Synthesis and properties of a biotin-tagged NHC-gold complex

Article abstract of DOI:10.1016/j.tetlet.2015.01.023

The first synthesis of a biotin-tagged NHC-gold complex is described. The key step is the coupling of alkyne-substituted biotin derivative 4b with azido-imidazolium salt 8a by copper-catalyzed azide alkyne cycloaddition (CuAAC). Gold complex 2 catalyzes the cycloisomerization of α-hydroxyallenes to 2,5-dihydrofurans.

Full text of DOI:10.1016/j.tetlet.2015.01.023

Accepted Manuscript
Synthesis and properties of a biotin-tagged NHC-gold complex
Viola Breker, Hülya Sak, Giusy Baracchi-Krause, Norbert Krause
PII:
S0040-4039(15)00026-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.023
TETL 45692
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
3 December 2014
22 December 2014
2 January 2015
Please cite this article as: Breker, V., Sak, H., Baracchi-Krause, G., Krause, N., Synthesis and properties of a biotin-
tagged NHC-gold complex, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.01.023
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Synthesis and properties of a biotin-tagged
NHC-gold complex
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Viola Breker, Hülya Sak, Giusy Baracchi-Krause, Norbert Krause

1
Tetrahedron Letters
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Synthesis and properties of a biotin-tagged NHC-gold complex
Viola Brekera, Hülya Saka, Giusy Baracchi-Krausea, and Norbert Krausea,
aDortmund University of Technology, Organic Chemistry, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first synthesis of a biotin-tagged NHC-gold complex is described. The key step is the
coupling of alkyne-substituted biotin derivative 4b with azido-imidazolium salt 8a by copper-
catalyzed azide alkyne cycloaddition (CuAAC). Gold complex 2 catalyzes the cycloisomeri-
zation of -hydroxyallenes to 2,5-dihydrofurans.
Available online
2015 Elsevier Ltd. All rights reserved.
Keywords:
Gold Catalysis
Carbene Ligands
Biotin
Streptavidin
Allenes
Dedicated to Elga R. Wasserman and Harry H.
Wasserman, eminent scientists who will always be
remembered for their human touch.
The combination of transition metals and enzymes opens new
avenues in catalysis. In order to avoid mutual deactivation by
binding of a transition metal complex to an enzyme, the concept
of compartmentalization by specific encapsulation of the metal
catalyst in the enzyme scaffold has been employed with
considerable success. Already in 1978, Wilson and Whitesides
reported the formation of a homogeneous enantioselective
hydrogenation catalyst by complexation of the biotin-tagged
rhodium complex 1 (Scheme 1) with avidin.1 Streptavidin and
avidin are proteins which are frequently used in molecular
biology since they undergo extremely strong non-covalent inter-
actions with biotin (vitamin H). Whitesides’ seminal contribution
was extended by Ward2 who used the streptavidin-biotin affinity
for such diverse enantioselective transformations as rhodium- or
ruthenium-catalyzed (transfer) hydrogenation,3 rhodium-cataly-
zed C–H activation,4 and palladium-catalyzed allylic alkylation.5
Moreover, the biotin-labeling should allow the immobilization of
transition metal complexes on streptavidin-loaded surfaces and
their use as recyclable catalyst in microarrays or nanoreactors.6
which take advantage of stabilization by ionic liquids,9
micelles,10 or a suitable ligand.11 Hence, we became interested in
using the biotin-streptavidin technology to render a gold catalyst
immobilizable and recyclable. In this paper, we report initial
results of our effort in synthesizing the first biotin-tagged NHC-
gold complex (2; Scheme 1) and in studying its catalytic activity.
Scheme 1. Biotin-tagged rhodium complex 1 synthesized by Whitesides et
al.,1 and gold catalyst 2 prepared in this work.
Homogeneous gold catalysis relies on the -activation of
alkynes, allenes, and alkenes in the presence of other hard Lewis-
basic sites which opens the door for inter- or intramolecular CH,
CC, and Cheteroatom bond formation by (cyclo)addition,
cycloisomerization, or rearrangement.7 Under standard condi-
tions, however, the gold catalyst cannot be recycled since it is
readily reduced to catalytically inactive metallic gold.8 There is
only a limited number of examples for recyclable gold catalysts
———
For the successful synthesis and application of a biotin-tagged
transition metal complex, the choice of the optimal linker and
ligand type are of crucial importance. Based on our recent
experience with functionalized NHC-gold complexes,11b we
selected an N-heterocyclic carbene instead of a phosphine as
ligand to gold, and tried to connect several imidazolium salts
with biotin via an amide linkage. Unfortunately, this approach,
 Corresponding author. Tel.: +49-231-755-3882; fax: +49-231-755-3884; e-mail: norbert.krause@tu-dortmund.de

2
which was inspired by Whitesides’ work1 (1; Scheme 1), was not
successful. We therefore selected Huisgen’s 1,3-dipolar cyclo-
addition of azides and alkynes which, as its copper-catalyzed
(CuAAC) variant, is the most widely used example of click
chemistry.13 Hence, the azide or alkyne-substituted biotin
derivatives 4 and NHC-gold complex 9a were synthesized
(Scheme 2).
Next, we shifted our attention to the click reaction of biotin
alkyne 4b with the azido-substituted imidazolium salt 8a. Once
again, the use of CuBr and ascorbic acid21 did not afford any
cycloaddition product. An attempt to accelerate the coupling by
addition of tris(benzyltriazolylmethyl)amine (TBTA)22 to the
reaction mixture was fruitless, as was the replacement of CuBr
by [Cu(MeCN)4]PF6. However, application of the standard
coupling conditions (CuSO4, sodium ascorbate, DIPEA)13,18,20 in
a degassed THF/water mixture finally afforded the desired
triazole 10 with 50% yield (Scheme 3). With NHC-gold complex
9a instead of imidazolium salt 8a, decomposition with formation
of a gold mirror took place under these conditions.
12
Scheme 2. Synthesis of azido- or alkyne-substituted biotin derivatives 4 and
NHC-gold complex 9a.
The azido-substituted biotin derivative 4a is known14 and was
prepared by coupling of (+)-biotin (3) with 3-azidopropylamine15
under Steglich conditions. Likewise, the known biotin alkyne 4b
was obtained by activation of 3 with N-hydroxysuccinimide and
subsequent treatment with propargylamine.16 The synthesis of
NHC-gold complex 9a started from 4-(chloromethyl)benzoyl
chloride (6) which was coupled with 3-azidopropylamine.15 After
conversion of 7a into the corresponding iodide and reaction with
1-mesityl-1H-imidazole, the resulting imidazolium salt 8a was
transformed into NHC-gold complex 9a by treatment with Ag2O
and Au(SMe2)Cl.17 In an analogous manner, imidazolium salt 8b
was obtained from 6 via propargyl ester 7b.
Scheme 3. Synthesis of biotin-tagged NHC-gold complex 2 via triazole 10.
For the final transformation of biotin-tagged imidazolium salt
10 into the desired gold complex 2, we first applied the
conditions reported by Nolan and coworkers.17 Treatment of 10
with Ag2O and Au(SMe2)Cl in CH2Cl2 failed due to the low
solubility of the imidazolium salt in this solvent. The use of
methanol afforded no gold complex as well, even though the
solubility of 10 is much higher. Finally, we adapted a procedure
described by Li et al.23 for the synthesis of NHC-copper
complexes. Treatment of 10 with t-BuOK and Au(SMe2)Cl in
methanol at 65°C for 24 h afforded biotin-tagged NHC-gold
complex 2 with 67% yield (Scheme 3).
At the outset of the crucial coupling by copper-catalyzed azide
alkyne cycloaddition (CuAAC), it was not clear whether the
imidazolium salt or NHC-gold complex is better suited for this
reaction. Numerous experimental protocols can be found in the
literature, among which the use of CuSO4 in the presence of
sodium ascorbate as reducing agent appears frequently.13,18
Unfortunately, all attempts to couple biotin azide 4a with
imidazolium salt 8b in the presence of different stoichiometries19
of CuSO4 and sodium ascorbate in aqueous solution resulted in
no conversion. Variation of the cosolvent (THF or acetonitrile),
the temperature (room temperature…60°C), the application of
ultrasound, or the addition of diisopropylethylamine (DIPEA)20
did not increase the reactivity. For CuAAC reactions of imidazo-
lium salts, the use of CuBr and ascorbic acid in water/t-BuOH
mixtures under careful exclusion of oxygen has been described
by Zeitler and Mager,21 but also these conditions did not afford
any coupling product of 4a with 8b.
At the outset of our work, it was not clear whether a biotin-
tagged gold catalyst would be sufficiently reactive. After all, it is
well known that gold complexes form strong carbon-sulfur bonds
which render sulfides potent poisons for gold catalysts.24 As a
consequence, the number of examples for gold-catalyzed CS
bond formation is limited.25 A benchmark reaction for testing the
catalytic activity is the cycloisomerization of -hydroxyallenes to
2,5-dihydrofurans which is catalyzed by numerous (simple or
functionalized) neutral or cationic gold catalysts in different
reaction media.7,8b,9c,10a,11b,26 Fortunately, treatment of allene 11
with 5 mol% of biotin-tagged NHC-gold catalyst 2 in CH2Cl2 for
24 h at room temperature afforded dihydrofuran 12 with 80%
yield. As expected, 2 is less reactive than biotin-free catalyst 9a
which gave 12 with 98% yield under identical conditions. Thus,
only a slight deactivation of the catalyst by the biotin residue is
observed. It should be noted that an activation of the catalyst with
a silver salt to form a cationic gold species7 is not necessary.11b

3
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Scheme 4. Gold-catalyzed cycloisomerization of -hydroxyallene 11 to
2,5-dihydrofuran 12.
In summary, the first synthesis of a biotin-tagged NHC-gold
complex is described. The key step is the coupling of alkyne-
substituted biotin derivative 4b with azido-imidazolium salt 8a
by copper-catalyzed azide alkyne cycloaddition (CuAAC) which
required carefully controlled conditions with strict exclusion of
oxygen. Gold complex 2 shows sufficient reactivity in the
cycloisomerization of -hydroxyallenes to 2,5-dihydrofurans.
Thus, the biotin-tagged NHC-gold complex is ready for applica-
tion in streptavidin-loaded microarrays or nanoreactors. We are
currently examining further reactions catalyzed by gold complex
2, as well as, CuAAC reactions of building blocks 8 and 9 with
other coupling partners of interest for applications in biology or
materials science.
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Supplementary Material
Supplementary data (experimental procedures and characteri-
1
zation data of selected compounds and copies of H NMR and
13C NMR spectra) are given in supplementary material associated
with this article which can be found, in the online version, at…
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