Enantioselective CuII-catalyzed Diels-Alder and Michael addition reactions in water using bio-inspired triazacyclophane-based ligands

Article abstract of DOI:10.1002/ejoc.201001522

A triazacyclophane (TAC) scaffold decorated with three histidine amino acid residues was used as a tridentate ligand in asymmetric copper(II)-catalysed Diels-Alder and Michael addition reactions in water. Enantiomeric excesses up to 55 % were obtained in

Full text of DOI:10.1002/ejoc.201001522

FULL PAPER
DOI: 10.1002/ejoc.201001522
Enantioselective CuII-Catalyzed Diels–Alder and Michael Addition Reactions
in Water Using Bio-Inspired Triazacyclophane-Based Ligands
H. Bauke Albada,[a][‡] Fiora Rosati,[b][‡] David Coquière,[b] Gerard Roelfes,[b] and
Rob M. J. Liskamp*[a]
Keywords: Biomimetic synthesis / Enzyme models / Ligand design / Michael addition / Diels–Alder reaction / Histidine /
Copper
A triazacyclophane (TAC) scaffold decorated with three hist-
idine amino acid residues was used as a tridentate ligand
in asymmetric copper(II)-catalysed Diels–Alder and Michael
addition reactions in water. Enantiomeric excesses up to 55%
were obtained in Diels–Alder reactions using ligands in
which the histidine residues were directly attached to the
TAC scaffold. Additional amino acid residues on the N-ter-
mini of the histidine residues or positioned between the hist-
idine residues and the TAC scaffold, resulted in almost com-
plete loss of enantioselectivity. Modelling studies of the coor-
dination complex of the most specific ligand indicated the
presence of a substrate binding pocket in proximity to the
catalytically active centre.
and bio-mimetic fashion. Using this ligand we were able to
construct a close structural mimic of the di-copper centre
of enzymes such as hemocyanin and tyrosinase oxidases, in
which each copper(II) centre is surrounded by three hist-
idine residues. Recently, a derivative of this mimic was used
in the construction of a novel class of drugs, the so-called
scorpionate antibiotics.[6]
The TAC scaffold is particularly attractive for the con-
struction of ligands because it can be orthogonally pro-
tected;[7] this allows a large chemical diversity to be
achieved.[8] For instance, an orthogonally protected TAC
scaffold decorated with three different amino acid residues
may result in up to 8000 (203) different ligands,[9] provided
that at least one metal-coordinating atom is present in each
amino acid residue. Previously, we have shown that small
TAC-based constructs were able to bind iron(III) and fluo-
rescently labelled dipeptides.[10]
Introduction
Metalloenzymes are a continuing source of inspiration
for the development of new bio-inspired catalysts, and sev-
eral approaches have been developed that mimic the way
metalloenzymes work. For example, artificial metalloen-
zymes have been constructed by anchoring a transition
metal complex to a binding pocket of a natural protein scaf-
fold or by creating a novel active site on a biomolecular
species.[1] Using this approach, artificial metalloenzymes
that are capable of catalyzing a variety of enantioselective
reactions in water have been created. This includes some
of the archetypical carbon–carbon bond forming reactions,
such as the copper(II)-catalyzed Diels–Alder (DA), Michael
addition (MA) and Friedel–Crafts alkylation reactions.[2,3]
An alternative strategy that can be used to create cata-
lysts with enzyme-like activities and selectivities involves the
design of bio-mimetic catalysts in which a catalytically
active transition metal complex is incorporated into a de-
signed (peptide) scaffold.[4] For example, we recently re-
In this paper, we describe the application of acylated hist-
idine residues attached to a symmetrical TAC scaffold[11]
in copper(II)-catalysed DA and MA reactions in water. In
addition, the effects of N- and C-terminal extensions on the
attached histidine residues and on the C-terminus of the
TAC scaffold were explored.
ported on
a tris-histidine-containing triazacyclophane
(TAC) scaffold that mimics the structure of the tris-histidine
triad metal-binding site that is found in several metalloen-
zymes.[5] Around neutral pH, the three histidine residues of
this mimic coordinated to one copper(II) ion in a tridentate
Results and Discussion
[a] Utrecht Institute for Pharmaceutical Sciences, Medicinal
Chemistry & Chemical Biology,
P. O. Box 80082, 3508 TB Utrecht, The Netherlands
Fax: +31-30-2536655
For the synthesis of the ligands, a tris-o-NBS protected
symmetrical TAC scaffold (1) was used.[11] This N-protected
TAC scaffold was conveniently prepared from bis-bromide
2 and tris-o-NBS protected triamine 3 followed by attaching
the deprotected carboxylic acid functionality to an amine-
containing polystyrene resin using BOP and N,N-diiso-
E-mail: r.m.j.liskamp@uu.nl
[b] Stratingh Institute for Chemistry, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001522.
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Enantioselective Diels–Alder and Michael Addition Reactions
propylethylamine (DiPEA) (Scheme 1). The o-NBS groups Two variants containing bulky acyl groups Ϫ the achiral
of the resin-bound scaffold 4 were removed using 2-mer- isovaleric acid to afford 9 and a chiral acetylated valine resi-
captoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) due to afford 10 Ϫ were also prepared. In this manner, the
in N,N-dimethylformamide (DMF), liberating the secondary effect of N-terminal extensions, with or without a chiral
amines to afford resin-bound scaffold 5 to which the dif- centre, on the outcome of the DA and MA reactions were
ferent amino acid building blocks were coupled. In our ini- probed. Attachment of acetyl-l-valine was realized by cou-
tial design, both l- and d-histidine residues were attached pling of Fmoc-l-Val-OH to the unprotected N-α-amine
as Fmoc-His(Trt)-OH building blocks to two different group of the histidine residues, followed by replacement of
batches of scaffold 5 and N-terminally protected with an the Fmoc group by an acetyl group.
acetyl group. This capping ensured that the coordination to
The second generation of ligands contained additional
the catalytically active copper(II) ion occurred through the amino acid residues, such as achiral glycine, and chiral and
nitrogen atoms of the imidazole rings of histidine only.[5] bulky l- and d-tryptophan, between the TAC scaffold and
Scheme 1. Solid-phase synthesis of the 1st generation of TAC-based tridentate ligands in which the tris-histidine triads are directly attached
to the TAC scaffold. Structure of ligand 21 is also shown.[6]
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R. M. J. Liskamp et al.
FULL PAPER
the coordinating histidinyl imidazole rings. These insertions Azachalcone (22) and α,β-unsaturated 2-acylimidazole (23)
allow the effect of the larger distance between the scaffold were used as substrates; these substrates were selected be-
and the catalytically active site and the presence of steric cause of their ability to bind CuII efficiently in aqueous me-
bulk and chirality on this extension to be assessed.
dia.[12] In the absence of ligand, but in the presence of CuII,
The synthesis of this second generation of ligands was no enantioselectivity was observed in either the MA or DA
performed analogously to that described for the first gener- reactions (Table 1, entry 1). Ac-l-His-NH2 and tripeptide
ation of ligands (Scheme 2). Resin-bound scaffold
5
Ac-(l-His)3-NH2, obtained by solid-phase peptide synthe-
(Scheme 1) was divided into three equal portions, which sis, were used as reference ligands. In the absence of ligand,
were treated with either Fmoc-Gly-OH, Fmoc-l-Trp(Boc)- but in the presence of CuII, no enantioselectivity was ob-
OH or Fmoc-d-Trp(Boc)-OH, respectively. After removal served in either the MA or DA reactions (Table 1, entries
of the Fmoc groups, each of three portions of resin-bound 2–3).[13] Furthermore, no enantioselectivity was observed in
scaffolds containing Gly (12), l-Trp(Boc) (13) or d- the presence of Ac-l-His-NH2 using 1 or 3 equiv. of ligand
Trp(Boc) (14) was divided in two equal portions. Sub- (entry 2).[14] A linear tripeptide containing only l-histidine
sequently, Fmoc-l-His(Trt)-OH or Fmoc-d-His(Trt)-OH residues did not give rise to any enantiomeric excess (ee) in
were coupled so that six different resin-bound precursors the DA reaction and only a small ee was detected in the
were obtained. After replacement of the Fmoc group with MA reaction (entry 3).
an acetyl group, the ligands were deprotected and cleaved
from the resin by acidolysis.
Using ligand 8, which contains three l-histidine residues
attached directly to the TAC scaffold and with acetylated
The ligands were evaluated in the copper(II)-catalyzed α-amino groups, ee values up to 55% were observed for the
Diels–Alder and Michael addition reactions (Scheme 3). DA reaction and – depending on the substrate – 14 or 24%
Scheme 2. Solid-phase synthesis of the 2nd generation TAC-based tridentate ligands in which glycine or tryptophan residues were incorpo-
rated between the TAC scaffold and the tris-histidine triads.
Scheme 3. Diels–Alder (left) and Michael addition (right) reactions studied with TAC-based ligands.
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Enantioselective Diels–Alder and Michael Addition Reactions
Table 1. Asymmetric Diels–Alder (DA) or Michael addition (MA) reaction between azachalcone (22) or α,β-unsaturated 2-acylimidazole
(23) and cyclopentadiene (for DA) or dimethyl malonate (for MA) using TAC-based tris-histidine residues containing ligands and
Cu(NO3)2.[a]
Entry
Ligand[b]
endo-Product ee for DA (%)
ee for MA (%)
Pyr (22)
Pyr (22)
MeIm (23)
MeIm (23)
1
2
3
none[13]
Ac-l-His-NH2
Ac-(l-His)3-NH2
Ͻ5
Ͻ5
Ͻ5
Ͻ5
Ͻ5
5
Ͻ5
nd
n.d.
Ͻ5
Ͻ5
7/S
[c]
TAC(Xxx)3 in which Xxx is:
l-His-Ac 8
4
5
6
7
55/(–)
50/(+)
9/(+)
Ͻ5
51/RR
51/SS
Ͻ5
–14 (2nd fraction)[g]
24/S
20/R
Ͻ5
d-His-Ac 6
+13 (1st fraction)[g]
l-His-l-Val-Ac 10
l-His-Isovaleric amide 9
Ͻ5
Ͻ5
Ͻ5
Ͻ5
8
9
10
11
12
13
Gly-l-His-Ac 15
Gly-d-His-Ac 16
l-Trp-l-His-Ac 17
l-Trp-d-His-Ac 18
d-Trp-l-His-Ac 19
d-Trp-d-His-Ac 20
10/(–)
10/(+)
Ͻ5[d]
Ͻ5[e]
Ͻ5[f]
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Ͻ5
Ͻ5
10/R
7/S
12/R
5/S
Ͻ5[f]
14
l-Gln(propylene-N3)-TAC(l-His-Ac)3 21 48/(–)
47/RR
n.d.
18/S
[a] Most conversions were Ͼ90% except where noted; (+) and (–) refer to the sign of the optical rotation of the product. [b] See Schemes 1
and 2 for the ligands and Scheme 3 for the catalysed reactions. [c] Both 1 and 3 equiv. of this ligand compared to copper were used.
Conversions lower than 90%. [d] Conversions lower than 60%. [e] Conversions lower than 65%. [f] Conversions lower than 70%. [g]
Refers to the order of elution of the products from the HPLC column.
ee values were obtained for the for the MA reaction (entry previously in the construction of scorpionate antibiotics
4). Furthermore, using the l- and d-histidine-containing li- and can be applied for conjugation to other structures such
gands, the same ee values for the opposite enantiomers were as surfaces, dendrimers or proteins by using copper-cata-
obtained within experimental error (entries 4 and 5). Sur- lysed alkyne–azide cycloaddition reactions.[15] With this li-
prisingly, N-terminal extensions larger than acetyl groups – gand ee values of 47–48% and 18% were obtained in the
as with ligands 9 and 10 – resulted in dramatically reduced Diels–Alder and Michael addition reaction, respectively
ee values for the DA reaction and lower ee values for the (entry 14). Apparently, extensions on the C1 atom of the
MA reaction (entries 6 and 7).
aromatic ring of the TAC scaffold did not affect the out-
Based on these initial results, a 2nd generation of ligands come of the reactions substantially.
in which amino acid residues were inserted between the
Modelling studies were performed to gain insight into
TAC scaffold and the coordinating histidinyl imidazole the interaction between substrates and on the structure of
rings, were evaluated. As can be inferred from the results, the ligand–CuII complex. A coordination complex of CuII
the enantioselectivity of the catalysed reactions were signifi- with ligand 6 or 8 and with substrate 23 was loaded in DS
cantly reduced when catalysts containing the inserted ad- Viewer Pro (see the Supporting Information). A square-py-
ditional amino acid residues were used (Table 1, entries 8– ramidal coordination geometry was assumed for the CuII
13). Whereas conversions in the Diels–Alder reactions using with four nitrogen atoms (three from the ligand and one
Gly-containing ligands were still more then 90% (entries 8 from the substrate) positioned in the square plane of the
and 9), with the Trp-containing ligands, substantially lower pyramid.[16] The carbonyl oxygen atom from the coordinat-
conversions were obtained in some cases (entries 10–13). ing substrate was placed in one of the axial positions of the
This result suggests that the catalytically active site in these copper(II) ion.[17] This complex between ligand 8, substrate
ligands is less accessible for the incoming diene. Remark- 23 and CuII (complex A) was loaded into YASARA and a
ably, the conversion was affected less in the Michael ad- simulation cell was placed automatically around the com-
dition reaction. Moreover, the insertion of amino acid resi- plex.[18] To the simulation cell, either the diene or dimethyl
dues between the scaffold and the tris-histidine triad led to malonate were added and docked ten times onto complex
the formation of the opposite enantiomer of the Michael A using AutoDock 4 (Figure 1).[19]
adduct to those obtained with ligands containing histidine
These modelling studies suggested a small indentation
residues attached directly onto the TAC scaffold (compare was present just above the triazacyclophane ring, which
for example Table 1, entry 4 with entries 10 and 12), albeit could function as a hydrophobic binding pocket for the
with low ee values.
hydrophobic substrates. This may explain why positioning
Because the highest enantioselectivities were obtained of the histidine residues directly onto the TAC scaffold is
with ligands in which the histidine residues were attached required to achieve significant enantioselectivity. However,
directly to the TAC scaffold, a similar ligand (21, see for the reaction to occur, the catalyst needs to undergo a
Scheme 1) containing an extension on the C1 atom of the structural rearrangement to bring together the enone and
triazacyclophane core, was tested.[6] This ligand was used the cyclopentadiene or dimethyl malonate.
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R. M. J. Liskamp et al.
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Figure 1. Modelling of the complex between ligand 8, copper(II) and substrate 23 (left). Structures of ten dockings of cyclopentadiene
(middle) or dimethyl malonate (right) molecules onto this complex are shown.
The resin used for the synthesis of the ligands was obtained from
Rapp Polymere and was, in all cases, PS S RAM resin (loading:
0.69 mmol/g). All other chemicals were obtained from Acros or
Aldrich and were used without purification. Substrates 23 and 24
were prepared following published procedures.[22] Reported reten-
tion times for the ligands (tR) were obtained with a Shimadzu
HPLC system with a standard gradient of water/MeCN/TFA,
95:5:0.1 (v/v) to MeCN/water/TFA, 95:5:0.1 (v/v) in 25 min using
an Alltima C18 column (300 Å; 5 μm; 250ϫ 4.6 mm) and a UV
detector (operating at 220 and 254 nm).
It should be emphasized that this is just one of the pos-
sible geometries the catalyst and copper(II) complexes can
adopt. For example, when the catalysis reaction mixture is
held at pH 6.5, one histidine ligand might dissociate from
complex A,[20] allowing the formation of a square-planar
coordination complex involving the bidentate bound sub-
strate through its nitrogen and oxygen atoms and two nitro-
gen atoms from two remaining coordinating histidine resi-
dues. It has been stated that such a square-planar geometry
is most effective for catalysis.[21] Therefore, supporting spec-
troscopic data is needed to confirm the calculated structure.
Tris-D-Histidine-Containing Ligand 6: The synthesis of this con-
struct was performed with resin-bound TAC scaffold 5 (0.25 g)
using Fmoc-d-His(Trt)-OH (2 equiv., 650 mg, 1 mmol). This amino
acid building block was coupled using BOP (442 mg, 1 mmol) and
DIPEA (348 mL, 2 mmol) in NMP (3 mL). A chloranil test was
performed after washing with NMP (3ϫ 6 mL, each 2 min) and
CH2Cl2 (3ϫ 6 mL, each 2 min) until successful coupling was indi-
cated. After removal of the Fmoc group by treatment with a 20%
solution of piperidine in NMP followed by washing with NMP
(3ϫ 6 mL, each 2 min) and CH2Cl2 (3ϫ 6 mL, each 2 min) the N-
terminus was protected with acetyl groups using a capping solution
consisting of Ac2O (0.5 m), DiPEA (0.125 m) and HOBt (0.015 m)
in NMP (3ϫ 3 mL, each 10 min). The resin-bound construct was
Conclusions
In this paper we have demonstrated the first application
of TAC scaffolded amino acids in asymmetric catalysis. Sig-
nificant enantioselectivities were obtained in two of the ar-
chetypical C–C bond-forming reactions. Enantiomeric ex-
cesses up to 55% in the Diels–Alder cycloaddition and 24%
in the Michael addition reactions were observed. Surpris-
ingly, extensions at the N-termini of the histidine residues
other than the acetyl group, or the insertion of amino acid simultaneously cleaved from the resin and deprotected. Purification
was performed by column chromatography [CHCl3/MeOH/
NH4OH (aq. 25%), 8:3:0.5 (v/v)] and lyophilisation to give
TACzyme 6 as a white solid; yield 132.5 mg (163 mmol; 93%).
HRMS: calcd. for [M + 2H]2+ 407.7095; found 407.7079. HPLC:
tR = 12.10 min (C18).
residues between the histidine residues and the TAC scaf-
fold, led to significant decreases in the ee values. Appar-
ently, the additional steric bulk and/or conformational free-
dom are not beneficial for high enantioselectivity. A ligand
containing an extension at the C1-position of the TAC scaf-
fold, which enables conjugation to moieties such as dendri-
mers and proteins, was used successfully in the catalysed
reactions. Application of such TAC-based ligands in other
copper(II)-based asymmetric reactions can be envisioned.
Tris-L-Histidine-Containing Ligands 9 and 10: The synthesis of
these constructs was identical to the synthesis of construct 8 –
which is described in detail elsewhere[5] – until the Fmoc-removal
step. After this, the resin was divided in two equal portions (0.5 g
each; loading = 0.7 mmol/g): one portion was used for the synthesis
of 9 and the second portion was used for 10. For the synthesis of 9,
the N-terminus was acylated with isovaleric acid (4 equiv., 4 mmol,
464 mL) using BOP (4 equiv., 4 mmol, 1.86 g) and DiPEA
(8 equiv., 8 mmol, 1.46 mL) in NMP (3 mL). After coupling, the
resin was thoroughly washed with NMP (3ϫ 6 mL, each 2 min)
Experimental Section
General: Fmoc-protected amino acid residues were purchased from
GL Biochem; solvent and reagents were purchased from Biosolve.
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Enantioselective Diels–Alder and Michael Addition Reactions
and CH2Cl2 (3ϫ 6 mL, each 2 min) and the coupling was verified
by applying a Kaiser test. For the synthesis of 10, the N-terminus
was acylated with Fmoc-l-Val-OH (4 equiv., 4 mmol, 1.43 g) using
BOP (4 equiv., 4 mmol, 1.86 g) and DiPEA (8 equiv., 8 mmol,
1.46 mL) in NMP (3 mL). After coupling, the resin was thoroughly
washed with NMP (3ϫ 6 mL, each 2 min) and CH2Cl2 (3ϫ 6 mL,
each 2 min) and coupling was also verified with a Kaiser test. To
complete the synthesis of 10, the Fmoc group was removed using
20% piperidine/NMP and the resin was washed with NMP (3ϫ
6 mL, each 2 min) and CH2Cl2 (3ϫ 6 mL, each 2 min). Deprotec-
tion of the amine functionality was monitored with Kaiser tests
and the liberated amine was acetylated using a capping solution
that consisted of Ac2O (0.5 m), DiPEA (0.125 m) and HOBt
(0.015 m) in NMP (3ϫ 3 mL, each 10 min). After completion of
the solid phase synthesis, the constructs were cleaved from the resin
and 50 mg of the crude material of both 9 and 10 were purified by
preparative RP-HPLC. Pure fractions were pooled and lyophilised.
After this, TACzymes 9 and 10 were dissolved in water, the pH of
the solution was adjusted to approximately 7 with NaOH (1 m),
and the samples were again lyophilised.
calcd. for [M + H]+ 197.1038; found 197.1035. Ac-(l-His)3-NH2:
HRMS: calcd. for [M + 2H]2+ 236.1147; found 236.1138.
Typical Catalytic Procedure: A stock solution of Cu(NO3)2(H2O)6
(10 mm in water, 31 μL) and a TAC-based ligand solution (2 mm in
water, 197 μL) were mixed at 0 °C. To 50 μL of this catalyst solu-
tion, MOPS-buffer (20 mm, 250 μL, pH 6.5) and an aliquot (5 μL)
of a stock solution of substrate 22 or 23 in CH3CN (60 mm, final
conc. 1 mm) were added, resulting in a final concentration in Cu
of 0.23 mm (CuII/ligand, 1:1.2). The mixture was cooled to 0 °C
and the reaction was initiated by addition of freshly distilled cyclo-
pentadiene (1.5 μL) or dimethyl malonate (3 μL, 100 equiv.). This
reaction mixture was mixed for 3 d by continuous inversion at 5 °C.
The organic products were isolated by extraction with Et2O
(2ϫ1.5 mL). Conversion and ee values were determined by HPLC
analysis on a chiral stationary phase [DA and MA products of
22: Chiralpak AD heptane/2-propanol, 99:1 (v/v); for DA and MA
products of 23: Chiralcel ODH heptane/2-propanol, 98:2 (v/v)].
Note: Ligands 15–20 were initially dissolved in a minimal amount
of DMSO, and subsequently MOPS buffer was added until the
final concentration was obtained.
Compound 9: Crude yield 68.7 mg (73 mmol, 22%); purified yield
37.1 mg (39 mmol, 12%). HRMS: m/z calcd. for [M + 2H]2+
470.7805; found 470.7805. HPLC: tR = 15.14 min (C18).
Supporting Information (see footnote on the first page of this arti-
cle): Detailed description of the procedures used during the model-
ling are provided.
Compound 10: Crude yield 101.2 mg (91 mmol, 27%); purified yield
72.9 mg (66 mmol, 20%). HRMS: m/z calcd. for [M + 2H]2+
556.3122; found 556.3091. HPLC: tR = 14.00 min (C18).
Acknowledgments
Tris-histidine-Containing Ligands 15–20: Synthesis of these con-
structs was similar to that for the synthesis of ligand 10, in this case
using Fmoc-Gly-OH, Fmoc-l-Trp(Boc)-OH or Fmoc-d-Trp(Boc)-
OH instead of Fmoc-l-His(Trt)-OH for the first coupling and
Fmoc-l-His(Trt)-OH or Fmoc-d-His(Trt)-OH instead of Fmoc-l-
Val-OH for the second coupling. For this, resin-bound scaffold 5
(1.5 g) was used, which was initially divided in three equal portions;
the first set of amino acid residues was coupled, one residue to
each portion. Each of the three portions was divided in two equal
portions and the histidine residues were coupled so that six resin-
bound ligand precursors were obtained. After coupling of this last
amino acid residue, the N-terminal Fmoc group was removed and
the liberated amine was acetylated using a capping solution that
consisted of Ac2O (0.5 m), DiPEA (0.125 m) and HOBt (0.015 m)
in NMP (3ϫ 3 mL, each 10 min). After completion of the solid-
phase synthesis, the constructs were cleaved from the resin and the
crude material (50 mg) was purified by preparative HPLC. Pure
fractions were pooled and lyophilised and ligands 15–20 were dis-
solved in water, the pH of the solution was adjusted to ca. 7 with
NaOH (1 m), and the samples were again lyophilised.
We thank the Integrated Design for Catalytic Nanomaterials for a
Sustainable Production (IDECAT), the European Research Area
(ERA) Chemistry program and the National Research School
Combination Catalysis Controlled by Chemical Design (NRSC-
Catalysis) for financial support of this research. We thank Cees
Versluis for determining HRMS values.
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b) R. Sambasivan, Z. T. Ball, J. Am. Chem. Soc. 2010, 132,
9289–9291; c) A. C. Laungni, J. M. Slattery, I. Krossing, B.
Breit, Chem. Eur. J. 2008, 14, 4488–4502; d) C. A. Christensen,
M. Meldal, J. Comb. Chem. 2007, 9, 79–85; e) A. Agarkov, S.
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Compound 15: tR
= 10.60 min (C18); HRMS: calcd. for
[M + 2H]2+ 493.2417; found 493.2438.
Compound 16: tR 10.60 min (C18); HRMS: calcd. for
[M + 2H]2+ 493.2417; found 493.2435.
Compound 17: tR 20.20 min (C18); HRMS: calcd. for
[M + 2H]2+ 686.8285; found 686.8305.
Compound 18: tR 20.20 min (C18); HRMS: calcd. for
[M + 2H]2+ 686.8285; found 686.8281.
Compound 19: tR 20.20 min (C18); HRMS: calcd. for
[M + 2H]2+ 686.8285; found 686.8296.
=
=
=
=
Compound 20: tR
= 20.20 min (C18); HRMS: calcd. for
[M + 2H]2+ 686.8285; found 686.8276.
HRMS Data for Ligands: Ligand 21: HRMS: calcd. for
[M + 2H]2+ 513.2630; found 513.2624. Ac-l-His-NH2: HRMS:
Eur. J. Org. Chem. 2011, 1714–1720
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. M. J. Liskamp et al.
FULL PAPER
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This is in line with results obtained from simple protected histi-
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[18]
[19] Docking was performed using AutoDock 4, see: G. M. Morris,
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Received: November 11, 2010
Published Online: February 7, 2011
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Eur. J. Org. Chem. 2011, 1714–1720