Biotinylated metathesis catalysts: Synthesis and performance in ring closing metathesis

Article abstract of DOI:10.1007/s10562-013-1179-z

Nine biotinylated Grubbs-Hoveyda and Grubbs-type metathesis catalysts were synthesized and evaluated in ring closing metathesis reactions of N-tosyl diallylamine and 5-hydroxy-2-vinylphenyl acrylate. Their catalytic activity in organic-and aqueous solvents was compared with the second generation Grubbs-Hoveyda catalyst. The position of the biotin-moiety on the N-heterocyclic carbene was found to critically influence the catalytic activity of the corresponding ruthenium-based catalysts. Springer Science+Business Media New York 2013.

Full text of DOI:10.1007/s10562-013-1179-z

Catal Lett (2014) 144:373–379
DOI 10.1007/s10562-013-1179-z
Biotinylated Metathesis Catalysts: Synthesis and Performance
in Ring Closing Metathesis
•
Anna Kajetanowicz Anamitra Chatterjee
•
•
Raphael Reuter Thomas R. Ward
Received: 18 October 2013 / Accepted: 27 November 2013 / Published online: 13 December 2013
Ó Springer Science+Business Media New York 2013
Abstract Nine biotinylated Grubbs–Hoveyda and Grub-
bs-type metathesis catalysts were synthesized and evaluated
in ring closing metathesis reactions of N-tosyl diallylamine
and 5-hydroxy-2-vinylphenyl acrylate. Their catalytic
activity in organic- and aqueous solvents was compared
with the second generation Grubbs–Hoveyda catalyst. The
position of the biotin-moiety on the N-heterocyclic carbene
was found to critically influence the catalytic activity of the
corresponding ruthenium-based catalysts.
metathesis for the conversion of biomass into useful pro-
ducts [19–24], and metathesis as a bioorthogonal ligation
tool [25–27]. Despite these great achievements, aqueous-
phase metathesis remains a challenge [28–36].
To address this challenge, we and others have relied on
the creation of artificial metalloenzymes for olefin metath-
esis [37–40]. For this purpose, a catalytically competent
Hoveyda–Grubbs moiety is anchored within a protein scaf-
fold to afford an artificial metathesase. In this context, we
and others have been exploiting the biotin–streptavidin
technology to create artificial metalloenzymes for a variety
of transformations [41–44], including hydrogenation [45],
transfer hydrogenation [46], allylic alkylation [47], benz-
annulation [48], sulfoxidation [49], dihydroxylation [50] as
well as olefin metathesis [37–40]. Traditionally, a chemo-
genetic optimization scheme is used to improve catalytic
performance of artificial metalloenzymes. Genetic diversity
is created by introducing point mutations on the streptavidin
gene. Chemical diversity is achieved upon varying the
position of the biotin anchor and the spacer between the
anchor and the Ru-moiety. Previous experience in artificial
metalloenzymes clearly demonstrates that catalytic activity
is critically dependent on the first coordination sphere
around the active metal and thus requires screening a variety
of different catalyst precursors. With this goal in mind, we
report on the synthesis and evaluation of the catalytic per-
formance of nine biotinylated metathesis catalysts.
Keywords Fluorescence assay Á Aqueous catalysis Á
Ring closing metathesis Á Coumarin Á Hoveyda–Grubbs
1 Introduction
In the past 40 years, the olefin metathesis reaction has
emerged and matured as a very efficient and elegant method
for formation of C=C double bonds [1–6]. It is widely used
not only in small-scale laboratory research, but also in large-
scale industrial production [7, 8]. Among the frontiers in
olefin metathesis, one should mention: (i) control of E/
Z selectivity [9–13], (ii) enantioselective ring-closing
metathesis (RCM hereafter) [14–18], (iii) the application of
Anna Kajetanowicz and Anamitra Chatterjee have contributed
equally to the work.
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-013-1179-z) contains supplementary
material, which is available to authorized users.
2 Results and Discussion
We previously reported on an artificial metathesase relying
on combining either avidin or streptavidin with either Biot-
1 or Biot-m-ABA-1 [37]. In this study, we set out to vary
the position of the enantiopure biotin-moiety and to
A. Kajetanowicz Á A. Chatterjee Á R. Reuter Á T. R. Ward (&)
Department of Chemistry, University of Basel, Spitalstrasse 51,
4056 Basel, Switzerland
e-mail: thomas.ward@unibas.ch
123

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A. Kajetanowicz et al.
O
S
NH
H
HN
H
PCy3
N
N
Cl
Cl
O
Ru
Biot
Cl Ru
O
Cl
O
O
S
O
NH
H
HN
H
H
Hov I
N
Hov II
O
Biot-m-ABA
RHN
N
N
N
N
N
N
RHN
N
Cl
Cl
Cl
R
Ru
Ru
O
Ru
O
Cl
Cl
Cl
O
Biot 1, R = Biot
Biot 2, R = Biot
Biot 3, R = Biot
m-
Biot-m-ABA-1, R = Biot-m-ABA Biot-m-ABA-2, R = Biot-m-ABA
Biot- ABA-3, R = Biot- ABA
m-
O
O
N
N
N
N
N
Cl
RHN
Biot
Cl
Ru
O
Ru
Cl
Ph
Cl
PCy3
Biot 4, R = Biot
Biot-m-ABA-4, R = Biot-m-ABA
Biot 5
Fig. 1 Biotinylated metathesis catalysts used in this study
identify the most promising catalyst under various catalytic
conditions. All complexes tested in this study are presented
in Fig. 1. For complexes Biot-1 or Biot-m-ABA-1 and
Biot-4 or Biot-m-ABA-4, the presence of an asymmetric
carbon between the enantiopure biotin anchor and the N-
heterocyclic carbene moiety, leads to diastereomeric mix-
tures. No effort was made to separate these prior to cata-
lytic evaluation.
gaseous hydrogen chloride and coupling with either acti-
vated biotin or activated biotin m-aminobenzoic acid
afforded Biot-2 and Biot-m-ABA-2 respectively
(Scheme 1).
The next biotinylated catalysts included two mesityl
groups with a biotin linked to one of these. For this pur-
pose, we used the procedure reported by Gilbertson et al.
relying on the unsymmetrical diamine 9 [53]. Rosenmund-
von Braun cyanation followed by reduction and Boc-pro-
tection yielded compound 11. This latter was reacted with
triethylorthoformate in the presence of ammonium chloride
to provide the imidazolium salt 12. Reaction of 12 with
chloroform and KOH yielded the chloroform adduct 13
[54]. Ligand exchange with Hov I catalyst provided the
ruthenium NHC complex Boc-3 which, after Boc-depro-
tection, was reacted with activated biotin and biotin m-
aminobenzoic acid to afford Biot-3 and Biot-m-ABA-3
respectively (Scheme 2).
While one N-mesityl substituent is critical for high
catalytic activity [51], we set out to link the biotin anchor
on the other N-substituent of the N-heterocyclic carbene
moiety. We evaluated both aromatic (e.g. Biot-3, Biot-m-
ABA-3, and Biot-4, Biot-m-ABA-4), as well as aliphatic
substituents (e.g. Biot-2, Biot-m-ABA-2, and Biot-5) at
this position.
With this aim, we set out to prepare the key Boc-pro-
tected imidazolium intermediate Boc-2. Reductive amina-
tion of the alkylated aniline 6 [52] yielded the 1,2-diamine
7. Cyclisation with triethyl orthoformate provided the im-
idazolium salt 8. Ligand exchange with Hoveyda–Grubbs
first generation catalyst Hov I afforded the Boc-protected
ruthenium NHC complex Boc-2. Deprotection with
To evaluate the influence of the spacer length between
the biotin-anchor and the NHC, we synthesized another
type of catalysts (Biot-4 and Biot-m-ABA-4) which bear
an additional carbon when compared to Biot-3 and Biot-m-
123

Synthesis and Performance in Ring Closing Metathesis
375
O
N
, DCE
1)
H
N
NH HN
Boc
HC(OEt)3, NH4Cl
120 °C, 78%
H2N
N
Boc
2) NaBH3CN, RT
98%
7
6
N
N
Hov I
toluene
N
Cl
Boc
KHMDS,
65 °C, 64%
N+
Cl-
N
Ru
O
Cl
N
Boc
8
Boc-2
Biot
or
N
N
N
N
N
H
1) HCl (g), DCM
N
N
Cl
Cl
Biot
Boc-2
Ru
Ru
O
2) Biot-OC6F5, NEt3, DMF
O
67%
or
Biot-m-ABA-OC6
Cl
Cl
O
F
5,
Et3N, DMF, 83%
Biot-2
Biot-m-ABA-2
Scheme 1 Synthesis of the biotinylated complexes Biot-2 and Biot-m-ABA-2
1) LiAlH4, THF, 67 °C, 88%
2) Boc2O, DMAP, DCM, 85%
CuCN, NMP
160 °C, 55%
NH HN
NH HN
NC
Br
9
10
N+
Cl-
N
NH4Cl, HC(OEt)3
120 °C, 95%
NH HN
11
BocHN
BocHN
12
N
N
BocHN
Cl
N
N
KOH, CHCl3, toluene
60 °C, 45%
Hov I, toluene
70 °C, 60%
Ru
O
BocHN
Cl
Boc-3
CCl3
13
Biot
N
H
N
N
N
N
H
N
1) HCl (g), DCM
Boc-3
N
H
Biot
Cl
Cl
F5
2) Biot-OC6
O
Ru
O
Ru
or
NEt3, DMF, 67%
Cl
or
Cl
Biot-3
Biot-m-ABA-OC6F5,
O
Et3N, DMF, 83%
Biot-m-ABA-3
Scheme 2 Synthesis of the biotinylated complexes Biot-3 and Biot-m-ABA-3
ABA-3. The NHC ligand 14 was synthesized according to
a published procedure [53]. Preparation of the chloroform
adduct followed by reaction with Hov I yielded the
ruthenium NHC complex Boc-4. After Boc deprotection
and reaction with activated biotin derivatives, Biot-4 and
Biot-m-ABA-4 were obtained (Scheme 3).
was reacted with N-mesitylimidazole 17 to produce the
imidazolium salt 18. Reaction of the carbene, generated
in situ from 18 in the presence of KHMDS, with the Grubbs
first generation catalyst gave complex Boc-5. After depro-
tection of the amino group by HCl and reaction with acti-
vated biotin, the desired Biot-5 was obtained (Scheme 4).
The performance of the biotinylated catalysts was
evaluated in the ring closing metathesis of two model
Finally, the Grubbs type catalyst Biot-5 was prepared.
The Boc-protected (3-chloropropyl)-N-methyl amine 16
123

376
A. Kajetanowicz et al.
NHBoc
NHBoc
N+
Cl-
N
N
N
O
O
KOH, CHCl3, toluene
60 °C, 22%
CCl3
O
O
15
14
NHBoc
N
N
O
1) HCl (g), DCM
2) Biot-OC6F5
Hov I, toluene
70 °C, 45%
Cl
O
Ru
O
NEt3, DMF, 50%
Cl
Boc-4
or
Biot-m-ABA-OC6F5,
Et3N, DMF, 50%
O
O
O
O
O
N
N
N
N
H
N
Biot
Cl
Cl
N
H
Biot
N
or
H
Ru
O
Ru
O
Cl
Cl
Biot-m-ABA-4
Biot-4
Scheme 3 Synthesis of the biotinylated complexes Biot-4 and Biot-m-ABA-4
1. KHMDS, THF, RT
N+
Cl-
N
100 °C
56%
N
Cl
N
N
N
+
Boc
Boc
2. Gr I, 65 °C
63%
16
18
17
N
N
N
N
N
N
1. HCl(g), DCM, RT
Boc
Biot
Cl
Cl
2. Biot-OC6F5, NEt3, DMF, RT
29%
Ru
Biot-5
Ru
Boc-5
Ph
Ph
Cl
Cl
PCy3
PCy3
Scheme 4 Synthesis of the biotinylated complex Biot-5
O
presented in Table 2 and on Fig. 3. All RCM reactions
were analysed by reversed phase HPLC and revealed no
product isomerization.
PPh3CH3Br
Acryloyl chloride
NEt3, DCM
tBuOK, THF
85 %
90
%
THPO
OH
THPO
OH
21
22
As a starting point, we performed the RCM of diallyl
tosylamide 19 with 1 mol% biotinylated catalysts and a
0.1 M substrate concentration at 37 °C in dichloromethane.
The results reveal that most of biotinylated catalysts with
two mesityl moieties bound to imidazoline ring, viz. Biot-
1, Biot-m-ABA-1 and Biot-m-ABA-4 exhibit the same
activity as the parent Hov II catalyst and reached almost
full conversion. Similar results were also observed for
structurally related complexes, namely Biot-3, Biot-m-
ABA-3 and Biot-4 with conversion around 70–80 %.
These results are consistent with previous observations
suggesting that catalysts containing two bulky aromatic
substituents in the NHC ligand have the highest activity
and stability. Accordingly, Biot-2 and Biot-m-ABA-2, are
less active. In stark contrast, Biot-5 is a good RCM cata-
lyst, affording product 20 in 85 % yield.
pTsOH
MeOH/THF
86
THPO
O
O
%
HO
O
O
23
24
Scheme 5 Synthesis of coumarin precursor 24, substrate for RCM
reaction [56–59]
substrates: the diallyl tosylamide 19 and the coumarin
precursor 24. The second substrate was produced from
aldehyde 21 [55] via a Wittig reaction followed by esteri-
fication with acryloyl chloride and deprotection of the
hydroxy group (Scheme 5).
The activity of the new biotinylated precatalysts was
compared with that of second-generation Grubbs–Hoveyda
complex Hov II. The results for RCM reaction of diallyl
tosylamide 19 are summarized in Table 1 and Fig. 2 and
results for RCM reaction of coumarin precursor 24 are
Upon decreasing the substrate concentration to 0.01 M,
similar trends were observed. The presence of a biotin
moiety led to marked decrease in conversion, especially
123

Synthesis and Performance in Ring Closing Metathesis
377
Table 1 Comparison of activity of catalysts in RCM of diallyl to-
Table 2 Comparison of activity of catalysts in RCM reaction of
coumarin precursor 24
sylamide 19
Tos
N
Tos
N
[Ru]
[Ru]
HO
O
O
HO
O
O
19
20
25
24
Catalysta
Yield (%)b
Yield (%)c
Entry
Catalysta
Yield (%)b
Yield (%)c
Yield (%)d
Entry
1
2
Hov II
[99
93
96
43
41
79
76
69
97
85
[99
83
76
18
19
70
49
35
84
21
75
13
28
1
1
2
Hov II
Biot-1
[99
97
70
99
88
50
48
52
50
22
4
1
3
1
1
4
1
1
1
1
Biot-1
3
Biot-m-ABA-1
Biot-2
3
Biot-m-ABA-1
Biot-2
4
4
5
Biot-m-ABA-2
Biot-3
1
5
Biot-m-ABA-2
Biot-3
6
17
7
6
7
Biot-m-ABA-3
Biot-4
7
Biot-m-ABA-3
Biot-4
8
12
10
2
8
9
Biot-m-ABA-4
Biot-5
9
Biot-m-ABA-4
Biot-5
10
10
Experiments were performed in triplicate (yields 2 %). See SI for
experimental details
See SI for experimental details
a
5 mol% of [Ru], 37 °C, 24 h; experiments performed in triplicate
CH2Cl2, [24] = 0.025 M (yield 5 %)
a
1 mol% of [Ru], 37 °C, 24 h
CH2Cl2, [19] = 0.1 M
b
c
b
H2O/DMSO 84:16, [24] = 0.025 M
c
CH2Cl2, [19] = 0.01 M
d
H2O/DMSO 84:16, [19] = 0.1 M
100
90
80
70
60
50
40
30
20
10
0
Hov II
100
90
80
70
60
50
40
30
20
10
0
Biot-1
Biot-m-ABA-1
Biot-2
Biot-m-ABA-2
Biot-3
Biot-m-ABA-3
Biot-4
Fig. 3 Comparison of catalysts activity in RCM reaction of
5-hydroxy-2-vinylphenyl acrylate 24 in CH2Cl2
Biot-m-ABA-4
DCM 0.1M
DCM 0.01M
Water 0.1M
Fig. 2 Comparison of catalysts activity in RCM reaction of diallyl
tosylamide
DCM. However, as the RCM reaction is significantly faster
in DCM, the decomposition does not affect the yields as
much.
with complexes bearing an alkyl substituent on the NHC
(e.g. Biot-2 and Biot-m-ABA-2 and Biot-5).
As the umbelliferone precursor 24 bears an electron
withdrawing olefinic moiety which decreases its reactivity,
the corresponding RCM reactions were performed with
5 mol% biotinylated catalyst (Table 2) in 0.025 M concen-
tration at 37 °C in dichloromethane. Under these conditions,
the two biotinylated catalysts, Biot-1 and Biot-2 reached near
quantitative conversions. The other biotinylated Hoveyda-
type catalysts gave moderate yields approaching 50 %. The
Grubbs type Grubbs-type catalyst Biot-5, gave only 22 %
yield. When reactions were performed in a water:DMSO
mixture, \5 % conversion was obtained for all catalysts,
including Hov II.
Next, the reactions were performed in a water:DMSO,
84:16 mixture (DMSO was required to dissolve both sub-
strate and catalyst as both substrates and catalysts exhibit
very low solubility in pure water). Except for Hov II (75 %
yield), the yields were dramatically lower. The best bio-
tinylated catalyst, Biot-m-ABA-1, reached only ca. 30 %
yield. We speculate that the low yields may be due to the
limited catalyst’s stability in a water. During the reactions,
all reaction mixtures changed colour from green (Hoveyda-
type catalysts) or purple (Grubbs-type catalyst) to brown-
ish. The biotinylated catalysts also decompose slowly in
123

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A. Kajetanowicz et al.
Acknowledgments The authors thank The Seventh Framework
Programme Project METACODE (KBBE, ‘‘Code-engineered new-to-
nature microbial cell factories for novel and safety enhanced bio-
production’’) as well as ITN BioChemLig (FP7-ITN-238434) for
financial support.
In the RCM reaction of diallyl tosylamide 19, the cat-
alyst Biot-2 displays only 43 turnovers (TONs, using
1 mol% catalyst loading). For the more challenging sub-
strate 24, 20 TONs were obtained (using 5 mol% catalyst
loading). We speculate that this is the result of a delicate
balance between catalyst’s activity and its decomposition:
the best TON is observed for the challenging substrate 24,
but only a modest TON is obtained for the standard dial-
lyltosylamide substrate 19 before the catalyst becomes
inactivated.
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3 Conclusion
In this study, a series of biotinylated ruthenium-based cat-
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two model RCM reactions with either diallyl tosylamide 19
or the umbelliferone precursor 24. While all biotinylated
catalysts performed reasonably well in concentrated
dichloromethane, their performance decreased significantly
in aqueous solution. We speculate that the presence of a
thioether moiety on the biotin anchor may interact with the
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