Synthesis of rigidified flavin-guanidinium ion conjugates and investigation of their photocatalytic properties

Article abstract of DOI:10.3762/bjoc.5.26

Flavin chromophores can mediate redox reactions upon irradiation by blue light. In an attempt to increase their catalytic efficacy, flavin derivatives bearing a guanidinium ion as oxoanion binding site were prepared. Chromophore and substrate binding site

Full text of DOI:10.3762/bjoc.5.26

Synthesis of rigidified flavin–guanidinium ion
conjugates and investigation of their
photocatalytic properties
Harald Schmaderer, Mouchumi Bhuyan and Burkhard König*
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 26.
Institute of Organic Chemisty, University of Regensburg,
Universitätsstr. 31, D-93040 Regensburg, Germany
doi:10.3762/bjoc.5.26
Received: 27 February 2009
Accepted: 07 May 2009
Published: 28 May 2009
Email:
Burkhard König* - burkhard.koenig@chemie.uni-regensburg.de
* Corresponding author
Associate Editor: J. Murphy
Keywords:
© 2009 Schmaderer et al; licensee Beilstein-Institut.
License and terms: see end of document.
flavin; guanidine; Kemp’s acid; photocatalysis; template
Abstract
Flavin chromophores can mediate redox reactions upon irradiation by blue light. In an attempt to increase their catalytic efficacy,
flavin derivatives bearing a guanidinium ion as oxoanion binding site were prepared. Chromophore and substrate binding site are
linked by a rigid Kemp’s acid structure. The molecular structure of the new flavins was confirmed by an X-ray structure analysis
and their photocatalytic activity was investigated in benzyl ester cleavage, nitroarene reduction and a Diels–Alder reaction. The
modified flavins photocatalyze the reactions, but the introduced substrate binding site does not enhance their performance.
Introduction
Flavins are redox-active chromophores [1-6] and represent one photoinduced electron transfer processes, which strongly
of the most abundant classes of natural enzyme co-factors [7-9]. depend on distance [44]. We present here the synthesis of
Recently, the photo redox properties of flavins have been used geometrically defined flavin-guanidinium ion conjugates based
to catalyze chemical reactions [10-30]. A general drawback of on a Kemp’s acid skeleton (Scheme 1). The guanidinium
photochemical processes in homogeneous solution is the limited moiety should serve as a hydrogen bonding site for oxoanions
preorganization of the reactants and the chromophore, which or carbonyl groups [45-49]. The structure of the new flavins
may lead to low selectivities and slow conversions in diffusion was determined in solid state and in solution and their
controlled reactions. To overcome this problem, Kemp’s acid photocatalytic properties were tested.
[31] derivatives have been used as sterically defined templates
Results and Discussion
enhancing the efficiency and selectivity of photoreactions
[32-43]. Flavins with geometrically defined substrate binding Synthesis
sites have not been reported so far and we expected that the The synthesis of the potential photocatalysts 1 and 2, consisting
close vicinity of substrate and flavin should enhance the rate of of the flavin chromophore, the guanidinium substrate binding
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Beilstein Journal of Organic Chemistry 2009, 5, No. 26.
Scheme 1: Flavin–guanidinium ion conjugates 1 and 2 and tetraacetyl riboflavin (3).
site and a Kemp’s acid derived rigid linker, starts from Kemp’s chloride salts 1 and 2 (Scheme 2). The guanidinium salts are
acid anhydride (5) [50-52]. The anhydride 5 was allowed to soluble in water and methanol, but also in chloroform and acet-
react with previously prepared flavins 4 and 8 [21] in the pres- onitrile.
ence of DMAP as catalyst. The amide formation of the carboxyl
group with Boc-protected guanidine was achieved using Structural investigations
standard peptide coupling conditions. Boc-deprotection with The structure of compounds 1, 2, 6, and 9 was examined in the
hydrogen chloride in diethyl ether yielded the guanidinium solid state and in solution. Figure 1 shows the X-ray crystal
Scheme 2: Synthesis of flavins 1 and 2. Conditions: (i) DMAP, H2O, Δ, 20 h, 71–78%, (ii) HOBt, EDC, NEt(iPr)2, mono-Boc guanidine, CH2Cl2, rt, 20
h, 58–82%, (iii) HCl/Et2O, CH2Cl2/CHCl3, rt, 24 h, 83–90%.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 26.
Figure 1: X-ray crystal structures of the flavin-Kemp’s acids 6 (left) and 9 (right).
structures of 6 and 9. The planar flavin chromophore is turned the flavin carbonyl oxygen atom and the guanidinium moiety
outward relative to the Kemp’s acid. Intermolecular π-π-interac- (distance ~2.1 Å). However, simple gas phase calculations over-
tions between the flavin heteroarenes are observed.
estimate the effect of hydrogen bonds [54-58] and in solution
the flavin chromophore is expected to rotate freely around the
The structure of compound 1 in the solid state (Figure 2) shows C–C single bonds of the ethane linker.
an almost identical orientation of the flavin group to that of the
acid 6. The acyl guanidinium ion group is almost planar and in
a parallel orientation relative to the Kemp’s acid imide group.
Figure 2: Structure of compound 1 in the solid state.
Figure 3: Calculated lowest energy conformation of 1 in the gas phase
(AM1, Spartan program package).
2-D NMR spectra of compounds 1 and 2 revealed several NOE
contacts, but the flexibility of the molecule did not allow the
determination of preferred conformations.
Photocatalytic reactions
Compounds 1 and 2 were tested as photocatalysts in three
different reactions and their performance was compared to
tetraacetyl riboflavin 3 or compound 8. Dibenzyl phosphate
esters are oxidatively cleaved by blue light irradiation (440 nm)
in the presence of compounds 1 and 2 (Scheme 3). The acceler-
ation of the reaction in acetonitrile by 1 and 2, bearing a guan-
The most stable conformer of compound 1 in the gas phase was
determined by computational methods (semi-empirical AM1,
Spartan program package, Figure 3, see also Supporting
Information File 1) [53]. In this structure the flavin is turned
towards the guanidinium ion forming a hydrogen bond between
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Beilstein Journal of Organic Chemistry 2009, 5, No. 26.
idinium ion binding site with phosphate affinity, is significantly was probed by UV/vis and emission spectroscopy in acetoni-
larger (Table 1, entries 1+2) in comparison to the ammonium trile and buffered aqueous solution. The emission intensity of
salt 8 (entry 3). In water, however, the accelerating effect is not the chromophore of 2 decreased slightly in the presence of the
observed (entries 5–8). The presence of the photocatalyst is anions in acetonitrile indicating a weak interaction. In aqueous
essential in all cases, as the non-catalyzed hydrolysis is slow solution the presence of the anions did not induce significant
under the reaction conditions (<5% conversion).
changes of the emission properties suggesting affinity constants
smaller than 103 L/mol.
Table 2: Results of nitrobenzene photoreduction.
Entry
Catalyst
Solvent
Conversion (%)
1
2
3
4
5
1
2
2
3
8
H2O
H2O
H2Oa
H2Oa
H2O
36
72
73
89
79
Scheme 3: Oxidative photocleavage of dibenzyl phosphate.
Table 1: Oxidative photocleavage of dibenzyl phosphate.
Entry
Catalyst Solvent
t (h)
Conversion (%)
6b
7b
8b
9b
1c
2
MeCN
MeCN
MeCN
MeCN
15
55
81
59
1a
2a
3a
4a
1
2
8
–
MeCN-d3
MeCN-d3
MeCN-d3
MeCN-d3
4
4
4
4
53
58
12
<5
3
8
Conditions: V = 5 mL, nitrobenzene 10−2 M, catalyst 10 mol%,
N(CH2CH2OH)3 10 equiv, t = 4 h, 40 °C, LED (440 nm), UV-lamp (370
nm). a10% DMSO added to increase solubility. b4-Nitrophenyl phos-
phate was neutralized previous to the reaction. cThe catalyst is barely
soluble in MeCN, which explains the lower conversion in this case.
5
6
7
8
1
2
8
–
D2O
D2O
D2O
D2O
2
2
2
2
44
15
50
<5
Conditions: V = 1 mL, dibenzyl phosphate 10−2 M, catalyst 20 mol%, 40
°C, LED (440 nm). aDibenzyl phosphate ester was neutralized previous
to the reaction.
Photo Diels–Alder reactions in the presence of a sensitizer and
light have been described [59-64]. Therefore flavins 1 and 2
were tested as catalyst for the cycloaddition of maleimide to
In the presence of sacrificial electron donor substrates, such as anthracene in toluene (Scheme 5). Table 3 summarizes the
aliphatic amines, flavins can photoreduce nitro arenes to results. A significantly higher yield of the cycloaddition product
anilines under blue light irradiation (Scheme 4). 4-Nitrophenyl was obtained after 8 h at 40 °C in the presence of compound 2
phosphate was used as a substrate for photoreduction in water (entry 3), if compared to the control reaction (entry 6). Upon
and in acetonitrile. The results summarized in Table 2 show that irradiation with blue light the yield after 8 h reaction time
10 mol% of flavin 2, the same amount of tetraacetyl riboflavin increased further (entry 2) and was significantly higher as in the
(3) or compound 8 catalyze the photoreaction equally well. The absence of a photocatalyst (entry 5). However, a comparison
guanidinium ion binding site of 1 and 2 does not lead to a more with tetraacetyl riboflavin (3) under identical reaction condi-
effective conversion.
tions showed an even more pronounced acceleration of the reac-
tion (entry 4). Blue light irradiated flavins accelerate the anthra-
cene maleimide cycloaddition significantly, but flavins 1 and 2
Scheme 4: Photoreduction of 4-nitrophenyl phosphate.
Scheme 5: Photo Diels–Alder-reaction of anthracene with N-methyl-
maleinimide.
The intermolecular interaction of the guanidinium ion binding
site of compound 2 with phosphate ester anions and dianions
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Beilstein Journal of Organic Chemistry 2009, 5, No. 26.
do not provide additional benefit if compared to tetraacetyl aminoethyl)-10-(2-methoxyethyl)-7,8-dimethylbenzo[g]pter-
flavin 3.
idine-2,4(3H,10H)-dione], Kemp’s acid anhydride 5 (1,5,7-
trimethyl-2,4-dioxo-3-oxa-bicyclo[3.3.1]nonane-7-carboxylic
acid) and mono Boc-protected guanidine were prepared by
known methods [21,50-52]. All other chemicals were purchased
from commercial suppliers, checked by 1H NMR spectrometry
and then used as received. Solvents were distilled before use.
Flash column chromatography was carried out on silica gel
35–70 μm, 60 Å from Acros. NMR spectra were recorded at a
Bruker Avance 300 spectrometer (300 MHz) or at a Bruker
Avance 600 spectrometer (600 MHz). Electrospray ionisation
(ES-MS) mass spectra were measured on ThermoQuest
Finnigan TSQ 7000 spectrometer. High resolution mass spec-
trometry (HRMS) was measured on ThermoQuest Finnigan
MAT 95 spectrometer. Melting points were measured on a
Büchi SMP-20 apparatus and are not corrected. IR spectra were
measured on Biorad Spectrometer Excalibur FTS 3000. UV/Vis
spectra were recorded at Varian Cary 50 Bio UV/VIS spectro-
meter against air. Fluorescence spectra were recorded at Varian
Table 3: Results of photoinduced Diels–Alder-reaction.
Entry Catalyst
hν
Yield (%) TON
TOF (h−1)
1
1
2
2
3
–
–
–
+
+
–
+
+
–
–
45
85
59
100
30
9
22.5
42.5
28.5
50
2.8
5.3
3.6
6.3
–
2
3
4
5
–
6
–
–
7a
100
–
–
Conditions: Toluene, V = 1.2 mL, anthracene 33 × 10−3 M, maleinimide
2.5 equiv, catalyst 2 mol%, t = 8 h, 40 °C, LED (440 nm). aAnthracene
500 μmol, methyl maleinimide 1.25 mmol, toluene 10 mL, 100 °C, 16 h.
Conclusion
We have prepared new flavin derivatives that bear an acyl guan- Cary Eclipse.
idinium group, which is linked to the chromophore via a rigid
Kemp’s acid spacer. The connectivity and expected relative
1,5,7-Trimethyl-2,4-dioxo-3-[2-(3,7,8-
trimethyl-2,4-dioxo-3,4-dihydrobenzo[g]pter-
idin-10(2H)-yl)ethyl]-3-
geometry of 1 and of the carboxylic acids 6 and 9 was
confirmed by X-ray structure analysis. Guanidinium cations are
known to bind oxoanions, such as phosphates, via hydrogen
bonds. Therefore a benefit to the photocatalytic activity of 1 and
azabicyclo[3.3.1]nonane-7-carboxylic acid;
2 was expected, as the binding site could keep reaction Flavin–Kemp’s acid 6
substrates in close proximity to the redox active chromophore, DMAP (230 mg, 1.9 mmol) and Kemp’s acid anhydride (5)
facilitating photoinduced electron transfer processes. Initial (180 mg, 750 μmol) were added successively to a solution of
exemplary photocatalytic experiments showed that flavin-deriv- flavin salt 4 (250 mg, 750 μmol) in water (22 mL) and the solu-
atives 1 and 2 catalyze oxidative benzyl ether cleavage, nitro tion was refluxed for 20 h. After cooling, the mixture was
arene reductions and Diels–Alder reactions. However, no signi- brought to pH 1 with hydrochloric acid (5 M), and the precipit-
ficant gain in photocatalytic performance by the guanidinium ating orange product was collected by filtration. As thin layer
ion substrate binding site was observed in comparison to flavins chromatography showed considerable amounts of the product in
lacking the binding site and the rigid Kemp’s acid skeleton. The the filtrate, it was concentrated and purified by flash column
primary interaction between the aromatic substrates and the chromatography (CHCl3:MeOH – 15:1), to yield another
heteroaromatic flavin chromophore seems to dominate the portion of orange solid. Yield: 302 mg, 580 μmol, 78%, orange
formation of the substrate–catalyst aggregate. Hydrogen bonds solid; Rf = 0.2 (CHCl3:MeOH − 10:1); mp 292 °C (decomp.);
between the substrate and the acylguanidinium group are not 1H NMR (DMSO-d6) δ = 0.87 (s, 6 H, 2 × Kemps-CH3), 1.00
decisive for their interaction. The rigidity of the Kemp’s triacid (s, 3 H, Kemps-CH3), 1.07–1.26 (m, 3 H, Hax), 2.20–2.24 (m, 3
skeleton is not effectively transferred in 1 and 2 to the relative H, Heq), 2.41 (s, 3 H, Ar-CH3), 2.50 (s, 3 H, Ar-CH3, hidden by
flavin–guanidinium ion orientation, which is due to the flexible DMSO), 3.28 (s, 3 H, N-CH3), 3.90 (s, 2 H, CH2), 4.87 (s, 2 H,
ethane linker between imide and flavin. Derivatives with a more CH2), 7.77 (s, 1 H, Ar-H), 7.98 (s, 1 H, Ar-H), 12.24 (br s, 1 H,
constrained conformation of the flavin chromophore and the COOH); 13C NMR (DMSO-d6) δ = 18.8 (Ar-CH3), 20.9 (Ar-
substrate binding sites may lead to chemical photocatalysts with CH3), 24.7 (2 × CH3), 28.0 (N-CH3), 29.7 (CH3), 37.3
better performance.
(N-CH2), 39.4 (2 × Cqu), 40.9 (2 × CH2), 41.1 (Cqu), 42.1
(CH2), 43.0 (N-CH2), 116.0(C-9), 131.1 (C-9a), 131.3 (C-6),
Experimental
134.2 (C-5a), 135.5 (C-4a), 136.2 (C-7), 146.9 (C-8), 149.4
General
(C-10a), 154.9 (C-2), 159.5 (C-4), 176.2 (2 × CO), 176.5 (CO);
T h e f l a v i n s a l t s
4
[ 1 0 - ( 2 - a m i n o e t h y l ) - 3 , 7 , 8 - ES-MS m/z (%): 522.4 (100) [M+H]+; HRMS–EI m/z: calcd for
trimethylbenzo[g]pteridine-2,4(3H,10H)-dione] and 8 [3-(2- C23H32N5O6 [M+H]+: 522.2353; found: 522.2342 [Δ 2.03
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Beilstein Journal of Organic Chemistry 2009, 5, No. 26.
ppm]; IR (ATR): ν = 1717, 1649, 1583, 1545, 1451, 1250, evaporated to yield an orange solid. The crude product was
1193, 1096, 1053, 970, 756 cm−1.
purified by flash column chromatography (CHCl3:MeOH –
50:1). Yield: 186 mg, 280 μmol, 58%, orange solid; Rf = 0.15
(CHCl3:MeOH – 50:1); mp 255–259 °C (decomp.); 1H NMR
(CDCl3) δ = 0.91–1.05 (m, 12 H, 3 × CH3 + 3 × Hax), 1.48 (s, 9
H, Boc-CH3), 2.39 (s, 3 H, Ar-CH3), 2.48 (s, 3 H, Ar-CH3),
2.64–2.69 (m, 3 H, Heq), 3.48 (s, 3 H, N-CH3), 3.98 (tr, J = 4.53
Hz, 2 H, CH2), 4.84 (br s, 2 H, CH2), 7.30 (s, 1 H, Ar-H) 7.99
(s, 1 H, Ar-H), 8.33 (br s, 1 H, N-H), 8.85 (br s, 1 H, N-H); 13C
3-{2-[10-(2-Methoxyethyl)-7,8-dimethyl-2,4-
dioxobenzo[g]pteridin-3(2H,4H,10H)-yl]ethyl}-
1,5,7-trimethyl-2,4-dioxo-3-
azabicyclo[3.3.1]nonane-7-carboxylic acid;
Flavin–Kemp’s acid 9
DMAP (460 mg, 2.8 mmol) and Kemp’s anhydride (5) (370 NMR (CDCl3) δ = 19.5 (Ar-CH3) 21.9 (Ar-CH3), 25.5 (2 ×
mg, 1.54 mmol) were added successively to a solution of flavin CH3), 28.1 (Boc-CH3), 28.8 (N-CH3), 31.3 (CH3), 37.2
salt 8 (570 mg, 1.50 mmol) in water (50 mL) and the solution (N-CH2), 40.1 (2 × Cqu), 42.3 (CH2), 43.3 (CH2), 44.1
was refluxed for 20 h. After cooling, the mixture was brought to (N-CH2), 44.5 (Cqu), 83.8 (Boc-Cqu), 115.1 (C9), 131.9 (C9a),
pH 1 with hydrochloric acid (5 M), and the precipitating dark 132.8 (C6), 134.7 (C5a), 135.8 (C4a), 136.3 (C7), 146.8 (C8),
orange product was collected by filtration. As thin layer chro- 149.3 (C10a), 153.0 (NHCO), 156.0 (C2), 158.7 (Boc-CO),
matography showed considerable amounts of the product in the 160.2 (C4), 177.5 (NHCO); ES-MS m/z (%): 681.4 [M+NH4]+,
filtrate, it was concentrated and purified by flash column chro- 663.4 (100) [M+H]+, 563.3 [M+H-Boc]+; HRMS–EI m/z: calcd
matography (CHCl3:MeOH – 15:1), to yield another portion of for C33H43N8O7 [M+H]+: 663.3255; found: 663.3242 [Δ 1.92
orange solid. Yield: 597 mg, 1.06 mmol, 71%, orange solid; Rf ppm] IR (ATR): ν = 1716, 1668, 1634, 1584, 1543, 1455, 1367,
= 0.2 (CHCl3:MeOH – 10:1); mp 305 °C (decomp.); 1H NMR 1327, 1236, 1144, 968, 756 cm−1.
(DMSO-d6) δ = 0.97 (s, 6 H, 2 × Kemps-CH3), 1.04 (s, 3 H,
Kemps-CH3), 1.15 (d, J = 13.72 Hz, 2 H, Hax), 1.32 (d, J =
N-(Boc-Carbamimidoyl)-3-{2-[10-(2-meth-
12.62 Hz, 1 H, Hax), 1.82 (d, J = 12.62 Hz, 1 H, Heq), 2.25 (d, J
oxyethyl)-7,8-dimethyl-2,4-dioxobenzo[g]pter-
= 13.17 Hz, 2 H, Heq), 2.41 (s, 3 H, Ar-CH3), 2.50 (s, 3 H,
idin-3(2H,4H,10H)-yl]ethyl}-1,5,7-trimethyl-
Ar-CH3, hidden by DMSO), 3.22 (s, 3 H, O-CH3), 3.74–3.77
2,4-dioxo-3-azabicyclo[3.3.1]nonane-7-
(m, 4 H, 2 × CH2), 4.06–4.07 (m, 2 H, N-CH2), 4.83 (tr, J =
5.35 Hz, 2 H, O-CH2), 7.91 (s, 1 H, Ar-H), 7.98 (s, 1 H, Ar-H), carboxamide; Flavin-Boc-guanidin 10
12.25 (br s, 1 H, COOH); 13C NMR (DMSO-d6) δ = 18.8 (Ar- To a solution of HOBt·H2O (226 mg, 1.67 mmol), EDC (226
CH3), 20.8 (Ar-CH3), 25.0 (CH3), 29.9 (CH3), 37.4, 41.0, 41.6 mg, 1.45 mmol) and DIPEA (498 μL, 970 μmol) in CHCl3 (10
and 43.1 (Cqu and CH2), 44.0 (10-N-CH2), 58.5 (O-CH3), 68.3 mL) was added compound 9 (548 mg, 969 μmol) and mono
(O-CH2), 116.9 (C9), 130.9 (C6), 131.5 (C9a), 134.0 (C5a), Boc-protected guanidine (231 mg, 1.45 mmol) at 0 °C. The
135.6 (C4a), 136.3 (C7), 147.0 (C8), 148.6 (C10a), 155.0 (C2), mixture was stirred at room temperature for 20 h, diluted with
159.7 (C4), 176.1 und 176.6 (COOH und CONH); ES-MS m/z CHCl3 (250 mL) and washed with water and brine. The organic
(%): 566.3 (100) [M+H]+; HRMS–EI m/z: calcd for phase was separated, dried over magnesium sulfate and the
C29H36N5O7 [M+H]+: 566.2615; found: 566.2623 [Δ −1.46 solvents were evaporated. The crude brown product was puri-
ppm]; IR (ATR): ν = 1719, 1673, 1621, 1581, 1548, 1234, fied by flash column chromatography (CHCl3:MeOH:N(Et)3 –
1119, 953, 886, 806, 758 cm−1.
70:1:1). Yield: 564 mg, 798 μmol, 82%, yellow solid; Rf = 0.1
(CHCl3:MeOH:TEA – 50:1:1); mp 229–231 °C (decomp.); 1H
NMR (CDCl3) δ = 0.93–1.21 (m, 12 H, 3 × CH3 + 3 × Hax),
1.46 (s, 9 H, Boc-CH3), 2.15 (d, J = 12.90 Hz, 1 H, Heq), 2.38
(s, 3 H, Ar-CH3), 2.48 (s, 3 H, Ar-CH3), 2.68 (d, J = 13.44 Hz,
2 H, Heq), 3.22 (s, 3 H, O-CH3), 3.80–3.84 (m, 4 H, 2 × CH2),
4.20–4.22 (m, 2 H, CH2), 4.79 (tr, J = 5.08 Hz, 2 H, CH2), 7.58
(s, 1 H, Ar-H) 7.94 (s, 1 H, Ar-H), 8.27 (br s, 1 H, N-H), 8.75
N-(Boc-Carbamimidoyl)-1,5,7-trimethyl-2,4-
dioxo-3-{2-[3,7,8-trimethyl-2,4-dioxo-3,4-
dihydrobenzo[g]pteridin-10(2H)-yl]ethyl}-3-
azabicyclo[3.3.1]nonane-7-carboxamide;
Flavin-Boc-guanidin 7
To a solution of HOBt·H2O (89 mg, 580 μmol), EDC (90 mg, (br s, 1 H, N-H); 13C NMR (CDCl3) δ = 19.5 (Ar-CH3) 21.5
580 μmol) and DIPEA (171 μL, 970 μmol) in CH2Cl2 (6.5 mL) (Ar-CH3), 25.5 (2 × CH3), 28.1 (Boc-CH3), 31.3 (CH3), 38.4
were added compound 6 (252 mg, 480 μmol) and mono Boc- (N-CH2), 40.2 (2 × Cqu), 40.8 (N-CH2), 43.2 (N-CH2), 44.2 (2
protected guanidine (86 mg, 530 μmol) at 0 °C. The mixture × CH2), 44.6 (Cqu), 45.2 (CH2), 59.2 (O-CH3), 69.6 (O-CH2),
was stirred at room temperature for 20 h, diluted with CHCl3 83.4 (Boc-Cqu), 116.6 (C9), 132.2 (C9a), 132.2 (C6), 134.9
(150 mL) and washed with brine twice. The organic phase was (C5a), 135.6 (C4a), 136.4 (C7), 147.2 (C8), 148.7 (C10a),
separated, dried over magnesium sulfate and the solvents were 153.4 (NHCO), 156.1 (C2), 158.5 (Boc-CO), 160.4 (C4), 177.5
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Beilstein Journal of Organic Chemistry 2009, 5, No. 26.
(NHCO), 188.7 (Cqu); ES-MS m/z (%): 707.3 (100) [M+H]+; 0.99 (s, 6 H, 2 × CH3), 1.17 (s, 3 H, CH3), 1.30 (d, J = 14.39
HRMS–EI m/z: calcd for C35H47N8O8 [M+H]+: 707.3517; Hz, 2 H, 2 × CHax), 1.38 (d, J = 12.59 Hz, 1 H, CHax), 1.84 (d,
found: 707.3531 [Δ −2.00 ppm]; IR (ATR): ν = 1706, 1655, J = 12.59 Hz, H, CHeq), 2.39 (s, 3 H, Ar-CH3), 2.51 (s, 3 H,
1634, 1583, 1540, 1457, 1366, 1325, 1226, 1146, 758 cm−1. Ar-CH3), 2.52 (d, J = 14.39 Hz, 2 H, 2 × CHax), 3.21 (s, 3 H,
O-CH3), 3.73–3.75 (m, 4 H, 2 × CH2), 4.02–4.04 (m, 2 H,
CH2), 4.82 (tr, J = 5.52 Hz, 2 H, CH2), 7.89 (Ar-H), 7.95 (Ar-
N-Carbamimidoyl-1,5,7-trimethyl-2,4-dioxo-3-
H), 8.34–8.43 (m, 4 H, NH), 11.42 (s, 1 H, NHCO); 13C NMR
{2-[3,7,8-trimethyl-2,4-dioxo-3,4-
(DMSO-d6) δ = 18.8 (Ar-CH3) 20.7 (Ar-CH3), 24.9 (2 × CH3),
dihydrobenzo[g]pteridin-10(2H)-yl]ethyl}-3-
28.6 (CH3), 37.3 (CH2), 39.5 (CH2), 40.1 (Cqu), 41.2 (CH2),
azabicyclo[3.3.1]nonane-7-carboxamide;
Flavin-guanidinium 1
42.1 (2 × CH2), 43.8 (Cqu), 44.0 (CH2), 116.9 (C9), 130.9 (C6),
131.4 (C5a), 134.1 (C9a), 135.5 (C4a), 136.3 (C7), 147.0 (C8),
Compound 7 (210 mg, 317 μmol) was dissolved in CHCl3 (25 148.5 (C10a), 154.9 (C2), 155.1 (Cqu), 159.7 (C4), 176.0 (CO),
mL) and hydrogen chloride saturated diethyl ether (3 mL) was 177.3 (CO); ES-MS m/z (%): 607.3 (100) [M+H]+; HRMS–EI
added dropwise. After stirring for 24 h, the solution was evapor- m/z: calcd for C30H39N8O6 [M]+: 607.2993; found: 607.2981
ated to 5 mL and diethyl ether (15 mL) was added to precip- [Δ 1.90 ppm]; IR (ATR): ν = 1692, 1669, 1579, 1545, 1456,
itate the product. The mixture was cooled to 0 °C and the solid 1328, 1235, 1173, 747 cm−1; UV/Vis (MeCN): λmax (ε) = 275
was filtered off, washed with diethyl ether and dried. Yield: 157 (96000), 344 (8760), 445 nm (10510); Fluorescence (MeCN):
mg, 262 μmol, 83%, orange-yellow solid; Rf = 0.1 λmax (emission) = 509 nm (excitation: 445 nm).
(CHCl3:MeOH – 10:1); mp 320–322 °C (decomp.); 1H NMR
(DMSO-d6) δ = 0.91 (s, 6 H, 2 × CH3), 1.16 (s, 3 H, CH3),
Supporting Information
1.28–1.31 (m, 4 H, 3 × CHax and CHeq), 2.41 (Ar-CH3), 2.47
(d, J = 14.39 Hz, 2 H, Heq), 2.50 (Ar-CH3, hidden by DMSO),
Photocatalytic experiments, UV/Vis and fluorescence
3.28 (s, 3 H, N-CH3), 3.90 (tr, J = 5.01 Hz, 2 H, CH2), 4.84 (s,
spectra of 1–3, calculated gas phase conformations, 1H and
2 H, CH2), 7.74 (Ar-H), 7.97 (Ar-H), 8.36–8.44 (m, 4 H, NH),
13C NMR spectra of 1, 2, 6, 7, 9, and 10.
11.38 (s, 1 H, NHCO); 13C NMR (DMSO-d6) δ = 18.7 (Ar-
Supporting Information File 1
Koenig_Supporting Information
CH3) 21.0 (Ar-CH3), 24.7 (2 × CH3), 28.0 (N-CH3), 29.0
(CH3), 36.8 (CH2), 40.1 (Cqu), 40.7 (CH2), 42.0 (CH2+Cqu),
43.6 (CH2), 116.0 (C9), 131.1 (C5a), 131.3 (C6), 134.0 (C9a),
135.5 (C4a), 136.2 (C7), 146.8 (C8), 149.3 (C10a), 154.9 (C2),
155.0 (Cqu), 159.4 (C4), 176.0 (CO), 177.3 (CO); ES-MS m/z
(%): 563.3 (100) [M+H]+; HRMS–EI m/z: calcd for
C28H35N8O5 [M+H]+: 563.2730; found: 563.2746 [Δ −2.77
ppm]; IR (ATR): ν = 1700, 1643, 1584, 1546, 1452, 1306,
1238, 1190, 1127, 1098, 1048, 753 cm−1; UV/Vis (MeCN):
λmax (ε) = 272 (41500), 343 (9130), 447 nm (11060); Fluores-
cence (MeCN): λmax (emission) = 507 nm (excitation: 445 nm).
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-26-S1]
Supporting Information File 2
CIF file of compound 1.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-26-S2]
Supporting Information File 3
CIF file of compound 6.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-26-S3]
N-Carbamimidoyl-3-{2-[10-(2-methoxyethyl)-
7,8-dimethyl-2,4-dioxobenzo[g]pteridin-
3(2H,4H,10H)-yl]ethyl}-1,5,7-trimethyl-2,4-
dioxo-3-azabicyclo[3.3.1]nonane-7-carbox-
Supporting Information File 4
CIF file of compound 9.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-26-S4]
amide; Flavin-guanidinium 2
Compound 10 (493 mg, 698 μmol) was dissolved in CHCl3 (50
mL) and hydrogen chloride saturated diethyl ether (6 mL) was
added dropwise. After stirring for 24 h, the solution was evapor-
ated to 5 mL and diethyl ether (25 mL) was added to precip- Acknowledgments
itate the product. The mixture was cooled to 0 °C and the solid This work was supported by the Deutsche Forschungsge-
was filtered off, washed with diethyl ether and dried. Yield: 402 meinschaft (GRK 640 fellowship to H.S.) and the Evonik
mg, 625 μmol, 90%, yellow solid; Rf = 0.15 (CHCl3:MeOH – foundation (fellowship to MB).
10:1); mp 245–247 °C (decomp.); 1H NMR (DMSO-d6) δ =
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Beilstein Journal of Organic Chemistry 2009, 5, No. 26.
27.Smit, C.; Fraaije, M. W.; Minnaard, A. J. J. Org. Chem. 2008, 73,
9482–9485. doi:10.1021/jo801588d
References
1. Müller, F., Ed. Chemistry and Biochemistry of Flavoenzymes; CRC:
Boca Raton, 1991.
28.Bruice, T. C. Acc. Chem. Res. 1980, 13, 256–262.
doi:10.1021/ar50152a002
2. Fritz, B. J.; Kusai, S.; Matsui, K. Photochem. Photobiol. 1987, 45,
113–117. doi:10.1111/j.1751-1097.1987.tb08411.x
3. Bowd, A.; Bysom, P.; Hudson, J. B.; Turnbull, J. H. Photochem.
Photobiol. 1968, 8, 1–10. doi:10.1111/j.1751-1097.1968.tb05839.x
4. Niemz, A.; Rotello, V. M. Acc. Chem. Res. 1999, 32, 44–52.
doi:10.1021/ar980046l
29.Piera, J.; Bäckvall, J.-E. Angew. Chem. 2008, 120, 3558–3576.
Angew. Chem., Int. Ed., 2008, 47, 3506–3523.
doi:10.1002/anie.200700604.
30.Hollmann, F.; Taglieber, A.; Schulz, F.; Reetz, M. T. Angew. Chem.
2007, 119, 2961–2964.
Angew. Chem., Int. Ed., 2007, 46, 2903–2906.
doi:10.1002/anie.200605169.
5. Gishla, S.; Massey, V. Eur. J. Biochem. 1989, 181, 1–17.
doi:10.1111/j.1432-1033.1989.tb14688.x
31.Kemp, D. S.; Petrakis, K. S. J. Org. Chem. 1981, 46, 5140–5143.
doi:10.1021/jo00338a014
6. Schmaderer, H.; Svoboda, J.; König, B. Flavin Photocatalysts with
Substrate Binding Sites. In Activating Unreactive Substrates: The Role
of Secondary Interactions; Bolm, C.; Hahn, E., Eds.; Wiley-VCH:
Weinheim, 2009.
32.Bach, T.; Bergmann, H.; Grosch, B.; Harms, K.; Herdtweck, E.
Synthesis 2001, 1395–1405. doi:10.1055/s-2001-15231
33.Grosch, B.; Orlebar, C. N.; Herdtweck, E.; Massa, W.; Bach, T. Angew.
Chem. 2003, 32, 3693–3696.
7. Mansoorabadi, S. O.; Thibodeaux, C. J.; Liu, H. J. Org. Chem. 2007,
72, 6329–6342. doi:10.1021/jo0703092
Angew. Chem., Int. Ed. 2003, 32, 3693–3696.
doi:10.1002/anie.200351567.
8. Hemmerich, P. Prog. Natl. Prod. Chem. 1976, 33, 451–525.
9. Massey, V. Biochem. Soc. Trans. 2000, 28, 283–296.
doi:10.1042/0300-5127:0280283
34.Bauer, A.; Westkämper, F.; Grimme, S.; Bach, T. Nature 2005, 436,
1139–1140. doi:10.1038/nature03955
10.Moonen, M. J. H.; Fraaije, M. W.; Rietjens, I. M. C. M.; Laane, C.; van
Berkel, W. J. H. Adv. Synth. Catal. 2002, 344, 1023–1035.
doi:10.1002/1615-4169(200212)344:10<1023::AID-ADSC1023>3.0.CO
;2-T
35.Svoboda, J.; König, B. Chem. Rev. 2006, 106, 5413–5430.
doi:10.1021/cr050568w
36.Breitenlechner, S.; Bach, T. Angew. Chem. 2008, 120, 8075–8077.
Angew. Chem., Int. Ed. 2008, 47, 7957–7959.
doi:10.1002/anie.200802479.
11.Murahashi, S.-I.; Ono, S.; Imada, Y. Angew. Chem. 2002, 114,
2472–2474.
37.Mori, K.; Murai, O.; Hashimoto, S.; Nakamura, Y. Tetrahedron Lett.
1996, 37, 8523–8526. doi:10.1016/0040-4039(96)01981-8
38.Amirsakis, D. G.; Elizarov, A. M.; Garcia-Garibay, M. A.; Glink, P. T.;
Stoddart, J. F.; White, A. J. P.; Williams, D. J. Angew. Chem. 2003,
115, 1158–1164.
Angew. Chem., Int. Ed. 2002, 41, 2366–2368.
doi:10.1002/1521-3773(20020703)41:13<2366::AID-ANIE2366>3.0.CO
;2-S.
12.Gelelcha, F. G. Chem. Rev. 2007, 107, 3338–3361.
doi:10.1021/cr0505223
Angew. Chem., Int. Ed. 2003, 42, 1126–1132.
doi:10.1002/anie.200390296.
13.Fitzpatrick, P. F. Acc. Chem. Res. 2001, 34, 299–307.
doi:10.1021/ar0000511
39.Bach, T.; Bergmann, H.; Harms, K. J. Am. Chem. Soc. 1999, 121,
10650–10651. doi:10.1021/ja992209m
14.Wiest, O.; Harrison, C. B.; Saettel, N. J.; Cibulka, R.; Sax, M.; König, B.
J. Org. Chem. 2004, 69, 8183–8185. doi:10.1021/jo0494329
15.Julliard, M.; Chanon, M. Chem. Rev. 1983, 83, 425–506.
doi:10.1021/cr00056a003
40.Bach, T.; Bergmann, H.; Brummerhop, H.; Lewis, W.; Harms, K.
Chem.–Eur. J. 2001, 7, 4512–4521.
doi:10.1002/1521-3765(20011015)7:20<4512::AID-CHEM4512>3.0.C
O;2-H
16.Murahashi, S.-I.; Oda, T.; Masui, Y. J. Am. Chem. Soc. 1989, 111,
5002–5003. doi:10.1021/ja00195a076
41.Bach, T.; Bergmann, H.; Harms, K. Angew. Chem. 2000, 112,
2391–2393.
17.Ball, S.; Bruice, T. C. J. Am. Chem. Soc. 1980, 102, 6498–6503.
doi:10.1021/ja00541a019
Angew. Chem., Int. Ed. 2000, 39, 2302–2304.
doi:10.1002/1521-3773(20000703)39:13<2302::AID-ANIE2302>3.3.CO
;2-Y.
18.Jonsson, S. Y.; Färnegårdh, K.; Bäckvall, J.-E. J. Am. Chem. Soc.
2001, 123, 1365–1371. doi:10.1021/ja0035809
19.Lindén, A. A.; Johansson, M.; Hermanns, N.; Bäckvall, J.-E. J. Org.
Chem. 2006, 71, 3849–3853. doi:10.1021/jo060274q
20.Cibulka, R.; Vasold, R.; König, B. Chem.–Eur. J. 2004, 10, 6223–6231.
doi:10.1002/chem.200400232
42.Bach, T.; Bergmann, H.; Grosch, B.; Harms, K. J. Am. Chem. Soc.
2002, 124, 7982–7990. doi:10.1021/ja0122288
43.Selig, P.; Bach, T. J. Org. Chem. 2006, 71, 5662–5673.
doi:10.1021/jo0606608
21.Svoboda, J.; Schmaderer, H.; König, B. Chem. Eur. J. 2008, 14,
1854–1865. doi:10.1002/chem.200701319
44.Marcus, R. A. Angew. Chem. 1993, 105, 1161–1172.
Angew. Chem., Int. Ed. 1993, 32, 1111–1121.
doi:10.1002/anie.199311113.
22.Imada, Y.; Iida, H.; Ono, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2003,
125, 2868–2869. doi:10.1021/ja028276p
45.Bailey, P. J.; Pace, S. Coord. Chem. Rev. 2001, 214, 91–141.
doi:10.1016/S0010-8545(00)00389-1
23.Behrens, C.; Ober, M.; Carell, T. Eur. J. Org. Chem. 2002, 3281–3289.
doi:10.1002/1099-0690(200210)2002:19<3281::AID-EJOC3281>3.0.C
O;2-I
46.Schug, K. A.; Lindner, W. Chem. Rev. 2005, 105, 67–113.
doi:10.1021/cr040603j
24.Legrand, Y.-M.; Gray, M.; Cooke, G.; Rotello, V. M. J. Am. Chem. Soc.
2003, 125, 15789–15795. doi:10.1021/ja036940b
25.Lindén, A. A.; Hermanns, N.; Ott, S.; Krüger, L.; Bäckvall, J.-E.
Chem.–Eur. J. 2005, 11, 112–119. doi:10.1002/chem.200400540
26.Bergstad, K.; Bäckvall, J.-E. J. Org. Chem. 1998, 63, 6650–6655.
doi:10.1021/jo980926d
47.Best, M. D.; Tobey, S. L.; Anslyn, E. V. Coord. Chem. Rev. 2003, 240,
3–15.
48.Bloudeau, P.; Segura, M.; Pérez-Fernández, R.; de Mendoza, J.
Chem. Soc. Rev. 2007, 36, 198–210. doi:10.1039/b603089k
Page 8 of 9
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2009, 5, No. 26.
49.Schmuck, C. Coord. Chem. Rev. 2006, 250, 3053–3067.
doi:10.1016/j.ccr.2006.04.001
50.Schmaderer, H.; Hohenleutner, A.; König, B. Synth. Commun. 2009.
In print.
51.Rebek, J., Jr.; Askew, B.; Kolloran, M.; Nemeth, D.; Lin, F.-T. J. Am.
Chem. Soc. 1987, 109, 2426–2431. doi:10.1021/ja00242a029
52.Askew, B.; Ballester, P.; Buhr, C.; Jeong, K.-S.; Jones, S.; Parris, K.;
Williams, K.; Rebek, J., Jr. J. Am. Chem. Soc. 1989, 111, 1082–1090.
doi:10.1021/ja00185a044
53.Semi-empirical AM1, Spartan program package.
54.Levy, R. M.; Gallicchio, E. Annu. Rev. Phys. Chem. 1998, 49, 531–567.
doi:10.1146/annurev.physchem.49.1.531
55.Davis, M. E.; McCammon, J. A. Chem. Rev. 1990, 90, 509–521.
doi:10.1021/cr00101a005
56.Rozanska, X.; Chipot, C. J. Chem. Phys. 2000, 112, 9691–9694.
57.Luo, R.; David, L.; Hung, H.; Devany, J.; Gilson, M. K. J. Phys. Chem.
B 1999, 103, 727–736. doi:10.1021/jp982715i
58.Matsunov, A.; Lazaridis, T. J. Am. Chem. Soc. 2003, 125, 1722–1730.
doi:10.1021/ja025521w
59.Fagnoni, M.; Dondi, D.; Ravelli, D.; Albini, A. Chem. Rev. 2007, 107,
2725–2756. doi:10.1021/cr068352x
60.Stuhlmann, F.; Jäschke, A. J. Am. Chem. Soc. 2002, 124, 3238–3244.
doi:10.1021/ja0167405
61.Helm, M.; Petermeier, M.; Ge, B.; Fiammengo, R.; Jäschke, A. J. Am.
Chem. Soc. 2005, 127, 10492–10493. doi:10.1021/ja052886i
62.Fukuzumi, S.; Yuasa, J.; Miyagawa, T.; Suenobu, T. J. Phys. Chem. A
2005, 109, 3174–3181. doi:10.1021/jp050347u
63.Fukuzumi, S.; Okamoto, T.; Ohkubo, K. J. Phys. Chem. A 2003, 107,
5412–5418. doi:10.1021/jp034080f
64.Sun, D.; Hubig, S. M.; Kochi, J. K. Photochem. Photobiol. A: Chem.
1999, 122, 87–94. doi:10.1016/S1010-6030(99)00007-6
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