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Article

A Click Chemistry Approach towards Flavin-Cyclodextrin Conjugates—Bioinspired Sulfoxidation Catalysts

by
Petra Tomanová
1,
Jiří Šturala
1,
Miloš Buděšínský
2 and
Radek Cibulka
1,*
1
Department of Organic Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic
2
Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic
*
Author to whom correspondence should be addressed.
Molecules 2015, 20(11), 19837-19848; https://doi.org/10.3390/molecules201119667
Submission received: 21 September 2015 / Revised: 13 October 2015 / Accepted: 14 October 2015 / Published: 4 November 2015
(This article belongs to the Special Issue Design and Synthesis of Novel Conjugated and Non Conjugated Small Molecules)
Browse Figures
Versions Notes

Abstract

:
A click chemistry approach based on the reaction between alkynylflavins and mono(6-azido-6-deoxy)-β-cyclodextrin has proven to be a useful tool for the synthesis of flavin-cyclodextrin conjugates studied as monooxygenase mimics in enantioselective sulfoxidations.

Graphical Abstract

1. Introduction

Within the last three decades, flavinium salts have been shown as useful tools for the organocatalytic activation of hydrogen peroxide and oxygen allowing various oxidations to proceed under mild conditions [1,2,3]. In particular, extensive research on H2O2-sulfoxidations catalyzed by flavinium salts has resulted in several useful synthetic procedures for mild, chemoselective and stereoselective transformations of sulfides to sulfoxides [4,5,6,7,8,9]. In these artificial systems, flavinium salts Fl mimic the function of flavin co-factors in monooxygenases [10] via the in situ formation of flavin-4a-hydroperoxide FlOOH, which subsequently oxidizes the substrate (Scheme 1).
Flavoenzymes usually give the corresponding oxygenated products chemoselectively and stereoselectively, which is provided by the stereoselective transfer of activated oxygen from flavin-4a-hydroperoxide to the substrate accommodated in an active site of the enzyme via non-covalent bonding interactions [11,12,13,14]. The efficiency of an enzyme is usually sensitive to the modification in its active site as well as to a change in the substrate; both of which can lead to a significant loss of stereoselectivity [12,14,15,16]. Cyclodextrins have been extensively studied as biomimetic catalysts by utilizing their hydrophobic cavity for non-covalent binding of lipophilic substrates in neat aqueous media [17,18,19]. Moreover, analogously to an enzyme active site, the cyclodextrin cavity offers a chiral environment for asymmetric transformations [20,21,22,23,24,25].
Souza and coworkers investigated artificial enzymes based on flavin and cyclodextrin moieties linked together with ether or ester functionality. The conjugates were tested in oxidation of mercaptans, NADH+ models and in photooxidation of benzyl alcohols [26,27,28]. Recently, we have designed sulfoxidation catalysts 1 and 2 (Figure 1) containing a redox-active flavinium “co-factor” and chiral substrate-binding site made using α- or β-cyclodextrin; both parts were attached by amide bonds [29,30,31]. The efficiency of these biomimetic catalysts was shown to depend strongly on the structure of the “co-factor”, the relative position of both parts of the catalyst as well as the size of the cyclodextrin cavity. The best sulfoxidation catalysts were found to be alloxazinium-β-cyclodextrin conjugates 1a and 1b, which achieved an ee of up to 91% for tert-butyl methyl sulfide, 80% ee for aromatic sulfides and up to 64% ee for aliphatic sulfides with only 1 mol % catalyst in neat aqueous media. It was noteworthy that a small change in the catalyst structure such as turning the alloxazine relative to the cyclodextrin cavity (see catalyst 2) caused the stereoselectivity of the reaction to be completely lost [31].
Molecules 20 19667 g002 550
Scheme 1. Formation of flavin-4a-hydroperoxide FlOOH in H2O2-sulfoxidations catalyzed by flavinium salts Fl (R5 = Et) (A) and in sulfoxidations taking place in class B monooxygenases (R5 = H) (B). Oxidation of sulfides by FlOOH takes place by electrophilic mechanism (C), i.e., by an attack of sulfur to electrophilic hydroperoxy group oxygen.
Scheme 1. Formation of flavin-4a-hydroperoxide FlOOH in H2O2-sulfoxidations catalyzed by flavinium salts Fl (R5 = Et) (A) and in sulfoxidations taking place in class B monooxygenases (R5 = H) (B). Oxidation of sulfides by FlOOH takes place by electrophilic mechanism (C), i.e., by an attack of sulfur to electrophilic hydroperoxy group oxygen.
Molecules 20 19667 g002
Molecules 20 19667 g001 550
Figure 1. Design of flavin-cyclodextrin conjugates.
Figure 1. Design of flavin-cyclodextrin conjugates.
Molecules 20 19667 g001
Herein, we report a new synthetic approach towards flavin-cyclodextrin conjugates based on click chemistry, specifically the copper-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC) [32,33,34,35]. We used the same co-factor (alloxazine) and cavity (β-cyclodextrin) as in 1, to prove if the CuAAC methodology is compatible with the alloxazine unit since although click chemistry is well established among cyclodextrins [34,36], its use among flavins is still limited to only one isoalloxazine example [37,38].

2. Results and Discussion

2.1. Synthesis of Conjugates 3 and 4

The strategy used towards the synthesis of new catalysts 3 and 4 corresponded to the synthetic pathway used for derivatives 1 and 2 (see Scheme 2). The synthetic route started with the preparation of flavin and cyclodextrin subunits functionalized with suitable groups for interconnecting both parts followed by the transformation of the neutral alloxazine into the corresponding alloxazinium moiety. Alkylation/quaternization of the N5 nitrogen is essential for the flavins to be active in the artificial oxygenations. Amide coupling of mono(6-amino-6-deoxy)-β-cyclodextrin with the corresponding flavin carboxylic acid used in the synthesis of 1 and 2 was replaced by a CuAAC between mono(6-azido-6-deoxy)-β-cyclodextrin 7 and an alloxazine possessing a terminal triple bond in its side chain. 1-(Alkynyl)-3-methylalloxazine 5 and 1-methyl-3-propargylalloxazine 6 were prepared by alkylation of 3-methylalloxazine or 1-methylalloxazine, respectively, with a triple-bond containing alkylating agent. Mono(6-azido-6-deoxy)-β-cyclodextrin 7 was readily available using standard procedures starting from commercial β-cyclodextrin [39].
Molecules 20 19667 g003 550
Scheme 2. Synthesis of catalysts 3 and 4 using click chemistry approach. Method A: CuI, N,N-diisopropylethylamine, DMF; method B: TBTA, sodium ascorbate, CuSO4, DMF.
Scheme 2. Synthesis of catalysts 3 and 4 using click chemistry approach. Method A: CuI, N,N-diisopropylethylamine, DMF; method B: TBTA, sodium ascorbate, CuSO4, DMF.
Molecules 20 19667 g003
The preliminary tests of the CuAAC reaction between 3-methyl-1-propargylalloxazine 5a and the model azides (benzylazide or p-tolylazide) gave the corresponding triazoles in excellent yield without decomposition of the alloxazine skeleton using conventional reaction conditions [32,33,34,35], i.e., copper iodide and Hünig’s base in N,N-dimethylformamide (DMF) (see Supplementary Materials). Therefore, this method (A) was applied for the cycloaddition of alkynylalloxazines 5 and 6 with azide 7. In all cases, the corresponding conjugates were formed in moderate yield with the exception of derivative 8b, which was not formed using method A despite great effort (Table 1). Lower yields of conjugates could be a result of redox activity of flavin moiety supporting undesired oxidation of Cu(I) during cycloaddition with less reactive azidocyclodextrine 7. Therefore we modified reaction conditions using copper sulfate, sodium ascorbate (to produce Cu(I) in-situ) and the tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) ligand which is known to stabilize Cu(I) towards disproportionation and oxidation (method B) [40]. Under these conditions, 8b was formed in good yield. Method B even gave the conjugates 8 and 9 in substantially higher yields, regardless of the position of the alkynyl group on the alloxazine subunit and the length of the spacer (Table 1). Importantly, the triazole spacer tolerated the subsequent reaction steps, which led to the transformation of the neutral alloxazine to alloxazinium moiety, i.e., the introduction of an ethyl group via reductive amination and oxidation, which proceeded in a quantitative yield in all cases.
Table
Table 1. Click reaction between flavins 5 or 6 and azidocyclodextrin 7 a.
Table 1. Click reaction between flavins 5 or 6 and azidocyclodextrin 7 a.
EntryAlloxazineConjugateMethodYield
15a8aA68
25a8aB82
35b8bA- b
45b8bB58
55c8cA23
65c8cB91
769A34
869B64
a For procedures, see Experimental Section; b Product formation was not observed.

2.2. Catalytic Activity

To demonstrate the activity of the modified biomimetic systems in a catalytic oxidation, the prepared conjugates were subjected to preliminary screening in the enantioselective sulfoxidation of alkyl methyl sulfides and aryl methyl sulfides using hydrogen peroxide as a model reaction. The oxidation was performed in a buffered aqueous medium under the reaction conditions recently used in reactions catalyzed by analogous conjugates bearing an amide linker. Among the conjugates bearing a triazole spacer, the efficiency in the enantioselective sulfoxidations decreased with an increase in the spacer length and by “turning” the alloxazine moiety going from 3 to 4 (see Supplementary Materials). In Table 2, the reaction conversions and enantioselectivities of the sulfoxidations catalyzed by 3a, the most efficient conjugate with triazole linker, are compared with the catalytic activity of 1b, one of the most efficient conjugate from “amide” series with the same length of spacer. The reaction conversions of the non-catalyzed oxidation reactions (blanks) are given for information. The observed enantioselectivities obtained using 3a were lower than those found when using 1b but still comparable or even better than those obtained using other flavin-cyclodextrin conjugates or other chiral flavinium catalysts [7,9,29,30,31]. Interestingly, the enantioselectivities obtained using 3a were relatively high with difficult substrates such as benzyl, hexyl and butyl methyl sulfides, which are usually oxidized with low enantioselectivities. The lower enantioselectivities compared to 1b are probably a result of the lower rate of reaction found when using 3a, which is demonstrated by the lower reaction conversions obtained after 1 h; while complete conversion was observed after 60 min when using catalyst 1 [29,30,31], the reaction was not finished when using catalyst 3a. This fact causes that the non-stereoselective oxidation of the substrate with hydrogen peroxide (blank) competes significantly with the reaction catalyzed by 3a. This was in accordance with the observation that a higher catalyst loading increased the enantioselectivity of the reactions up to 50% ee in the case of substrates, which are susceptible to non-catalyzed oxidation (e.g., t-BuSCH3 or BuSCH3).
Table
Table 2. H2O2-sulfoxidations catalyzed by conjugate 3a and comparison with data for 1b and non-catalyzed reaction a.
Table 2. H2O2-sulfoxidations catalyzed by conjugate 3a and comparison with data for 1b and non-catalyzed reaction a.
SulfideConversion b (%)/ee c (%)Conversion of Blank b,d (%)
3a1b e
n-C4H9SCH3quant. f/33-97
quant. f/50 g
n-C6H13SCH342/3992/6410
n-C8H17SCH39/1144/292
n-C10H21SCH334/1099/00
t-C4H9SCH3quant. f/1398/8698
quant. f/30 g
c-C6H11SCH377/2692/8039
BnSCH359/3592/5820
p-TolylSCH336/2696/694
PhSCH338/2070/362
a Conditions: substrate (0.1 mmol), H2O2 (2.3 equiv.), phosphate buffer pH 7.5, 25 °C, catalyst loading 1 mol % (related to the substrate) if not stated otherwise; vigorous shaking for 1 h; b conversion determined by 1H-NMR; c ee determined by HPLC on a chiral stationary phase (see Supplementary Material for details); d oxidations without catalyst; e data from ref. [30]; f quantitative conversion; g 5 mol % of the catalyst.
The results show the replacement of amide by triazole spacer influences the catalytic activity of flavin-cyclodextrin conjugates. Most probably higher hydrogen bonding ability of amide function compared to triazole could positively influence the efficiency of amide type catalysts 1. Hydrogen bonds could (i) increase the intrinsic reactivity of hydroperoxide function in flavin-4a-hydroperoxide during oxygen transfer to a substrate (see Figure S6 in Supporting Materials for illustration) [41]; and (ii) affect relative arrangement of flavin and cyclodextrin subunits. Nevertheless, as shown recently [31], the catalytic activity of flavin-cyclodextrin conjugates is very sensitive on only minor changes in their structure and thus, further studies are necessary to fully understand the structure activity relationship.
Although flavin-cyclodextrin conjugates do not achieve enantioselectivities exhibited by enzymes (see Table 3), they seem to be promising biomimetic catalysts of sulfoxidations. They provide the oxidations within a relatively short time and in contrast to enzymes, they usually work at higher substrate concentrations. Biocatalytic systems with monooxygenases are more complicated as they require regeneration of NADPH. Cofactor regeneration is usually provided by glucose-6-phosphate dehydrogenase using glucose-6-phosphate as sacrificial reductant. On the other hand biocatalytic systems use oxygen as stoichiometric oxidant, which, advantageously, avoids any background (non-stereoselective) oxidation without participation of the catalyst since oxygen itself is not reactive enough to oxidize most sulfides under mild conditions. Undesired non-catalyzed oxidation unfortunately occurs in oxidations with hydrogen peroxide (see blank experiments in Table 2) thus decreasing overall stereoselectivity. Probably, use of oxygen in place of hydrogen peroxide in oxidations with flavin-cyclodextrin conjugates, analogously to enzymes (combined with a sacrificial reducing agent [2]), would be a way to eliminate some background non-selective oxidations. The other way to improve our catalytic systems could be to optimize the solvent conditions or to increase the reactivity of flavin subunit by introduction of a strong electron-withdrawing group to flavin benzene ring [6].
Table
Table 3. Comparison of the catalytic activity of flavin-cyclodextrin conjugates 1a and 3a with enzymes in sulfoxidations of selected sulfides.
Table 3. Comparison of the catalytic activity of flavin-cyclodextrin conjugates 1a and 3a with enzymes in sulfoxidations of selected sulfides.
CatalystConcentration of Substrate (mM)Reaction Time (h)Conversion (%)/ee (%)
n-C4H9SCH3PhSCH3p-TolylSCH3t-C4H9SCH3
1a a1201-93/6499/8099/88
3a b1201quant. e/50--quant. e/30
HAPMO c10–202499/99 f96/9977/99-
CHMO d35overnight-88/9994/3798/99
a 1 mol %, data from ref. [30]; b 5 mol %; c Recombinant 4-hydroxyacetophenon monooxygenase from Pseudomonas fluorescens ACB, 1 U/mL, data from ref. [42]; d Cyclohexanone monooxygenase from Acinetobacter calcoaceticus, 0.5 U/mL, data from ref. [15]; e quantitative conversion; f data from ref. [43].

3. Experimental Section

3.1. General Information

NMR spectra were obtained on Varian Mercury Plus 300 (1H at 299.9 MHz, 13C at 75.5 MHz) (Varian, Palo Alto, CA, USA), Agilent 400-MR DDR2 (1H at 399.9 MHz, 13C at 100.6 MHz) (Agilent Technologies, Santa Clara, CA, USA), Bruker AVANCE 500 (1H at 500.1 MHz, 13C at 125.8 MHz) (Bruker Bioscience, Billerica, MA, USA) and Bruker AVANCE 600 (1H at 600.1 MHz, 13C at 150.9 MHz) spectrometers (Bruker Bioscience). Mass spectra were acquired using ES ionization on LTQ Orbitrap XL spectrometer (ThermoFisher Scientific Inc., Waltham, MA, USA). FT-IR spectra were measured on Nicolet 6700 equipped with ATR accessory (ThermoFisher Scientific Inc.), UV-VIS spectra on Varian Cary 50 spectrometer (Varian). Enantiomeric excess was determined by HPLC on columns with chiral stationary phase equipped with UV detector (wavelength 254 nm and 215 nm; Ingos, Prague, Czech Republic). TLC and RP-TLC chromatographies were performed with percoated Silica Gel DC Alufolien Kieselgel 60 F254 and 60 RP-18 F254 plates from Merc (Merck-Schuchardt, Hohenbrunn, Germany). Melting points were determined on Boetius microscopic apparatus (Hebenstreit-Rapido GmbH, Radebeul, Germany). Optical rotation was measured on Perkin-Elmer polarimeter 241 (PerkinElmer, Akron, OH, USA).
Alkylating agents 4-bromobut-1-yne [44] and 5-bromopent-1-yne [45,46,47], and alloxazines 3-methylalloxazine [48] and 1-methylalloxazine [31] were prepared according to previously published procedures.

3.2. Synthesis of Conjugates

3.2.1. Alkylation of 3-Methylalloxazine

General Procedure

Substituted alloxazine was dissolved in dry N,N-dimethylformamide (DMF) and 2 equivalents of alkynylbromide and 5 equivalents of potassium carbonate were added. Reaction mixture was stirred under nitrogen atmosphere for 24 h. The reaction was followed by TLC (chloroform/methanol 100:3). Solid salts were filtered off and solvent was evaporated in vacuo. Residue was dissolved in dichloromethane and washed with water. Water layer was separated and extracted with dichloromethane. Collected organic layers were washed with water and dried with sodium sulfate. After evaporation of solvents, solid product was dried in vacuo.
3-Methyl-1-propargylalloxazine (5a): Synthesis according to general procedure with 3-methylalloxazine (0.5 g, 2.2 mmol), propargylbromide (0.7 g, 4.4 mmol) and potassium carbonate (1.5 g, 11.0 mmol). 5a was obtained as yellow solid (0.5 g, 79%). M.p. 241–244 °C. 1H-NMR (300 MHz, CDCl3) δ 8.37 (dd, J = 8.4, 1.0 Hz, 1H), 8.10 (dd, J = 8.4 Hz, 1H), 7.93 (ddd, J = 8.5, 6.8, 1.5 Hz, 1H), 7.80 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 5.26 (d, J = 2.4 Hz, 2H), 3.63 (s, 3H), 2.23 (t, J = 2.5 Hz, 1H), 13C-NMR (75 MHz, CDCl3) δ 159.28, 149.60, 143.62, 142.87, 140.04, 133.77, 130.52, 129.23, 127.72, 71.18, 31.68, 28.98. HRMS-ESI+ m/z: [M + Na]+ calcd for C14H10N4NaO2 289.0696, found 289.0696.
1-(But-3-ynyl)-3-methylalloxazine (5b): Synthesis according to general procedure with 3-methylalloxazine (1.0 g, 4.4 mmol), 4-brombut-1-yn (1.1 g, 8.8 mmol) and potassium carbonate (3.0 g, 22.0 mmol). 5b was obtained (1.2 g, 95%) as yellow solid. M.p. 260–261 °C. 1H-NMR (300 MHz, CDCl3) δ 8.39–8.32 (m, 1H), 8.09–8.02 (m, 1H), 7.92 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.78 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 4.69 (t, J = 7.3 Hz, 2H), 3.61 (s, 3H), 2.78 (td, J = 7.3, 2.7 Hz, 2H), 1.97 (t, J = 2.7 Hz, 1H), 13C-NMR (75 MHz, CDCl3) δ 159.96, 150.50, 146.94, 145.56, 143.42, 140.41, 134.19, 131.04, 129.56, 128.14, 81.41, 70.56, 41.09, 29.45, 17.67. HRMS-ESI+ m/z: [M + Na]+ calcd for C15H12N4NaO2 303.0858, found 303.0855.
3-Methyl-1-(pent-4-ynyl)alloxazine (5c): Synthesis according to general procedure with 3-methylalloxazine (39 mg, 0.17 mmol), 5-brompent-1-yn (50 mg, 0.34 mmol) and potassium carbonate (118 mg, 0.85 mmol). 5c was obtained (45 mg, 90%) as yellow solid. M.p. 262–264 °C. 1H-NMR (300 MHz, CDCl3) δ 8.35 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.95–7.87 (m, 1H), 7.81–7.72 (m, 1H), 4.60 (t, 2H), 3.61 (s, 3H), 2.38 (td, J = 6.9, 2.5 Hz, 2H), 2.18–2.02 (m, 3H), 1.95 (t, J = 2.7 Hz, 1H), 13C-NMR (75 MHz, CDCl3) δ 150.83, 145.28, 143.70, 140.41, 134.06, 131.02, 129.42, 128.14, 98.52, 83.50, 68.99, 42.26, 34.87, 29.40, 26.46, 16.55. HRMS-ESI+ m/z: [M]+ calcd C16H14N4NaO2+ 317.1014, found 317.1011.
1-Methyl-3-propargylalloxazine (6): Synthesis according to general procedure with 1-methylalloxazine (0.5 g, 2.2 mmol), propargylbromide (0.7 g, 4.4 mmol) and potassium carbonate (1.5 g, 11.0 mmol). 6 was obtained (0.4 g, 69%) as yellow solid. M.p. 186–187 °C. 1H-NMR (300 MHz, CDCl3) δ 8.43–8.27 (m, 1H), 8.11–7.99 (m, 1H), 7.92 (ddd, J = 8.5, 6.8, 1.5 Hz, 1H), 7.78 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 4.97 (d, J = 2.5 Hz, 2H), 3.85 (s, J = 3.7 Hz, 3H), 2.26–2.23 (m, 1H). 13C-NMR (101 MHz, CDCl3) δ 159.01, 149.96, 145.55, 143.39, 140.07, 134.13, 130.85, 129.69, 129.36, 127.89, 77.58, 71.43, 31.69, 29.70. HRMS-ESI+ m/z: [M + Na]+ calcd for C14H10N4NaO2 289.0696, found 289.0696.

3.2.2. Click Reactions

General Procedure A

The mixture of alkynyl alloxazine 5 or 6 and 6-azido-6-deoxy-β-cyclodextrin 7 (1.2 equiv.) was stirred with copper (I) iodide (3 mol %) and N,N-diisopropylethylamine (2 equiv.) in dry N,N-dimethylformamide (DMF) at room temperature for 24 h. Conjugate was precipitated after addition of acetone and separated by centrifugation. Crude product was purified by flash chromatography on the column with reversed phase (gradient MeOH/H2O 1:9→MeOH/H2O 2:3). The obtained solid product 8 or 9 was dried in vacuo.

General Procedure B

The mixture of alkynyl alloxazine 5 or 6 and 6-azido-6-deoxy-β-cyclodextrin 7 (1.2 equiv.) was stirred with TBTA (tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine) (20 mol %), sodium ascorbate (20 mol %) and copper (II) sulfate (10 mol %) in dry N,N-dimethylformamide (DMF) at room temperature for 24 h. Conjugate was precipitated after addition of acetone and separated by centrifugation. Crude product was purified by flash chromatography on the column with reversed phase (gradient MeOH/H2O 1:9→MeOH/H2O 2:3). The obtained solid product 8 or 9 was dried in vacuo.
1-{[1-(6-Deoxy-β-cyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl]methyl}-3-methylalloxazine (8a): Synthesis according to general procedure A for click reactions using 3-methyl-propargylalloxazine (75 mg, 0.28 mmol), 6-azido-6-deoxy-β-cyclodextrin (390 mg, 0.34 mmol), copper (I) iodide (3 mg, 0.01 mmol), N,N-diisopropylethylamine (98 µL, 0.56 mmol) and 4 mL of dry DMF. Product 8a (270 mg, 68%) was obtained as yellowish powder.
Synthesis according to general procedure B for click reactions using 3-methyl-propargylalloxazine (28 mg, 0.11 mmol), 6-azido-6-deoxy-β-cyclodextrin (164 mg, 0.14 mmol), TBTA (11 mg, 0.02 mmol), sodium ascorbate (4 mg, 0.02 mmol), copper (II) sulfate (3 mg, 0.01 mmol), 4 mL of dry DMF. Product 8a (123 mg, 83%) was obtained as yellowish powder. M.p. 238–239 °C. 1H-NMR see Tables S2 and S4, 13C-NMR see Tables S1 and S3, HRMS-ESI+ m/z: [M + Na]+ calcd for C56H79N7NaO36 1448.4458, found 1448.4456. [α] D 20 = 105.2° (c = 0.107 g/100 mL, H2O).
1-{[1-(6-Deoxy-β-cyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl]ethyl}-3-methylalloxazine (8b): Synthesis according to general procedure B for click reactions using 1-but-3-ynyl-3-methylalloxazine (30 mg, 0.11 mmol), 6-azido-6-deoxy-β-cyclodextrin 7 (164 mg, 0.14 mmol), TBTA (11 mg, 0.02 mmol), sodium ascorbate (4 mg, 0.02 mmol), copper (II) sulfate (3 mg, 0.01 mmol), 4 mL of dry DMF. Product 8b (90 mg, 58%) was obtained as yellowish powder. M.p. 241–242 °C. 1H-NMR see Tables S2 and S4, 13C-NMR see Tables S1 and S3, HRMS-ESI+ m/z: [M + Na]+ calcd for C57H81N7NaO36 1462.4615, found 1462.4615. [α] D 20 = 104.6° (c = 0.108 g/100 mL, H2O).
1-{[1-(6-Deoxy-β-cyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl]propyl}-3-methylalloxazine (8c): Synthesis according to general procedure A for click reactions using 3-methyl-1-pent-4-ynylalloxazine (35 mg, 0.14 mmol), 6-azido-6-deoxy-β-cyclodextrin 7 (166 mg, 0.14 mmol), copper (I) iodide (1 mg, 0.01 mmol), N,N-diisopropylethylamine (41 µL, 0.24 mmol) and 2 mL of dry DMF. Product 8c (40 mg, 23%) was obtained as yellowish powder.
Synthesis according to general procedure B for click reactions using 3-methyl-1-pent-4-ynylalloxazine (35 mg, 0.12 mmol), 6-azido-6-deoxy-β-cyclodextrin 7 (182 mg, 0.15 mmol), TBTA (12 mg, 0.02 mmol), sodium ascorbate (4 mg, 0.02 mmol), copper (II) sulfate (3 mg, 0.01 mmol), 4 mL of dry DMF. Product 8c (157 mg, 91%) was obtained as yellowish powder. M.p. 272–274 °C. 1H-NMR see Tables S2 and S4, 13C-NMR see Tables S1 and S3, HRMS-ESI+ m/z: [M + H]+ calcd for C58H84N7O36 1454.4952, found 1454.4958. [α] D 20 = 112.3° (c = 0.110 g/100 mL, H2O).
3-{[1-(6-Deoxy-β-cyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl]methyl}-1-methylalloxazine (9): Synthesis according to general procedure A for click reactions using 1-methyl-3-propargylalloxazine (25 mg, 0.07 mmol), 6-azido-6-deoxy-β-cyclodextrin 7 (130 mg, 0.11 mmol), copper (I) iodide (1 mg, 0.01 mmol), N,N-diisopropylethylamine (33 µL, 0.19 mmol) and 1 mL of dry DMF. Yellowish product 9 (46 mg, 34%) was obtained.
Synthesis according to general procedure B for click reactions using 1-methyl-3-propargylalloxazine (56 mg, 0.21 mmol), 6-azido-6-deoxy-β-cyclodextrin 7 (328 mg, 0.29 mmol), TBTA (22 mg, 0.04 mmol), sodium ascorbate (8 mg, 0.04 mmol), copper (II) sulfate (6 mg, 0.02 mmol), 4 mL of dry DMF. Product 9 (192 mg, 64%) was obtained as yellowish powder. M.p. 288–290 °C. 1H-NMR see Tables S2 and S4, 13C-NMR see Tables S1 and S3, HRMS-ESI+ m/z: [M + Na]+ calcd for C56H79N7NaO36 1448.4458, found 1448.4434. [α] D 20 = 90.6° (c = 0.102 g/100 mL, H2O).

3.2.3. Quaternization of Conjugates

General Procedure

Conjugate 8 or 9 was mixed with acetaldehyde (300 equiv.), palladium on carbon (10% w/w), ethanol, water and 0.1 M perchloric acid. Reaction mixture was stirred in autoclave for 21 h under hydrogen atmosphere (0.6 MPa). Palladium was filtered off and organic solvents were evaporated in vacuo. Residue was diluted with water to adjust the volume to exactly 2 mL.
Despite our great efforts, we were unable to record clear NMR spectra of the quaternized conjugates due to peak broadening as a result of the presence of radical species [29,30,31]. Nevertheless, in mass spectra only signals of alloxazinium ions were found. UV spectra of all the prepared catalysts showed maxima at approximately 445 and 382 nm, which are characteristic for alloxazinium salts. For details, see Supplementary Materials.
1-{[1-(6-Deoxy-β-cyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl]methyl}-3-methylalloxazinium perchlorate (3a): Synthesis according to general procedure for quarternisation of conjugates using conjugate 8a (15 mg, 10 µmol), acetaldehyde (170 µL, 3 mmol), palladium on carbon (2 mg, 10% w/w), ethanol (800 µL), perchloric acid (800 µL, 0.1 M), water (600 µL). HRMS-ESI+ m/z: [M + H]+ calcd for C58H84N7O36 1454.4952, found 1454.4955, UV-VIS (pH = 3.6, c = 5.0 × 10−5 mol/L): 382 nm, 441 nm.
1-{[1-(6-Deoxy-β-cyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl]ethyl}-3-methylalloxazinium perchlorate (3b): Synthesis according to general procedure for quarternisation of conjugates using conjugate 8b (11 mg, 7 µmol), acetaldehyde (120 µL, 2 mmol), palladium on carbon (2 mg, 10% w/w), ethanol (570 µL), perchloric acid (570 µL, 0.1 M) and water (430 µL). HRMS-ESI+ m/z: [M + H]+ calcd for C59H86N7O36 1468.5109, found 1468.5122. UV-VIS (pH = 3.6, c = 3.6 × 10−5 mol/L): 382 nm, 448 nm.
1-{[1-(6-Deoxy-β-cyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl)propyl)-3-methylalloxazinium perchlorate (3c): Synthesis according to general procedure for quarternisation of conjugates using conjugate 8c (12 mg, 8 µmol), acetaldehyde (130 µL, 2 mmol), palladium on carbon (2 mg, 10% w/w), ethanol (620 µL), perchloric acid (620 µL, 0.1 M) and water (460 µL). HRMS-ESI+ m/z: [M + H]+ calcd for C60H88N7O36 1482.5265, found 1482.5272. UV-VIS (pH = 4.1, c = 6.2 × 10−5 mol/L): 382 nm, 448 nm.
3-{[1-(6-Deoxy-β-cyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl]methyl}-1-methylalloxazinium perchlorate (4): Synthesis according to general procedure for quarternisation of conjugates using conjugate 9 (45 mg, 30 µmol), acetaldehyde (510 µL, 9 mmol), palladium on carbon (7 mg, 10% w/w), ethanol (2.4 mL), perchloric acid (2.4 mL, 0.1 M) and water (1.8 mL). HRMS-ESI+ m/z: [M + H]+ calcd for C58H84N7O36 1454.4952, found 1454.4954, UV-VIS (pH = 4.3, c = 1.6 × 10−5 mol/L): 385 nm, 448 nm.

3.3. Catalytic Oxidations

Catalytic oxidations of alkyl or aryl methyl sulfides were performed in 1 mL thick-walled screw-capped vial (Supelco). The reaction mixtures were prepared by addition of sodium-phosphate buffer (pH = 7.5, 0.05 M, 300 μL), liquid substrate (3 × 10−5 mol), appropriate volume of catalyst solution (1 mol %–5 mol %) and finally aqueous hydrogen peroxide (2.3 mol equiv.). Stirring of the reaction mixture was provided by wrist action shaker (900 rpm) for 1 h at 25 °C. Then the reaction was quenched by addition of a solution of sodium dithionite in water (1.4 M, 170 μL). The mixture was extracted with CDCl3 (3 × 0.5 mL). Collected organic layers were dried with molecular sieves (3Å) and used for 1H-NMR determination of the conversion. Enantiomeric excess was determined by HPLC analysis on column with chiral stationary phase of the sample obtained by evaporation of CDCl3 and dissolving a residue in heptane (0.5 mL).

4. Conclusions

We have demonstrated the CuAAC concept is useful for the preparation of flavin-cyclodextrin conjugates. The click chemistry represents alternative approach to the original procedure based on amide coupling and seems to be slightly more advantageous especially by reducing the number of reaction steps and improving the overall yield. Recently, Rotello found the isoalloxazine ring tolerates “click chemistry” when preparing flavin-polymer conjugates [37,38]; we have shown the CuAAC approach was tolerated by alloxazines. Therefore, it seems CuAAC can be used as a general tool for the construction of flavin (isoalloxazin or alloxazine) based supramolecular systems, which can be useful not only in organocatalysis, but also in photocatalysis [3,26,27,28] and molecular recognition [49]. The new conjugates show lower efficiency in the enantioselective sulfoxidation reaction when compared with catalyst 1, which possesses an amide linker. However, 3a is comparable with the other chiral flavin catalysts [1,2,3] and even overcomes efficiency of flavin conjugates with amide linker in butyl methyl sulfide oxidation achieving ee up to 50%. One should bear in mind that cyclodextrin-based catalysts usually achieve rather moderate enantioselectivities and the results found with conjugate 1 are rather exceptional. The extreme sensitivity to small structural changes observed among the flavin-cyclodextrin conjugates is a typical phenomenon that also occurs in the natural enzymes and its elucidation is currently being investigated in our laboratory.

Supplementary Materials

Supplementary materials can be accessed at: https://www.mdpi.com/1420-3049/20/11/19667/s1.

Acknowledgments

The authors wish to thank the Czech Science Foundation (Grant No. P207/12/0447) and Ministry of Education, Youth and Sports of the Czech Republic (Specific university research No. 20/2015) for financial support. We thank Jan Zelenka for preparation of samples of conjugates.

Author Contributions

P.T. performed the experiments and analyzed the data, J.Š. contributed to optimization of click chemistry procedure and to results discussion, M.B. measured and analyzed NMR data of conjugates and R.C. contributed to discussion and wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds 8 and 9 are available from the authors.

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MDPI and ACS Style

Tomanová, P.; Šturala, J.; Buděšínský, M.; Cibulka, R. A Click Chemistry Approach towards Flavin-Cyclodextrin Conjugates—Bioinspired Sulfoxidation Catalysts. Molecules 2015, 20, 19837-19848. https://doi.org/10.3390/molecules201119667

AMA Style

Tomanová P, Šturala J, Buděšínský M, Cibulka R. A Click Chemistry Approach towards Flavin-Cyclodextrin Conjugates—Bioinspired Sulfoxidation Catalysts. Molecules. 2015; 20(11):19837-19848. https://doi.org/10.3390/molecules201119667

Chicago/Turabian Style

Tomanová, Petra, Jiří Šturala, Miloš Buděšínský, and Radek Cibulka. 2015. "A Click Chemistry Approach towards Flavin-Cyclodextrin Conjugates—Bioinspired Sulfoxidation Catalysts" Molecules 20, no. 11: 19837-19848. https://doi.org/10.3390/molecules201119667

APA Style

Tomanová, P., Šturala, J., Buděšínský, M., & Cibulka, R. (2015). A Click Chemistry Approach towards Flavin-Cyclodextrin Conjugates—Bioinspired Sulfoxidation Catalysts. Molecules, 20(11), 19837-19848. https://doi.org/10.3390/molecules201119667

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