 1H NMR and 13C NMR spectra were recorded on Bruker Avance II 400. Chemical shifts are reported in ppm relative to solvent signals (CDCl3: δH = 7.26 ppm, δC = 77.0 ppm; DMSO-d6: δH =
6
2.49 ppm, δC = 39.7 ppm; CD3OD: δH = 4.78 ppm, δC = 49.3 ppm). Signals were assigned by first-order analysis andassignments were supported, where feasible, by two-dimensional 1H, 1H and 1H, 13C correlation spectroscopy. 3JH–H and 1JH–C coupling constants are reported in Hz. Mass spectra were recorded on a Finnigan MAT8200 spectrometer. Elemental analysis was performed on an elementar CHNS vario EL instrument. All azido-compounds and tris-triazoles are commercially available (from MCAT www.mcat.de order numbers tris-triazoles: MC 9292 (TManTA) and MC 9293 (TGlcNAcTA)); all other chemicals and reagents were purchased from Acros, Sigma-Aldrich or ABCR and were used as received.
3.2 General procedure for the synthesis of ferrocenyl-sugars Azido-sugar compound (0.67 mmol) and ethynylferrocene (0.67 mmol) were dissolved in 9ml of a 10:10:3 mixture of DCM/MeOH/H2O. CuSO4 (4.7 mg, 29 µmol), sodiumascorbate (30 mg, 0.15 mmol) and the corresponding tris-triazole (7 umol) were added. The mixture was stirred at 60 °C. After a defined time (see table) the mixture was diluted with 50 ml H2O and extracted with DCM (2 x 40 ml). The organic layer was dried (Na2SO4) and the solvent was evaporated. Purification by flash chromatography (petroleum ether-EtOAc 2:1) yielded an orange to red solid (yields see table).
2-Deoxy-2-(4-Ferrocenyl-1H-1,2,3-triazol-1-yl)-1,3,4,6-tetra-Oacetyl-α-D-mannopyranose 13 Rf 0.62 (petroleum ether/EtOAc 3:1); 1H-NMR (400.1 MHz, CDCl3): δ = 7.90 (s, 1 H, triazole-H), 6.44 (s, 1 H, H-1), 5.51 (dd, J = 10.0, 5.0, 1 H, H-3), 5.42 (d, J = 5.0, 1 H, H-2), 5.39 (‘t’, J = 10.0 1 H, H-4), 4,79 (s, 1 H, Cp-H), 4.70 (s, 1 H, Cp-H), 4.39 (dd, J = 12.2, 2.8, 1 H, H-6a), 4.33 (s, 2 H, Cp-H), 4.25-4.18 (m, 2 H, H-5, H-6b), 4.09 (s, 5 H, Cp-H), 2.25 (s, 3H, C(O)CH3), 2.20 (s, 3H, C(O)CH3), 2.04 (s, 3H, C(O)CH3), 1.98 (s, 3H, C(O)CH3); 13C7
NMR (100.6 MHz, CDCl3): δ = 170.3 (C(O)CH3), 170.1 (C(O)CH3), 169.0 (C(O)CH3), 167.9 (C(O)CH3), 147.6 (quaternary triazole C), 118.1 (triazole CH), 90.6 (C-1), 70.6 (C-5), 69.6 (Cp-Cs), 68.8 (Cp-Cs), 68.4 (C-3), 66.8 (Cp-C), 66.4 (Cp-C), 64.1 (C-4), 61.6 (C-6), 59.2 (C2), 20.8 (CH3), 20.7 (CH3), 20.5 (CH3), 20.4 (CH3); (FAB-MS): m/z [M+H]+: 584.0; Anal. Calcd for C26H29FeN3O9: C, 53.53; H, 5.01; N, 7.20; Found: C, 53.08; H, 5.13; N, 7.12;
2-Deoxy-2-(4-Ferrocenyl-1H-1,2,3-triazol-1-yl)-1,3,4,6-tetra-O-acetyl-D-glucopyranose 14 (anomeric mixture, α:β = 4:1) Rf 0.16 (petroleum ether/EtOAc 2:1); 1H-NMR (400.1 MHz, CDCl3) alpha-compound: δ = 7.52 (s, 1 H, triazole-H), 6.44 (d, J = 3.6, 1 H, H-1), 5.99 (dd, J = 11.3, 9.3, 1 H, H-3), 5.29 (‘t’, J = 9.9 1 H, H-4),5.42 (dd, J = 11.4, 3.6, 1 H, H-2), 4,75 (s, 1 H, Cp-H), 4.66 (s, 1 H, CpH), 4.36 (dd, J = 12.5, 4.1, 1 H, H-6a), 4.30 (s, 2 H, Cp-H), 4.24 (ddd, J = 10.2, 3.8, 2.2, 1 H, H-5), 4.15 (dd, J = 12.5, 2.2, 1 H, H-6b), 4.03 (s, 5 H, Cp-H), 2.15 (s, 3H, C(O)CH3), 2.12 (s, 3H, C(O)CH3), 2.07 (s, 3H, C(O)CH3), 1.89 (s, 3H, C(O)CH3);
13
C-NMR (100.6 MHz,
CDCl3): δ = 170.5 (C(O)CH3), 169.9 (C(O)CH3), 169.3 (C(O)CH3), 167.5 (C(O)CH3), 147.3 (quaternary triazole C), 117.3 (triazole CH), 90.6 (C-1), 70.0 (C-5), 69.6 (Cp-Cs), 68.9 (C-3), 68.8 (Cp-Cs), 68.2 (C-4) 66.7 (Cp-C), 66.3 (Cp-C), 61.4 (C-6), 61.0 (C-2), 20.7 (CH3), 20.6 (CH3), 20.5 (CH3), 20.3 (CH3); 1
H-NMR (400.1 MHz, CDCl3) beta-compound: δ = 7.48 (s, 1 H, triazole-H), 6.20 (d, J = 8.9,
1 H, H-1), 5.77 (dd, J = 10.7, 9.4, 1 H, H-3); 13C-NMR (100.6 MHz, CDCl3): δ = 91.59 (C-1); (FAB-MS): m/z [M+H]+: 583.9; Anal. Calcd for C26H29FeN3O9: C, 53.53; H, 5.01; N, 7.20; Found: C, 53.62; H, 5.05; N, 7.06;
8
6-Deoxy-6-(4-Ferrocenyl-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetra-O-acetyl-α-D-glucopyranose 15 Rf 0.60 (petroleum ether/EtOAc 2:1); 1H-NMR (400.1 MHz, CDCl3) alpha-compound: δ = 7.56 (s, 1 H, triazole-H), 6.33 (d, J = 3.6, 1 H, H-1), 5.48 (‘t’, J = 9.7, 1 H, H-3), 5.05 (dd, J = 10.0, 3.7, 1 H, H-2), 4.88 (‘t’, J = 9.7, 1 H, H-4), 4,76 (s, 1 H, Cp-H), 4.71 (s, 1 H, Cp-H), 4.60 (dd, J = 14.4, 1.7, 1 H, H-6a), 4.40-4.27 (m, 4 H, Cp-H, H-5, H-6b), 4.06 (s, 5 H, Cp-H), 2.12 (s, 3H, C(O)CH3), 2.09 (s, 3H, C(O)CH3), 2.01 (s, 3H, C(O)CH3), 2.00 (s, 3H, C(O)CH3);
13
C-NMR (100.6 MHz, CDCl3): δ = 170.0 (C(O)CH3), 169.6 (C(O)CH3), 169.6
(C(O)CH3), 168.6 (C(O)CH3), 147.3 (quaternary triazole C), 120.2 (triazole CH), 88.6 (C-1), 70.5 (C-5), 70.3 (Cp-Cs), 69.5 (C-3), 69.3 (Cp-Cs), 69.2 (C-2), 69.1 (C-4), 67.2 (Cp-C), 67.1 (Cp-C), 50.5 (C-6), 20.7 (CH3), 20.6 (CH3), 20.5 (CH3), 20.4 (CH3); (FAB-MS): m/z [M+H]+: 583.8; Anal. Calcd for C26H29FeN3O9: C, 53.53; H, 5.01; N, 7.20; Found: C, 53.62; H, 5.24; N, 7.03;
2-(2-(4-Ferrocenyl-1H-1,2,3-triazol-1-yl)ethoxy)ethyl-2,3,4,6-tetra-O-acetyl-α-Dmannopyranosid 16 Rf 0.15 (petroleum ether/EtOAc 1:4); 1H-NMR (400.1 MHz, CDCl3): δ = 7.60 (s, 1 H, triazole-H), 5.36 (dd, J = 9.9, 3.5, 1 H, H-3), 5.31-5.26 (m, 2H, H-2, H-4), 4.87 (d, J = 1.6, 1 H, H-1), 4,73 (s, 2 H, Cp-H), 4.55 (t, J = 5.2, 2 H, CH2), 4.28 (s, 2 H, Cp-H), 4.26 (dd, J = 12.1, 5.4, 1 H, H-6a), 4.09 (dd, J = 12.3, 2.5, 1 H, H-6b), 4.06 (s, 5 H, Cp-H), 4.00 (ddd, J = 9.8, 5.3, 2.5, 1 H, H-5), 3.91 (t, J = 5.3, 2 H, CH2), 3.80-3.53 (m, 4 H, CH2), 2.15 (s, 3H, C(O)CH3), 2.07 (s, 3H, C(O)CH3), 2.03 (s, 3H, C(O)CH3), 2.00 (s, 3H, C(O)CH3); 13C-NMR (100.6 MHz, CDCl3): δ = 170.5 (C(O)CH3), 170.1 (C(O)CH3), 169.9 (C(O)CH3), 169.7 (C(O)CH3), 146.6 (quaternary triazole C), 120.0 (triazole CH), 97.7 (C-1), 70.2 (CH2), 69.8 (CH2), 69.6 (Cp-Cs), 69.6 (C-4), 69.0 (Cp-C), 68.7 (C-3), 68.6 (C-5), 67.3 (CH2), 66.7 (CpC), 66.1 (C-2), 62.5 (C-6), 50.2 (CH2), 20.9 (CH3), 20.7 (CH3), 20.7 (CH3), 20.6 (CH3); 9
(FAB-MS): m/z [M+H]+: 672.6; Anal. Calcd for C26H29FeN3O9: C, 53.66; H, 5.55; N, 6.26; Found: C, 53.51; H, 5.79; N, 6.16;
2-(4-Ferrocenyl-1H-1,2,3-triazol-1-yl)ethyl-2-deoxy-2-acetamido-3,4,6-tri-O-acetyl-β-Dglucopyranosid 16 Rf 0.22 (DCM/MeOH 9:1); 1H-NMR (400.1 MHz, CDCl3): δ = 7.61 (s, 1 H, triazole-H), 5.45, (d, J = 9.1, 1 H, NH), 5.10 (‘t’, J = 9.3, 1 H, H-3), 5.07 (‘t’, J = 9.3, 1 H, H-4), 4,82 (s, 1 H, Cp-H), 4.71 (s, 1 H, Cp-H), 4.61 (m, 1H, CH2), 4.51 (m, 1H, CH2), 4.50 (d, J = 8.4, 1 H, H-1), 4.30-4.22 (m, 4 H, Cp-Hs, CH2, H-6a), 4.14 (dd, J = 12.4, 2.4, 1 H, H-6b), 4.08 (s, 5 H, CpH), 4.04 (m, 1 H, H-2), 3.90 (m, 1H, CH2), 3.66 (ddd, J = 9.3, 4.8, 2.5, 1 H, H-5), 2.08 (s, 3H, C(O)CH3), 2.02 (s, 3H, C(O)CH3), 2.01 (s, 3H, C(O)CH3), 1.76 (s, 3H, C(O)CH3); 13C-NMR (100.6 MHz, CDCl3): δ = 171.0 (C(O)CH3), 170.6 (C(O)CH3), 170.3 (C(O)CH3), 169.3 (C(O)CH3), 146.8 (quaternary triazole C), 120.6 (triazole CH), 101.0 (C-1), 72.4 (C-3), 72.1 (C-5), 69.2 (Cp-Cs), 68.3 (Cp-C), 67.5 (C-4), 67.1 (CH2), 61.9 (C-6), 54.1 (C-2), 49.9 (CH2), 23.3 (CH3), 20.7 (CH3), 20.6 (CH3), 20.6 (CH3); (FAB-MS): m/z [M-H]- : 627.7; Anal. Calcd for C26H29FeN3O9: C, 53.68; H, 5.47; N, 8.94; Found: C, 53.54; H, 5.58; N, 8.85;
Analytical data of TManTA 5 1
H-NMR (400.1 MHz, CDCl3): δ = 7.86 (s, 3 H, triazole-Hs), 5.34-5.22 (m, 9 H, 3 x H-2, 3 x
H-3, 3 x H-4), 4.86 (s, 3 H, 3 x H-1), 4,54 (m, 6 H, 3 x CH2), 4.26 (dd, J = 12.4, 5.0, 3 H, 3 x H-6a), 4.09 (dd, J = 12.8, 2.6, 3 H, 3 x H-6b), 4.00 (ddd, J = 8.5, 4.9, 2.5, 3 H, 3 x H-5), 3.90 (t, J = 5.2, 6 H, 3 x CH2), 3.83-359 (m, 18 H, 9 x CH2), 2.14 (s, 9 H, C(O)CH3), 2.08 (s, 9 H, C(O)CH3), 2.04 (s, 9 H, C(O)CH3), 1.98 (s, 9 H, C(O)CH3); 13C-NMR (100.6 MHz, CDCl3):
δ = 170.6 (C(O)CH3), 170.0 (C(O)CH3), 169.9 (C(O)CH3), 169.7 (C(O)CH3), 124.7 (triazole CH), 97.7 (C-1), 70.1 (CH2), 69.7 (CH2), 69.5 (C-4), 69.0 (C-2), 68.5 (C-5), 67.3 (CH2), 66.1 (C-4), 62.5 (C-6), 50.1 (CH2), 47.11 (CH2), 20.9 (CH3), 20.7 (CH3), 20.7 (CH3), 20.6 (CH3); 10
Analytical data of TGlcNAcTA 6 1
H-NMR (400.1 MHz, CDCl3): δ = 8.14 (s, 3 H, triazole-Hs), 7.35, (d, J = 8.7, 3 H, NHs),
5.42 (‘t’, J = 9.7, 3 H, 3 x H-3), 5.03 (‘t’, J = 9.7, 3 H, 3 x H-4), 4.96 (d, J = 8.4, 3 H, 3 x H1), 4.61 (m, 6 H, 3 x CH2), 4.21 (dd, J = 12.3, 4.4, 3 H, 3 x H-6a), 4.12 (dd, J = 12.1, 2.2, 3 H, 3 x H-6b), 4.00-3.62 (m, 30 H, 3 x H-2, 3 x H-5, 12 x CH2), 2.03 (s, 9 H, C(O)CH3), 2.00 (s, 9 H, C(O)CH3), 1.96 (s, 9 H, C(O)CH3), 1.90 (s, 9 H, C(O)CH3);
13
C-NMR (100.6 MHz,
CDCl3): δ = 170.6 (C(O)CH3), 170.6 (C(O)CH3), 170.5 (C(O)CH3), 169.5 (C(O)CH3), 142.3 (quaternary triazole C), 125.7 (triazole CH), 100.6 (C-1), 72.6 (C-3), 71.8 (C-5), 70.3 (CH2), 69.2 (C-4), 69.1 (CH2), 68.6 (CH2), 62.3 (C-6), 54.4 (C-2), 50.4 (CH2), 46.6 (CH2), 23.2 (CH3), 20.7 (CH3), 20.6 (CH3), 20.6 (CH3);
References:
[1] Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.; Angew. Chem., Int. Ed. 2002, 41, 2596-2599. [2] Tornoe, C. W.; Christensen, C.; Meldal, M., J. Org. Chem. 2002, 67, 3057-3064. [3] Laughlin, S. T.; Baskin, J. M.; Amacher, S. L.; Bertozzi, C. R.; Science 2008, 320, 664667. [4] Lin, P.-C.; Ueng, S.-H.; Yu, S.-C.; Jan, M.-D.; Adak, A. K.; Yu, C.-C.; Lin, C.-C.; Org. Lett. 2007, 9, 2131-2134. [5] Geng, J.; Lindqvist, J.; Mantovani, G. D.; Haddleton, M.; Angew. Chem., Int. Ed. 2008, 47, 4180-4183. [6] Beckmann, H. S. G.; Wittmann, V.; Org. Lett. 2007, 9, 1-4. [7] Ortega-Munoz, M.; Morales-Sanfrutos, J.; Perez-Balderas, F.; Hernandez-Mateo, F.; Giron-Gonzalez, M.; Sevillano-Tripero, D. N.; Salto-Gonzalez, R.; Santoyo-Gonzalez, F.; Org. Biomol. Chem. 2007, 5, 2291-2301. 11
[8] Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V.; Org. Lett. 2004, 6, 2853-2855 [9] Donnelly, P. S.; Zanatta, S. D.; Zammit, S. C.; White, J. M.; Williams, S. J.; Chem. Commun., 2008, 2459–2461. [10] Hong, V.; Udit, A. K.; Evans R. A.; Finn, M. G.; ChemBioChem, 2008, 9, 1481-1486. [11] Kumar, A.; Li, K.; Cai, C.; Chem. Commun., 2011, 47, 3186-3188. [12] Lewis, W. G.; Magallon, F. G.; Fokin, V. V.; Finn, M. G.; J. Am. Chem. Soc., 2004, 126, 9152-9153. [13] Herrmann, C.; Salas P. F.; Patrick B.O.; de Kock C.; Smith P. J.; Adam M.J.; Orvig C.; Dalton Trans. 2012 41(21), 6431-42. [14] Casas-Solvas, J. M.; Vargas-Berenguel, A.; Capitan-Vallvey, L. F.; Santoyo-Gonzalez, F.; Org. Lett. 2004, 6, 3687-3690. [15] Casas-Solvas, J. M.; Ortiz-Salmeron, E., Garcia-Fuentes, L.;Vargas-Berenguel, A.; Org. Biomol. Chem. 2008, 6, 4230-4235. [16] Trivedi, R.; Deepthi, S. B.; Giribabu, L.; Sridhar, B.; Sujitha, P.; Kumar, C. G.; Ramakrishna, K. V. S.; Eur. J. Inorg. Chem. 2012, 2267-2277. [17] Casas-Solvas, J. M.; Ortiz-Salmeron, E., Gimenez-Martinez, J. J.; Garcia-Fuentes, Capitan-Vallvey, L. F.; Santoyo-Gonzalez, F.; Vargas-Berenguel, A.; Chem. Eur. J 2009, 15, 710-725.
12
azide 7
8
9
10
11
copper(I)-ligand none 5 TBTA 6 none 5 TBTA 6 none 5
TBTA 6 none 5 TBTA 6 none 5 TBTA 6
conditions 60°C for 1h
60°C for 1h
60°C for 1h 60°C for 1h 60°C for 2h 60°C for 1h 60°C for 1h 60°C for 1h
60°C for 1h
13
Yield (%) 26 95 93 93 36 92 89 94 9 42 79 23 35 29 94 81 91 33 89 78 91
product 13
14
15
16
17
Highlights
New carbohydrate-based Cu(I) stabilizing ligands are used in CuAAC. The ligands evaluated in some cases proved to be more efficient than TBTA. The synthesis of carbohydrate-ferrocene conjugates is shown with high yields.
14
Graphical abstract
15