Optically active (peptido-carbene)palladium complexes: Towards true solid-phase combinatorial libraries of transition metal catalysts

Article abstract of DOI:10.1002/ejoc.200800234

This work explores the potential of forming transition metal catalysts by combinatorial solid-phase peptide chemistry to produce catalysts with enzyme-like properties of stereoselectivity, regioselectivity and even substrate selectivity. A series of new functionalised carbene precursors/donors - imidazolium salts - each containing both amino acid and carboxylic acid functionality was synthesised in solution. The readily accessible carbene precursors were incorporated within the backbones of peptides attached to PEGA resin, by standard solid-phase peptide coupling techniques. The synthetic strategy gave easy access to both mono- and didentate ligand systems, providing folded structures around the central transition metal atoms, with different degrees of steric congestion and bite angles. Changing the number of incorporated amino acids between the two carbene donors facilitated variation of the properties of the complexes. Both ligand systems were complexed to palladium(II) by standard base treatment, and the Pd complexes were studied by mass spectrometry and NMR spectroscopy. The monodentate (carbene) palladium complexes were each the product of enolisation of a neighbouring carbonyl group and loss of a proton, followed by coordination of the oxy anion to the palladium atom. The established methods are suitable for the combinatorial synthesis of palladium catalysts on solid support. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800234

FULL PAPER
DOI: 10.1002/ejoc.200800234
Optically Active (Peptido-carbene)palladium Complexes: Towards True Solid-
Phase Combinatorial Libraries of Transition Metal Catalysts
Jakob F. Jensen,[a] Kasper Worm-Leonhard,[a] and Morten Meldal*[a]
Keywords: Palladium catalysts / Solid phases / Combinatorial chemistry / Chiral catalysts / Carbenes
This work explores the potential of forming transition metal
catalysts by combinatorial solid-phase peptide chemistry to
produce catalysts with enzyme-like properties of stereoselec-
tivity, regioselectivity and even substrate selectivity. A series
of new functionalised carbene precursors/donors – imid-
azolium salts – each containing both amino acid and carbox-
ylic acid functionality was synthesised in solution. The read-
ily accessible carbene precursors were incorporated within
the backbones of peptides attached to PEGA resin, by stan-
dard solid-phase peptide coupling techniques. The synthetic
strategy gave easy access to both mono- and didentate li-
gand systems, providing folded structures around the central
transition metal atoms, with different degrees of steric con-
gestion and bite angles. Changing the number of incorpo-
rated amino acids between the two carbene donors facili-
tated variation of the properties of the complexes. Both li-
gand systems were complexed to palladium(II) by standard
base treatment, and the Pd complexes were studied by mass
spectrometry and NMR spectroscopy. The monodentate (car-
bene)palladium complexes were each the product of enolis-
ation of a neighbouring carbonyl group and loss of a proton,
followed by coordination of the oxy anion to the palladium
atom. The established methods are suitable for the combina-
torial synthesis of palladium catalysts on solid support.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
opment of new synthesis methods that facilitated applica-
tions of carbenes and their metal complexes in a broad vari-
ety of catalytic transformations, including cross-coupling,[7]
olefin metathesis,[8,9] hydrosilylation,[10] telomerisation,[11]
hydrogenation,[12] ethylene/CO copolymerisation[13] and
ring-opening polymerisation.[14]
Introduction
The development of polymer-bound organometallic
complexes for homogeneous catalysis of organic reactions
has progressed significantly in recent years.[1] The major
contributions have been based on solid-supported phospha-
nes, which form complexes with the transition metals.[1]
Only little attention has been paid to N-heterocyclic carb-
enes on solid supports, even though carbenes are emerging
as an important family of ligands with electronic character-
istics similar to those of the phosphanes.[2,3] However, the
metal–carbon bonds in the carbene complexes have been
shown to be much stronger than the metal–phosphorus
bonds in common phosphane complexes, thus reducing the
problems associated with weak ligand–metal interactions,
which cause deposition of metal residues or metal leaching
from the supported complex.[2,4]
The efficiency of a given catalytic system depends cru-
cially on subtle interplay between the metal atom and its
coordinated ligand(s). Steric, geometric and electronic li-
gand parameters are important, but not easily predicted
factors, especially in enantioselective catalysis. Therefore,
the process of stepwise variation and selection is still com-
monly used in the discovery and optimisation of new cata-
lysts.[15] With respect to the chiral carbene ligands and their
metal complexes, both mono- and didentate chelate systems
have been prepared by several groups.[2,16] At present, there
are reports on solid-supported peptide-based chiral mono-
and didentate N-heterocyclic carbene complexes, particu-
larly because solid-phase synthesis of this type should facili-
tate combinatorial chemistry and give access to a diverse
set of transition metal ligands. The well-developed nature
of peptide chemistry and the great structural variety and
functional diversity displayed by the amino acids provide a
powerful tool for generating diverse on-bead libraries for
the search for highly active and selective catalysts. So far,
only a few research groups have applied peptides as transi-
tion metal ligands or as backbones for other attached li-
gand donors. Gilbertson,[17] Hoveyda[18] and Christensen[19]
demonstrated that phosphane-containing peptides could be
Application of N-heterocyclic carbenes in catalysis can
be traced back to two important events. Öfele and Wanzlick
prepared the first examples of (N-heterocyclic carbene)-
metal complexes.[5] Later and importantly, Arduengo and
co-workers reported the synthesis of a stable free carbene,[6]
which turned out to be an important feature for the devel-
[a] Centre for Solid Phase Organic Combinatorial Chemistry &
Molecular Recognition, Carlsberg Laboratory,
Gamle Carlsberg Vej 10, 2500 Valby, Denmark
Fax: +45-33274708
E-mail: mpm@crc.dk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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J. F. Jensen, K. Worm-Leonhard, M. Meldal
FULL PAPER
Figure 1. Schematic representation of the peptide-based carbene ligand system. Parameters n, x, y and z are variable.
applied effectively as ligands for transition-metal-catalysed for the nature of N-substituents.[2] In this work we sought
(palladium and copper) asymmetric synthesis while the cat- for a synthetic method that would give access to unsymmet-
alyst was still attached to the polymer. Recently, Adolfsson rical N-substituted imidazolium ions each containing a
used dipeptide-derived ligands for ruthenium-catalysed masked/protected amino and acid functionality. Such car-
enantioselective transfer hydrogenation.[20]
bene precursor building blocks would be well suited for
Inspired by these contributions, we now report the first standard solid-phase peptide chemistry. From the available
solid-phase synthesis of carbene ligands and their palla- tert-butyl esters of different amino acids, three amino-acid-
dium complexes with peptide backbones as chiral architec- derived imidazoles were synthesised in a modified one-pot
tures. With a suitable carbene precursor containing the nec- Arduengo condensation,[22,23] in which the amino acid ester,
essary functional groups for incorporation into the peptide glyoxal, formaldehyde and aqueous ammonia reacted to
chain, the combinatorial synthesis of carbene ligands is generate the N-substituted imidazole ring as outlined in
feasible.[21] The combinatorial strategy enables the genera- Scheme 1.
tion of structurally diverse binding sites and allows the syn-
The halide precursors for alkylation of the imidazoles to
thesis of monodentate, didentate and possibly polydentate provide imidazolium ions were synthesised in two steps
ligands with a variety of different bite angles. In a didentate from commercially available amino alcohols as depicted in
system, the bite angle itself may be varied by variation of Scheme 2. The amino groups were protected as azides, and
the type (α-, β- and γ-) and number of amino acids incorpo- the alcohols were subsequently converted into the iodides
rated between the ligand binding sites in the peptide chain, via the mesylates with sodium iodide in acceptable yields
as outlined in Figure 1. The two flanking regions may simi- and in agreement with previous synthesis of analogues.[24,25]
larly be optimised for substrate interaction by variation in
length, constitution and stereochemistry.
The imidazoles and alkyl iodides were employed in the
synthesis of four different imidazolium salts as shown in
Scheme 3. SN2 iodide displacements in compounds 2 by the
imidazoles 1 generated the imidazolium iodides in moderate
yields (40–42%) after purification on silica gel. Before hy-
drolysis of the tert-butyl ester, iodide (I–) was ion-exchanged
Results and Discussion
Preparation of Chiral Imidazolium Building Blocks as
Precursors for N-Heterocyclic Carbenes
–
either with hexafluorophosphate (PF6 ) or with tetrafluo-
–
roborate (BF4 ), which in our hands generated imidazolium
In previous studies it has been shown that imidazolium salts more stable toward the subsequent TFA treatment,
ions can be generated by several efficient methods, involving which completed the synthesis in good yields. MS analysis
either one or several steps, depending on the requirement of the final compounds revealed that hexafluorophosphate
Scheme 1. Functionalised imidazole synthesis by a four-component condensation.
Scheme 2. 2-Azidoalkyl iodides synthesised from amino alcohols.
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Optically Active (Peptido-carbene)palladium Complexes
Scheme 3. Synthesis of imidazolium trifluoroacetate 3.
and tetrafluoroborate ions were exchanged during TFA azolium ions as outlined in Scheme 4. The products were
treatment, thereby generating the corresponding imid- released from the resin with aqueous TFA (95%). ESMS
azolium trifluoroacetates in acceptable yields.
revealed that trifluoroacetate was the counterion to the cat-
ionic imidazolium ion. However, when the synthesis was
performed on a photolabile linker[30] instead of the Rink
amide linker, it was possible to isolate the tetrafluoroborate
Solid-Phase Synthesis and Characterisation of (Carbene)-
palladium Complexes
–
(BF4 ) salt.
In order to investigate the potential of the new imid-
Further analysis of the leucine-derived imidazolium ion
azolium ion building blocks for the preparation of more 4c, with a stereogenic centre in the α-position to the imid-
elaborate carbene ligands for palladium complexation, both azolium ring and the carbonyl group, revealed, not surpris-
monodentate and didentate ligands with different distances ingly, that the product had racemised.
between the two carbene donors were synthesised. The
With the resin-bound imidazolium ions to hand, the car-
structural variation should provide a means of control of bene formation and complexation to palladium(II) was in-
the bite angle.[26] Starting from amino-functionalised vestigated directly on resin. Each imidazolium salt was
PEGA resin,[27] the acid-labile Fmoc-protected Rink amide treated with the base 2-(tert-butylimino)-2-(diethylamino)-
linker was attached by the standard TBTU activation pro- 1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) to
cedure,[28] followed by Fmoc cleavage effected with piperi- deprotonate the imidazolium ion and to give the corre-
dine/DMF and another TBTU coupling of Fmoc-Val-OH. sponding N-heterocyclic carbene, which was subsequently
After Fmoc cleavage, each of the four different imidazolium trapped with PdCl2COD.[31] However, as revealed by
ions 3 was attached to the PEGA-Rink-Val-NH2 resin by HRMS (ESI) analysis of the palladium complex formed un-
activation with TBTU. Subsequently, the azide was reduced der these reaction conditions, a β-enolate oxygen atom was
by treatment with a DMF solution of dithiothreitol (DTT, coordinated to the palladium atom in addition to the car-
0.25 ) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, bene coordination. This enolate was generated during the
2 equiv.). The free amine was subjected to TBTU coup- base treatment. The optimised reaction conditions afforded
ling,[29] followed by one additional cycle of Fmoc cleavage/ clean conversions of compounds 4 to 5. According to
TBTU coupling to afford four different resin-bound imid- HRMS (ESI), however, it was difficult to obtain quantita-
Scheme 4. Solid-phase synthesis of resin-bound peptides each containing one imidazolium ion.
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J. F. Jensen, K. Worm-Leonhard, M. Meldal
FULL PAPER
tive conversion, and conversion was further reduced with seven-membered chelate 5e. However, MS analysis of the
increased peptide chain length after the imidazolium ion product mixture containing 5e clearly demonstrated that
(e.g., in 4d). During initial experiments it had been observed this complex was less favoured than the six-membered che-
that no complex formation took place with commonly used lates (5a–5d; Scheme 5). This was further substantiated by
bases such as DBU and tBuOK.[32,33] Only a few examples unsuccessful attempts to transform compound 4f into 5f.
of anionic ligands derived from carbenes are known,[34] but
The imidazolium ion 4a and the corresponding Pd-com-
recent results from Waymouth et al.[35] demonstrated a pref- plexed chelate 5a were studied by 1D and 2D NMR spec-
erence for N-heterocyclic carbene enolate complexation troscopy, and their chemical shifts, shown in Table 1, were
when a carbonyl group is positioned β to the carbene do- structurally assigned to the two compounds. While the spec-
nor, enabling the formation of very stable six-membered tra of 4a yielded sharp and well defined resonances, the
chelates. No decomposition of these complexes could be ob- spectra of 5a showed a higher degree of line broadening,
served by MS (ESI) even after three months in a TFA buffer particularly of those protons in the vicinity of the palladium
(0.1% aq.).
atom. Full interpretation of the NMR data could still be
Chelate formation with enolates in similar systems could achieved, however, and both these and the HRMS data
be avoided by formation of the (carbene)silver complexes were in agreement with the structure 5a.
and transmetallation with the appropriate palladium
Another, simpler way to generate (carbene)palladium
salts.[36,37] While this reaction works well with Ag2O in solu- complexes is through direct reactions between palladium(II)
tion reactions, experiments showed that the insoluble Ag2O acetate and the imidazolium ions in the absence of base.[38]
did not function with resin swollen in DCM.
By this method, the resin-bound Fmoc-protected imid-
Subjection of imidazolium ion 4e to the same reaction azolium ion 6 was treated with Pd(OAc)2 at 75 °C in a sol-
conditions as described above resulted in some carbene vent mixture of DMSO and THF for 2 h, as outlined in
enolate complexation, thereby generating the less favoured Scheme 6. After TFA cleavage from the resin, the structure
Scheme 5. Synthesis of N-heterocyclic carbene enolate palladium(II) complexes 5a–5e.
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Optically Active (Peptido-carbene)palladium Complexes
Table 1. NMR spectroscopic data for compounds 4a and 5a.
of the formed complex 7 was determined and was found to
be similar to the structures described above, with the forma-
tion of a six-membered chelate. On repetition of the reac-
tion in solution, the same compound was obtained and
characterised by 13C NMR spectroscopy. According to MS
(ESI), the solid-phase procedure forced the complexation to
completion, although at the same time undesired precipi-
tation of palladium black inside the PEGA beads was ob-
served.
Uncomplexed ligand 4a Pd-complexed ligand 5a
Palladium particles encapsulated inside the polymer are
known to catalyze a range of less specific, unpredictable
reactions, which is inconvenient when specific catalysts are
prepared for use in solid-phase catalysis.[39] While the
Pd(OAc)2 procedure was useful for solution-phase synthesis
of 7, it was therefore not further employed in the synthesis
of supported catalysts.
1H
13C
1H
13C
Naph. C-1
Naph. C-2
Naph. C-3
Naph. C-4
Naph. C-5
Naph. C-6
Naph. C-7
Naph. C-8
Naph. C-9
Naph. C-10
C-0
8.498
127.5
130.8
124.0
127.6
127.4
127.5
126.6
128.6
131.9
134.0
166.6
8.529
127.6
131.1
124.0
127.4
127.4
127.5
126.6
128.6
132.0
134.0
166.6
7.979
8.015
7.997
7.633
7.615
8.028
7.998
7.982
7.980
7.633
7.615
8.015
With these results to hand, the scope of the didentate
ligand systems for complex formation was investigated.
Three ligand precursors 8 for didentate complexation were
synthesised in acceptable purity (Ͼ80%) by the TBTU
coupling procedure as described in Schemes 7 and 8. The
distance between the two imidazolium ions was modified
by variation of the number (n = 2 or 3; see Figure 1) of
amino acids between the carbenes. In two instances (8a, 8b)
proline was incorporated between the imidazolium ions,
with the purpose of facilitating a β-turn, thereby spatially
arranging the two donors for the complexation.[17a] In a
mixture of THF and DMF as solvent, the didentate com-
plexes were prepared by treatment with BEMP and
PdCl2COD. When DMF alone was used as solvent, approx-
imately 30% of byproduct was formed, due to nucleophilic
displacement α to the N1 atom of the imidazolium ion. Af-
ter TFA cleavage, the palladium complexes could be charac-
terised by electrospray ionisation HRMS in positive mode,
showing clean ca. 80% conversions into 9a and 9b, respec-
tively. Cleavage with 95% TFA showed that the complexes
were acid-stable, and they could be stored for several
months in a 0.1% TFA solution of water and acetonitrile.
Only one palladium atom coordinated to each molecule,
substantiating didentate complexation.
N-1
8.935
3.775
3.705
8.909
3.795
3.760
C-1α
42.7
42.6
C-1
168.9
168.6
N-2
C-2α
C-2β
8.013
4.362
2.887
2.754
7.977
4.475
2.889
2.830
50.2
36.7
51.9
37.8
C-2γ
C-2δ
C-2ε
C-2ζ
C-2
137.3
128.9
128.0
126.2
51.7
137.7
128.8
128.0
126.1
51.1
7.248
7.288
7.214
4.447
4.252
8.971
7.746
7.698
5.199
5.097
7.230
7.245
7.193
3.990
3.827
–
7.495
7.381
4.914
Im
Im
137.6
122.1
123.4
50.4
–
122.4
122.7
54.6
Im
C-3α
C-3
N-4
164.7
–
8.554
4.198
2.022
0.889
0.876
8.793
4.834
1.989
0.835
1.037
C-4α
C-4β
C-4γ1
C-4γ2
C-4
57.5
30.3
19.1
17.5
172.2
68.3
30.2
19.0
17.3
171.4
Finally, complexation with precursor 8c, without a pro-
line between the two potential donors, resulted in similar
coordination of palladium(II) under the BEMP/PdCl2COD
N-5
7.515
7.134
7.515
7.134
Scheme 6. Synthesis of a (carbene)palladium(II) complex with use of Pd(OAc)2.
Eur. J. Org. Chem. 2008, 3785–3797
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J. F. Jensen, K. Worm-Leonhard, M. Meldal
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Scheme 8. Synthesis of a (didentate carbene)palladium(II) complex
without an induced turn.
Conclusions
We have succeeded in developing a new general synthetic
procedure for highly functionalised imidazolium ion build-
ing blocks each containing both a masked amine (azide)
and a carboxylic acid group. The readily available com-
pounds, which serve as N-heterocyclic carbene precursors,
were easily incorporated into peptide chains on solid phase,
by standard peptide coupling chemistry. The developed
strategy is well suited for combinatorial library synthesis.
Nine different model compounds that provided the neces-
sary structural variations for the first model studies of pal-
ladium(II) complexation were synthesised, and complex-
ation was achieved on solid support. Palladium complexes
of monodentate and didentate carbenes with different dis-
tances between the donors were generated by treatment
with the strong base BEMP. The complexes formed were
surprisingly stable towards air and moisture and could be
characterised by mass spectrometry and by NMR spec-
troscopy. Currently, the combination of carbenes and phos-
Scheme 7. Synthesis of (didentate carbene)palladium(II) complexes
with induced turns in the peptides.
reaction conditions as shown in Scheme 8. Clearly, this re- phanes in the same peptide framework on PEG-based res-
sult indicates that the strong effect of carbene coordination ins is being investigated for formation of combinatorial li-
in the complex can force a turn in the flexible part of the gand libraries. The use of the resin-supported (carbene)pal-
peptide chain (n = 2), overcoming the loss in entropy upon ladium complexes in Suzuki reactions will be reported sepa-
complex formation.
rately.
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Optically Active (Peptido-carbene)palladium Complexes
tert-Butyl Imidazol-1-ylpropionate (1c): At 20 °C, a solution of gly-
oxal (40% wt. solution in water, 20.90 g, 0.144 mol), formaldehyde
(37% wt. solution in water, 11.70 g, 0.144 mol) and iPrOH
(100 mL) was added dropwise to a stirred suspension of H-β-Ala-
OtBu·HCl (25.00 g, 0.144 mol), ammonia (25% wt. solution in
water, 0.144 mol, 10.7 mL) and iPrOH (250 mL). After complete
addition, the reaction mixture was heated to 80 °C and stirred for
an additional 6 h. The final homogeneous and slightly yellow solu-
tion was cooled to 20 °C and diluted with DCM (500 mL). The
organic layer was washed with NaOH (1.0 , 300 mL) and dried
(Na2SO4). Concentration in vacuo afforded a yellow oil. Purifica-
tion by kugelrohr distillation yielded tert-butyl imidazol-1-ylpro-
pionate (7.20 g, 27%) as a yellow solid. 1H NMR (250 MHz,
CDCl3): δ = 7.49 (dd, app [br. s], 1 H, CH), 7.02 [dd, app [t],
Experimental Section
General Remarks: All new compounds prepared in solution were
characterised by 1H and 13C NMR (250 MHz, Bruker DRX 250 or
600 MHz, Bruker DRX 600), MS-ESI, and microanalysis or
HRMS. New compounds prepared on PEGA800 resins were cleaved
off and characterised by HRMS electrospray (ESI) in positive
mode with a Micromass QTOF instrument using a mixture of
buffer (A) and buffer (B) (see below). MS (ESI) in negative mode
was performed in a solvent mixture of water/acetonitrile (1:1) with
a Bruker esquire3000plus mass spectrometer. Selected examples of
carbene-peptides and precursors were fully characterised by 1H
NMR spectroscopy, and 13C NMR spectroscopy was also em-
ployed. All solvents were of HPLC quality and were stored over
molecular sieves or distilled from sodium before use (THF). For
all reactions on solid support, PEGA800 resin (0.30–0.32 mmolg–1,
VersaMatrix A/S) was used. Prior to use, the resin was washed with
methanol (6ϫ), acetonitrile (6ϫ), DMF (6ϫ) and DCM (6ϫ) and
dried in vacuo overnight. All commercially available reagents were
used as received without further purification. Analysis of solid-
phase reactions was performed after cleavage of the products as
their free amides from the resin. Analytical and preparative re-
versed-phase HPLC separations were performed with a Waters
HPLC system using analytical chromolith speedrod RP-18E
(50ϫ4.6 mm) and delta PAK (25ϫ200 mm) columns with flow
rates of 5 and 10 cm3 min–1, respectively; detection ocurred at
215 nm with a multi-wavelength detector (Waters 490 E) for analyt-
ical purposes, and a photodiode array detector (Waters M991) was
used for preparative separations. A solvent gradient system con-
sisting of 0.1% TFA in water(A) and 0.1% TFA in acetonitrile/
water (9:1) (B) was used.
3
3J(H,H) = 1.3 Hz, 1 H, CH], 6.92 {dd, app [t], J(H,H) = 1.3 Hz,
3
3
1 H, CH}, 4.21 [t, J(H,H) = 6.6 Hz, 2 H, CH2], 2.67 [t, J(H,H)
= 6.6 Hz, 2 H, CH2], 1.41 (s, 9 H, CH3) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 169.69, 137.17, 129.39, 118.82, 81.64,
42.50, 37.05, 28.05 ppm. HRMS (ESI): calcd. for C10H17N2O2 [M
+ H]+ 197.1285; found 197.1293.
(S)-2-Azido-3-methylbutan-1-ol: TfN3 was prepared as a DCM
solution from NaN3 and Tf2O. (–)--Valinol (5.00 g, 0.049 mol)
and CuSO4·H2O (242 mg, 0.02 equiv.) were dissolved in H2O
(180 mL), and the pH was adjusted to 9–10 with K2CO3; MeOH
(360 mL) and the crude TfN3 in DCM (ca. 0.4 , 1.5 equiv.,
0.073 mol) was added, and the pH was readjusted to 9–10 with
K2CO3. The two-phase system was stirred vigorously for 20 h. The
layers were separated by addition of DCM, and the organic phase
was washed with H2O (2ϫ200 mL). The combined aqueous phases
were acidified with HCl (aq., 3 ) to pH ≈ 2. The aqueous phase
was extracted with DCM (4ϫ100 mL), and the combined organic
phases were dried (Na2SO4), filtered and concentrated to 20 mL
and purified directly by flash chromatography on silica gel (EtOAc/
hexane, 1:9) to afford 2-azido-3-methylbutan-1-ol (5.16 g, 82%) as
a slightly yellow oil. 1H NMR (250 MHz, CDCl3): δ = 3.76 [dd,
tert-Butyl Imidazol-1-ylacetate (1a): A solution of glyoxal (40% wt.
solution in water, 17.30 g, 0.119 mol), formaldehyde (37% wt. solu-
tion in water, 9.70 g, 0.119 mol) and iPrOH (100 mL) was added
dropwise at 20 °C to a stirred suspension of H-Gly-OtBu·HCl
(20.00 g, 0.119 mol), ammonia (25% wt. solution in water,
0.125 mol, 9.3 mL) and iPrOH (400 mL). After complete addition,
the reaction mixture was heated to 80 °C and stirred for an ad-
ditional 6 h. The final homogeneous and slightly yellow solution
was cooled to 20 °C and diluted with DCM (300 mL). The organic
layer was washed with NaOH (1.0 , 300 mL) and dried (Na2SO4).
Concentration in vacuo afforded a yellow oil. Purification by flash
or VLC chromatography on silica gel (60H silica gel, 100% EtOAc)
yielded tert-butyl imidazol-1-ylacetate (13.00 g, 60%) as a yellow
solid. 1H NMR (250 MHz, CDCl3): δ = 7.45 (dd, app [s], 1 H,
CH), 7.05 (dd, app [s], 1 H, CH), 6.91 (dd, app [t], J = 1.2 Hz, 1
H, CH), 4.56 (s, 2 H, CH2), 1.44 (s, 9 H, CH3) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 166.39, 137.82, 129.41, 119.86, 83.13,
48.71, 27.84 ppm. HRMS (ESI): calcd. for C9H15N2O2 [M + H]+
183.1128; found 183.1134.
3
3
3J(H,H) = 3.5, J(H,H) = 11.4 Hz, 1 H, CH], 3.60 [dd, J(H,H) =
3
7.9, J(H,H) = 11.4 Hz, 1 H, CH], 3.28 (m, 1 H, CH), 2.00 (br. s,
1 H, OH), 1.85 (m, 1 H, CH), [d, 3J(H,H) = 6.8 Hz, 6 H, CH3]
ppm. 13C NMR (62.9 MHz, CDCl3): δ = 70.71, 63.62, 29.84, 19.42,
18.47 ppm.
(S)-2-Azido-3-phenylpropan-1-ol: On application of the procedure
described above to (–)--phenylalaninol (20.00 g, 0.132 mol), the
reaction afforded (S)-2-azido-3-phenylpropan-1-ol (20.80 g, 89%)
as a clear oil. 1H NMR (CDCl3, 250 MHz): δ = 7.30–7.10 (m, 5
H), 3.60 (m, 2 H), 3.46 (m, 1 H), 2.76 (m, 2 H), 2.15 (s, 1 H) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 136.93, 129.17, 128.61, 126.84,
65.18, 64.32, 36.92 ppm.
(S)-2-Azido-1-iodo-3-methylbutane (2a): (S)-2-Azido-3-methylbu-
tan-1-ol (5.06 g, 0.039 mol) and mesyl chloride (5.15 g, 1.15 equiv.,
0.045 mol) were dissolved in THF (100 mL). The solution was co-
oled to 0 °C, before dropwise addition of triethylamine (5.14 g,
1.3 equiv., 0.051 mol). After complete addition, the reaction mix-
ture was stirred at 0 °C for 1 h and then warmed to 20 °C. The
tert-Butyl (S)-2-(Imidazol-1-yl)-4-methylpentanoate (1b): According
to the procedure described above, the product was isolated as a
1
light yellow oil, yield 25.00 g (58%). H NMR (250 MHz, CDCl3): precipitate was removed by filtration, and the residue was poured
δ = 7.53 (br. s, 1 H, CH), 7.05 (br. s, 1 H, CH), 7.00 {dd, app [t],
3J(H,H) = 1.2 Hz, 1 H, CH}, 4.62 [t, 3J(H,H) = 7.9 Hz, 1 H, CH],
2.41–2.32 (m, 1 H, CH), 1.18 [dd, 3J(H,H) = 7.9, 3J(H,H) = 7.2 Hz,
2 H, CH2], 1.42 (s, 9 H, CH3), 0.92 [d, 3J(H,H) = 4.1 Hz, 3 H,
into water (40 mL) and DCM (100 mL). The organic layer was col-
lected and dried (Na2SO4). Filtration and concentration in vacuo
afforded the crude yellow mesylate as a yellow oil. The freshly pre-
pared mesylate was dissolved in acetone (200 mL). NaI (17.50 g,
CH3], 0.89 [d, 3J(H,H) = 4.2 Hz, 3 H, CH3] ppm. 13C NMR 0.117 mol) was added in one portion, and the reaction mixture was
(62.9 MHz, CDCl3): δ = 169.11, 136.81, 129.29, 117.94, 82.75,
59.01, 41.49, 27.80, 24.52, 22.58, 21.52 ppm. HRMS (ESI): calcd.
for C13H23N2O2 [M + H]+ 239.1754; found 239.1757.
heated to reflux. After 16 h at reflux, the reaction mixture was co-
oled to 20 °C, and the precipitate was removed by filtration. The
solution was concentrated in vacuo to give a red oil. Further purifi-
Eur. J. Org. Chem. 2008, 3785–3797
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3791

J. F. Jensen, K. Worm-Leonhard, M. Meldal
FULL PAPER
cation by flash chromatography on silica gel (EtOAc/hexane, 1:18)
yielded 2-azido-1-iodo-3-methylbutane (5.75 g, 61%) as a clear oil.
ter 1 h of stirring, the reaction mixture was diluted with DCM
(300 mL). The organic layer was isolated and concentrated in vacuo
1H NMR (250 MHz, CDCl3): δ = 3.30 (m, 2 H, CH2), 1.95 (m, 1 and then treated with DCM (10 mL) and trifluoroacetic acid
3
3
H, CH), 0.99 [d, J(H,H) = 5.9 Hz, 3 H, CH3], 0.96 [d, J(H,H) = (10 mL). After 1 h of stirring at 20 °C, the reaction mixture was
5.9 Hz, 3 H, CH3] ppm. 13C NMR (62.9 MHz, CDCl3): δ = 69.35, concentrated in vacuo. The crude product was dissolved in DCM
32.84, 19.46, 17.27, 6.82 ppm. C5H10IN3 (239.06): calcd. C 25.12,
H 4.22, N 17.58; found C 25.35, H 3.97, N 17.52.
(50 mL) and then concentrated in vacuo. This cycle was repeated
three more times to give 1-(2-azido-3-methylbutyl)-3-(carboxy-
methyl)-3H-imidazol-1-ium trifluoroacetate (3b, 2.90 g, 88%) as a
(S)-(2-Azido-3-iodopropyl)benzene (2b): On application of the pro-
cedure described above to 2-azido-3-phenylpropan-1-ol (20.50 g,
0.116 mol), the reaction afforded (2-azido-3-iodopropyl)benzene
(28.00 g, 84%) as a clear oil. 1H NMR (250 MHz, CDCl3): δ =
1
pure red oil. H NMR (250 MHz, [D6]DMSO): δ = 9.20 (dd, app
3
[s], 1 H, CH), 7.85 {dd, app [t], J(H,H) = 1.6 Hz, 1 H, CH}, 7.79
3
{dd, app [t], J(H,H) = 1.6 Hz, 1 H, CH}, 5.17 (s, 2 H, CH2), 4.49
[dd, 3J(H,H) = 3.5, 3J(H,H) = 14.1 Hz, 1 H, CH], 4.28 [dd, 3J(H,H)
3
7.44–7.24 (m, 5 H, CH), 3.70 {dt, app [q], J(H,H) = 6.2 Hz, 1 H,
3
= 9.9, J(H,H) = 14.1 Hz, 1 H, CH], 3.95 (m, 1 H, CH), 1.90 (m,
CH}, 3.27 (m, 2 H, CH2), 2.99 (m, 2 H, CH2) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 136.24, 129.21, 128.69, 127.13, 63.43,
40.37, 7.99 ppm. C9H10IN3 (287.10): calcd. C 37.65, H 3.51, N
14.64; found C 37.85, H 3.38, N 14.49.
3
3
1 H, CH), 1.03 [d, J(H,H) = 6.6 Hz, 3 H, CH3], 0.97 [d, J(H,H)
= 6.7 Hz, 3 H, CH3] ppm. 13C NMR (62.9 MHz, DMSO): δ =
167.91, 137.83 (N+=CN), 123.96, 122.32, 66.94, 50.33, 49.72, 30.44,
18.95, 17.23 ppm. HRMS (ESI): calcd. for C10H16N5O2 [M –
CF3COO–]+ 238.1299; found 238.1301. MS (ESI): calcd. for
C12H15F3N5O4 [M – H]– 350.1; found 350.0.
1-[(S)-2-Azido-3-methylbutyl]-3-[(tert-butoxycarbonyl)methyl]-3H-
imidazol-1-ium Iodide (Precursor to 3b): A solution of (S)-2-azido-
1-iodo-3-methylbutane (5.65 g, 0.024 mol) and tert-butyl imidazol-
1-ylacetate (4.30 g, 0.024 mol) in dry DMF (70 mL) was stirred at
100 °C for 72 h. The reaction mixture was concentrated in vacuo
and purified by flash chromatography on silica gel [first 100%
EtOAc, then EtOAc/acetone (1:1), and finally EtOAc/MeOH (9:1)]
to yield 1-[(S)-2-azido-3-methylbutyl]-3-[(tert-butoxycarbonyl)-
methyl]-3H-imidazol-1-ium iodide (3.95 g, 40%) as a red oil. 1H
NMR (250 MHz, [D6]DMSO): δ = 9.22 {dd, app [t], 3J(H,H) =
1-[(S)-2-Azido-3-phenylpropyl]-3-(carboxymethyl)-3H-imidazol-1-
ium Trifluoroacetate (3a): On application of the procedure de-
scribed above to 1-(2-azido-3-phenylpropyl)-3-[(tert-butoxycar-
bonyl)methyl]-3H-imidazol-1-ium iodide (5.56 g, 11.85 mmol), the
reaction afforded 1-(2-azido-3-phenylpropyl)-3-(carboxymethyl)-
3H-imidazol-1-ium trifluoroacetate (3a, 4.10 g, 87%) as a red oil.
1H NMR (250 MHz, [D6]DMSO): δ = 9.20 (dd, app [s], 1 H, CH),
3
3
1.5 Hz, 1 H, CH}, 7.88 {dd, app [t], J(H,H) = 1.6 Hz, 1 H, CH},
7.83 {dd, app [t], J(H,H) = 1.6 Hz, 1 H, CH}, 7.78 {dd, app [t],
7.80 {dd, app [t], 3J(H,H) = 1.6 Hz, 1 H, CH}, 5.19 (s, 2 H, CH2),
4.51 [dd, 3J(H,H) = 3.6, 3J(H,H) = 14.1 Hz, 1 H, CH], 4.29 [dd,
3J(H,H) = 1.6 Hz, 1 H, CH}, 7.40–7.24 (m, 5 H, CH), 5.16 (s, 2
3
3
H, CH2), 4.53 [dd, J(H,H) = 2, J(H,H) = 12 Hz, 1 H, CH], 4.36
3
3J(H,H) = 9.9, J(H,H) = 14.1 Hz, 1 H, CH], 3.97 (m, 1 H, CH),
(m, 1 H, CH), 4.30 (dd, app [m], overlap, 1 H, CH), 3.05 [dd,
3
3
3
1.90 (m, 1 H, CH), 1.45 (s, 9 H, CH3), 1.03 [d, J(H,H) = 6.8 Hz, 3J(H,H) = 3.6, J(H,H) = 13.0 Hz, 1 H, CH], 2.74 [dd, J(H,H) =
3
3 H, CH3], 0.97 [d, J(H,H) = 6.8 Hz, 3 H, CH3] ppm. 13C NMR
8.9, 3J(H,H) = 13.9 Hz, 1 H, CH], 1.46 (s, 9 H, CH3) ppm. 13C
(62.9 MHz, DMSO): δ = 165.46, 137.84 (N+=CN), 123.89, 122.36, NMR (62.9 MHz, [D6]DMSO): δ = 167.94, 137.85 (N+=CN),
82.93, 66.80, 50.32, 50.07, 30.40, 27.51, 18.93, 17.27 ppm. HRMS 136.57, 129.28, 128.60, 126.97, 123.92, 122.37, 62.29, 51.81, 50.36,
(ESI): calcd. for C14H24N5O2 [M – I]+ 294.1925; found 294.1916. 37.45 ppm. HRMS (ESI): calcd. for C1 4 H1 6 N5 O2 [M –
MS (ESI): m/z = 127.4 [I]–.
CF3COO–]+ 286.1299; found 286.1322. MS (ESI): calcd. for
C16H15F3N5O4 [M – H]– 398.1; found 398.8.
1-[(S)-2-Azido-3-phenylpropyl]-3-[(tert-butoxycarbonyl)methyl]-3H-
imidazol-1-ium Iodide (Precursor to 3a): A solution of (S)-(2-azido-
3-iodopropyl)benzene (8.00 g, 0.028 mol) and tert-butyl imidazol-
1-ylacetate (5.08 g, 0.028 mol) in dry DMF (150 mL) was stirred
at 100 °C for 72 h. The reaction mixture was concentrated in vacuo
and purified by flash chromatography on silica gel [first 100%
EtOAc, then EtOAc/acetone (1:1)] to yield 1-[(S)-2-azido-3-phen-
ylpropyl]-3-[(tert-butoxycarbonyl)methyl]-3H-imidazol-1-ium io-
1-[(S)-2-Azido-3-phenylpropyl]-3-(2-carboxyethyl)-3H-imidazol-1-
ium Trifluoroacetate (3d): A solution of (S)-(2-azido-3-iodopropyl)-
benzene (1.46 g, 5.1 mmol) and tert-butyl imidazol-1-ylpropionate
(1.00 g, 5.1 mmol) in dry DMF (15 mL) was stirred at 105 °C for
24 h. The reaction mixture was concentrated in vacuo and purified
by flash chromatography on silica gel [first 100% EtOAc, then
EtOAc/acetone (1:1), then 10% MeOH in EtOAc]. Subsequently,
the crude red oil was dissolved in MeOH (40 mL) and water
(20 mL). At 20 °C the vigorously stirred solution was treated drop-
wise with HPF6 (60% wt solution in water, ca. 10 equiv., 7.5 mL).
After 1 h of stirring, the reaction mixture was diluted with DCM
(100 mL). The organic layer was isolated, and the water phase was
extracted with DCM (2 ϫ 50 mL). The combined DCM phases
were dried (Na2SO4), filtered, and concentrated in vacuo and were
then treated with DCM (10 mL) and TFA (10 mL). After 1 h of
stirring at 20 °C, the reaction mixture was concentrated in vacuo.
The crude product was dissolved in DCM (50 mL) and then again
concentrated in vacuo. This cycle was repeated three more times to
give 1-(2-azido-3-methylbutyl)-3-(2-carboxyethyl)-3H-imidazol-1-
ium trifluoroacetate (3d, 0.84 g, 39%) as a red oil. This sample
was used without further purification for solid-phase synthesis (see
below). A sample for further analysis was purified by prep. HPLC
1
dide (5.56 g, 42%) as a red oil. H NMR (250 MHz, [D6]DMSO):
δ = 9.24 {dd, app [t], 3J(H,H) = 1.5 Hz, 1 H, CH}, 7.88 {dd, app [t],
3J(H,H) = 1.6 Hz, 1 H, CH}, 7.80 {dd, app [t], 3J(H,H) = 1.6 Hz, 1
H, CH}, 7.38–7.24 (m, 5 H, CH), 5.20 (s, 2 H, CH2), 4.59 [dd,
3
3J(H,H) = 2.2, J(H,H) = 12.6 Hz, 1 H, CH], 4.40 (m, 1 H, CH),
4.34 (dd, app [m], overlap, 1 H, CH), 3.10 [dd, 3J(H,H) = 3.6,
3
3
3J(H,H) = 13.7 Hz, 1 H, CH], 2.74 [dd, J(H,H) = 9.1, J(H,H) =
13.7 Hz, 1 H, CH], 1.46 (s, 9 H, CH3) ppm. 13C NMR (62.9 MHz,
[D6]DMSO): δ = 165.48, 137.87 (N+=CN), 136.44, 129.12, 128.49,
126.87, 123.82, 122.48, 120.81, 82.96, 62.16, 51.76, 50.32, 37.40,
27.51 ppm. HRMS (ESI): calcd. for C18H24N5O2 [M – I]+
342.1925; found 342.1912. MS (ESI): m/z = 126.9 [I]–.
1-[(S)-2-Azido-3-methylbutyl]-3-(carboxymethyl)-3H-imidazol-1-
ium Trifluoroacetate (3b): 1-(2-Azido-3-methylbutyl)-3-[(tert-bu-
toxycarbonyl)methyl]-3H-imidazol-1-ium iodide (3.95 g,
9.38 mmol) was dissolved in MeOH (70 mL) and water (70 mL). (reverse phase, acetonitrile/H2O, 0.1% TFA). 1H NMR (250 MHz,
3
At 20 °C the vigorously stirred solution was treated dropwise with
HPF6 (60% wt solution in water, 10 equiv., 0.094 mol, 22.90 g). Af-
[D6]DMSO): δ = 9.25 {dd, app [br. t], J(H,H) Ͻ 1 Hz, 1 H, CH},
3
7.84 {dd, app [t], J(H,H) = 1.5 Hz, 1 H, CH}, 7.82 {dd, app [t],
3792
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3785–3797

Optically Active (Peptido-carbene)palladium Complexes
3J(H,H) = 1.5 Hz, 1 H, CH}, 7.41–7.25 (m, 5 H, CH), 4.52–4.18 (5ϫ) and DCM (5ϫ), the Fmoc group was removed by repeated
3
(m, 5 H, CH, CH2), 3.04 [dd, 3J(H,H) = 3.9, J(H,H) = 14.0 Hz, 1
addition of 20% piperidine in DMF as described above. 1-[(S)-2-
H, CH], 2.92 [t, 3J(H,H) = 6.6 Hz, 2 H, CH2], 2.76 [dd, J(H,H) = Azido-3-phenylpropyl]-3-(carboxymethyl)-3H-imidazol-1-ium tri-
3
9.1, 3J(H,H) = 14.0 Hz, 1 H, CH] ppm. 13C NMR (62.9 MHz, [D6]- fluoroacetate (3a) was subsequently coupled to the resin by the
DMSO): δ = 171.55, 137.17 (N+=CN), 136.45, 129.19, 128.51,
standard TBTU procedure. After the standard washing procedure,
the resin was lyophilised. The azido group on the resin was reduced
126.89, 122.82, 122.53, 62.11, 51.71, 44.84, 37.29, 33.58 ppm.
HRMS (ESI): calcd. for C15H18N5O2 [M – CF3COO–]+ 300.1455; to an amino group by swelling of the resin in a DMF solution of
found 300.1452. MS (ESI): calcd. for C19H18F6N5O6 [M +
dithiothreitol (DTT, 0.25 ) and subsequent addition of DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene, 2 equiv.). After 16 h at 50 °C, the
resin was cooled to 20 °C and washed with DMF (6ϫ) and DCM
(6ϫ). The free amino group was coupled with Fmoc-Gly-OH ac-
cording to the standard coupling procedure. The final product was
released from the resin by treatment with 95% TFA (aq.) (2 h).
After purification by preparative HPLC, compound 6 was obtained
CF3COO–]– 526.1; found 525.9.
1-[(S)-2-Azido-3-phenylpropyl]-3-[(S)-1-carboxy-3-methylbutyl]-3H-
imidazol-1-ium Trifluoroacetate (3c): A solution of (2-azido-3-iodo-
propyl)benzene (2.40 g, 8.4 mmol) and tert-butyl (S)-2-(imidazol-1-
yl)-4-methylpentanoate (2.00 g, 8.4 mmol) in dry DMF (20 mL)
was stirred at 100 °C for 72 h. The reaction mixture was concen-
trated in vacuo and purified by flash chromatography on silica gel
[first 100% EtOAc, then EtOAc/acetone (1:1), then 10% MeOH in
EtOAc]. Subsequently, the crude red oil (1.90 g) was dissolved in
MeOH (60 mL) and water (20 mL). The stirred solution was then
treated with NH4BF4 (1.54 g, 14.7 mmol) in one portion. The final
reaction mixture was stirred at 20 °C for 1 h and then diluted with
DCM (100 mL). The organic phase was isolated and dried
(Na2SO4), filtered, and concentrated in vacuo. DCM (10 mL) and
trifluoroacetic acid (10 mL) were added to the tert-butyl ester and,
after 1 h of stirring at 20 °C, the reaction mixture was concentrated
in vacuo. The crude product was dissolved in DCM (50 mL) and
then concentrated in vacuo. This cycle was repeated three more
times to finally give 1-[(S)-2-azido-3-phenylpropyl]-3-[(S)-1-car-
boxy-3-methylbutyl]-3H-imidazol-1-ium trifluoroacetate (3d,
0.68 g, 18%) as a red oil. 1H NMR (250 MHz, [D6]DMSO): δ =
1
as a white powder. H NMR (250 MHz, [D6]DMSO): δ = 8.98 (s,
3
3
1 H, CH), 8.54 [d, J(H,H) = 8.9 Hz, 1 H, CH], 8.05 [d, J(H,H)
= 8.0 Hz, 1 H, CH], 7.90 {2 d, app [d], 3J(H,H) = 7.3 Hz, 2 H,
Fmoc aryl, CH2}, 7.75–7.65 (m, 4 H, CH), 7.58–7.10 (m, 12 H,
CH), 5.07 (br. s, 2 H, CH2), 4.50–4.08 (m, 7 H, CH, CH2), 3.45
3
3
(m, 2 H, CH2), 2.87 [dd, J(H,H) = 3.4, J(H,H) = 13.7 Hz, 1 H,
3
3
CH], 2.74 [dd, J(H,H) = 8.6, J(H,H) = 13.7 Hz, 1 H, CH], 2.00
(m, 1 H, CH), 0.84 (s, 6 H, CH3) ppm. 13C NMR (62.9 MHz, [D6]
DMSO): δ = 172.21, 169.11, 164.89, 164.71, 156.41, 143.69, 143.63,
140.59, 137.63, 137.34 (N+=CN), 136.53, 128.92 (2 C), 128.13 (2
C), 127.51 (2 C), 126.92 (2 C), 126.26, 125.10, 123.42, 122.22,
119.98, 119.07, 65.61, 57.60, 51.58, 50.44, 50.23, 46.48, 43.27,
36.81, 30.39, 19.09, 17.56 ppm. HRMS (ESI): calcd. for
C
36H41N6O5 [M – CF3COO–]+ 637.3133; found 637.3153. MS
(ESI): calcd. for C40H41F6N6O9 [M + CF3COO–]– 863.3; found
863.0.
3
3
9.42 [t, J(H,H) Ͻ 1 Hz, 1 H, CH], 7.96 [t, J(H,H) Ͻ 1 Hz, 1 H,
3
CH], 7.87 [t, J(H,H) Ͻ 1 Hz, 1 H, CH], 7.43–7.23 (m, 5 H, CH), The following monocarbene precursors were synthesised according
5.31 [dd, 3J(H,H) = 4.2, 3J(H,H) = 11.1 Hz, 1 H, CH], 4.54 [dd,
to the peptide synthesis procedure described above. The com-
pounds were finally capped with 2-naphthoic acid according to the
standard TBTU coupling procedure.
3J(H,H) = 3.0, J(H,H) = 13.4 Hz, 1 H, CH], 4.40 (m, 1 H, CH),
3
3
3
4.25 (m, 1 H, CH), 3.05 [dd, J(H,H) = 4.0, J(H,H) = 13.9 Hz, 1
H, CH], 2.72 [dd, 3J(H,H) = 9.1, 3J(H,H) = 13.9 Hz, 1 H, CH],
2.12 (m, 1 H, CH), 1.95 (m, 1 H, CH), 1.26 (m, 1 H, CH), 0.89 [d,
3J(H,H) = 6.7 Hz, 3 H, CH3], 0.84 [d, 3J(H,H) = 6.6 Hz, 3 H,
CH3] ppm. 13C NMR (62.9 MHz, [D6]DMSO): δ = 169.90, 137.22,
137.18, 136.42, 129.20, 128.52, 126.90, 122.66, 122.51, 122.46,
62.26, 60.36, 52.01, 37.40, 24.29, 22.36, 20.72, 20.65 ppm. HRMS
(ESI): calcd. for C18H24N5O2 [M – CF3COO–]+ 342.1925; found
342.1906. MS (ESI): calcd. for C20H23N5O4 [M – H]– 454.2; found
454.2.
(2-Naphthylcarbonyl-Gly-{1-[(S)-2-amino-3-phenylpropyl]-3-(2-oxo-
ethyl)-3H-imidazol-1-ium}-Val-NH2)+(CF3COO)– (4a): Crude pu-
rity ca. 85% after TFA cleavage, purity Ͼ95% after prep. HPLC;
21.0 mg (38%) was obtained from 350 mg of PEGA800 resin (load-
1
ing = 0.231 mmol/g resin). H NMR ([D6]DMSO, 600 MHz): δ =
8.97 (s, 1 H, CH), 8.94 [t, 3J(H,H) = 6.0 Hz, 1 H, CH], 8.55 [d,
3J(H,H) = 8.7 Hz, 1 H, CH], 8.50 (s, 1 H, CH), 8.04–7.97 (m, 5 H,
CH), 7.75 (s, 1 H, CH), 7.70 (s, 1 H, CH), 7.65–7.60 (m, 2 H, CH),
7.51 (s, 1 H, CH), 7.31–7.19 (m, 5 H, CH), 7.11 (s, 1 H, CH), 5.21
3
3
Solid-Phase Synthesis
[d, J(H,H) = 16.3 Hz, 1 H, CH], 5.11 [d, J(H,H) = 16.3 Hz, 1 H,
3
3
CH], 4.45 [dd, J(H,H) = 3.8, J(H,H) = 13.7 Hz, 1 H, CH], 4.37
(m, 1 H, CH), 4.27 [dd, 3J(H,H) = 9.1, 3J(H,H) = 13.5 Hz, 1 H,
CH], 4.20 [dd, 3J(H,H) = 6.1, 3J(H,H) = 8.7 Hz, 1 H, CH], 3.79
[dd, 3J(H,H) = 5.7, 3J(H,H) = 16.3 Hz, 1 H, CH], 3.72 [dd, 3J(H,H)
= 5.7, J = 16.3 Hz, 1 H, CH], 2.89 [dd, J(H,H) = 4.0, J(H,H) =
13.9 Hz, 1 H, CH], 2.76 [dd, J(H,H) = 9.4, J(H,H) = 13.5 Hz, 1
General Procedure for Monodentate Carbene Precursors. (Fmoc-
Gly-{1-[(S)-2-amino-3-phenylpropyl]-3-(2-oxoethyl)-3H-imidazol-1-
ium}-Val-NH2)+(CF3COO)– (6): Attachment of the 4-[(2,4-dimeth-
oxyphenyl)(Fmoc-amino)methyl]phenoxyacetic acid (Fmoc-Rink
amide linker) to the amino-functionalised resin (PEGA800) was car-
ried out by the standard amino acid coupling procedure (Fmoc-
AA-OH, TBTU, NEM, DMF). The Rink amide linker (3.0 equiv.),
N-ethylmorpholine (NEM, 4.0 equiv.) and N-[(1H-benzotriazol-1-
yl)(dimethylamino)methylene]-N-methylmethanaminium tetrafluo-
roborate N-oxide (TBTU, 2.88 equiv.) were mixed in DMF and al-
lowed to react for 5 min. The reaction mixture was added to a
preswollen PEGA800 resin to give a volume of 1.5ϫ the resin vol-
ume and allowed to react for 2 h, followed by washing with DMF
(5ϫ) and DCM (5ϫ). The Fmoc protecting group was sub-
sequently removed by double addition (2 and 18 min) of 20% pi-
peridine in DMF. The first Fmoc-protected amino acid, Fmoc-Val-
OH, was coupled to the Rink amide functionalised PEGA resin by
the standard procedure described above. After washing with DMF
3
3
3
3
3
3
H, CH], 2.04 (m, 1 H, CH), 0.88 {2 d, app [t], J(H,H) = 6.3 Hz,
6 H, CH3} ppm. 13C NMR (150.9 MHz, [D6]DMSO): δ = 172.23,
168.95 166.64, 164.71, 137.58, 137.32, 134.02, 131.94, 130.82,
128.91, 128.57, 128.03, 127.64, 127.53, 127.40, 126.64, 126.18,
124.03, 123.43, 122.07, 57.45, 51.67, 50.44, 50.21, 42.68, 36.65,
30.30, 19.08, 17.53 ppm. HRMS (ESI): calcd. for C32H37N6O4 [M –
CF3COO–]+ 569.2876; found 569.2875. MS (ESI): calcd. for
C36H37F6N6O8 [M + CF3COO–]– 795.3; found 795.2.
(2-Naphthylcarbonyl-Gly-{1-[(S)-2-amino-3-methylbutyl]-3-(2-oxo-
ethyl)-3H-imidazol-1-ium}-Val-NH2)+(CF3COO)– (4b): Crude pu-
rity ca. 80 % after TFA cleavage. HRMS (ESI): calcd. for
C28H37N6O4 [M – CF3COO–]+ 521.2876; found 521.2878. MS
Eur. J. Org. Chem. 2008, 3785–3797
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3793

J. F. Jensen, K. Worm-Leonhard, M. Meldal
FULL PAPER
(ESI): calcd. for C32H37F6N6O8 [M + CF3COO–]– 747.3; found
3
3
CH2), 4.16 [dd, J(H,H) = 6.1, J(H,H) = 18.6 Hz, 1 H, CH], 4.05
(m, 1 H, CH), 3.70–3.52 (m, 5 H, CH, CH2), 3.50 (m, 2 H, CH2),
3.40 [dd, 3J(H,H) = 5.6, 3J(H,H) = 16.5 Hz, 1 H, CH], 3.04 [dd,
747.0.
(2-Naphthylcarbonyl-Gly-{1-[(S)-2-amino-3-phenylpropyl]-3-(1-for-
myl-3-methylbutyl)-3H-imidazol-1-ium}-Val-NH2)+(CF3COO)–
(4c): Crude purity ca. 90% after TFA cleavage. Product HPLC: tR
= 4.93 min. HRMS (ESI): calcd. for C3 6 H4 5 N6 O4 [M –
CF3COO–]+ 625.3502; found 625.3502. MS (ESI): calcd. for
C40H45F6N6O8 [M + CF3COO–]– 851.3; found 851.1.
3J(H,H) = 4.8, J(H,H) = 14.3 Hz, 1 H, CH], 2.96–2.84 (m, 2 H,
3
CH2), 2.74 (m, 2 H, CH2), 2.47 (m, 1 H, CH), 2.22 (m, 1 H, CH),
2.10 (m, 1 H, CH), 2.00 (m, 3 H, CH, CH2), 1.94 (m, 1 H, CH),
1.86 (m, 1 H, CH), 1.82–1.72 (m, 2 H, CH), 1.19 [d, 3J(H,H) =
3
7.1 Hz, 3 H, CH3], 1.04 [d, J(H,H) = 6.7 Hz, 3 H, CH3], 0.99 [d,
3J(H,H) = 6.7 Hz, 3 H, CH3], 0.88 [d, 3J(H,H) = 7.1 Hz, 3 H, CH3],
3
3
(2-Naphthylcarbonyl-Val-Phe-Pro-Gly-{1-[(S)-2-amino-3-phenylpro-
pyl]-3-(2-oxoethyl)-3H-imidazol-1-ium}-Val-NH2)+(CF3COO)– (4d):
Crude purity Ͼ95% after TFA cleavage. HRMS (ESI): calcd. for
0.86 [d, J(H,H) = 7.2 Hz, 3 H, CH3], 0.73 [d, J(H,H) = 6.7 Hz,
3 H, CH3], 0.46 [d, J(H,H) = 6.5 Hz, 3 H, CH3] ppm. 13C NMR
3
(150.9 MHz, [D6]DMSO): δ = 173.28, 172.21, 171.94, 171.35,
171.33, 170.51, 168.56, 167.67, 164.78, 164.34, 158.52, 158.28,
158.04, 157.78, 137.30, 137.23 (N+=CN), 137.12 (N+=CN), 134.17,
131.92, 131.11, 129.03, 128.87, 128.74, 128.68, 128.14, 128.05,
128.02, 127.95, 127.92, 127.88, 127.69, 127.65, 127.54, 126.70,
126.30, 126.26, 126.22, 124.37, 123.63, 123.47, 122.24, 122.17,
116.44, 114.51, 69.67, 60.65, 60.45, 57.72, 54.76, 52.06, 50.49,
50.31, 50.22, 49.47, 46.27, 41.83, 37.13, 36.94, 36.54, 30.37, 29.58,
29.52, 29.23, 24.05, 19.26, 19.12 (2 C), 18.73, 18.34, 17.62,
17.26 ppm. HRMS (ESI): calcd. for C73H92N14O10 [M – 2
CF3COO–]2+/2 662.3558; found 662.3549. MS (ESI): calcd. for
C79H92F9N14O16 [M + CF3COO–]– 1663.7; found 1663.4.
C
51H62N9O7 [M – CF3COO–]+ 912.4767; found 912.4750. MS
(ESI): calcd. for C55H62F6N9O11 [M + CF3COO–]– 1138.4; found
1138.3.
(2-Naphthylcarbonyl-Gly-{1-[(S)-2-amino-3-phenylpropyl]-3-(3-oxo-
propyl)-3H-imidazol-1-ium}Val-NH2)+(CF3COO)– (4e): Crude pu-
rity ca. 80 % after TFA cleavage. HRMS (ESI): calcd. for
C
33H39N6O4 [M – CF3COO–]+ 583.3033; found 583.3037. MS
(ESI): calcd. for C37H39F6N6O8 [M + CF3COO–]– 809.3; found
809.2.
(2-Naphthylcarbonyl-Val-Phe-Pro-Gly-{1-[(S)-2-amino-3-phenylpro-
pyl]-3-(3-oxopropyl)-3H-imidazol-1-ium}-Val-NH2)+(CF3COO)–
(4f): Crude purity ca. 90% after TFA cleavage. HRMS (ESI): calcd.
for C52H64N9O7 [M – CF3COO–]+ 926.4929; found 926.4902. MS
(ESI): calcd. for C56H64F6N9O11 [M + CF3COO–]– 1152.5; found
1152.4.
(2-Naphthylcarbonyl-Val-Ala-Phe-Ala-{1-[(S)-2-amino-3-phenylpro-
pyl]-3-(2-oxoethyl)-3H-imidazol-1-ium}-Val-Pro-Gly-{1-[(S)-2-
amino-3-phenylpropyl]-3-(2-oxoethyl)-3H-imidazol-1-ium}-Val-
NH2)2+2(CF3COO)– (8b): Crude purity ca. 80% after TFA cleav-
age. Purity Ͼ95% after prep. HPLC; 27.3 mg (26%) was obtained
Synthesis of Didentate Carbene Precursors
1
from 360 mg of PEGA800 resin (loading = 0.191 mmol/g resin). H
(2-Naphthylcarbonyl-Val-Ala-Phe-Val-{1-[(S)-2-amino-3-phenylpro-
pyl]-3-(2-oxoethyl)-3H-imidazol-1-ium}-Pro-Gly-{1-[(S)-2-amino-
NMR (600 MHz, [D6]DMSO): δ = 8.98 (s, 1 H, N+CHN), 8.96 (s,
1 H, N+CHN), 8.76 [d, 3J(H,H) = 8.3 Hz, 1 H, CH], 8.61 [d,
3
3-phenylpropyl]-3-(2-oxoethyl)-3H-imidazol-1-ium}-Val-NH2)2+
-
3J(H,H) = 7.1 Hz, 1 H, CH], 8.57 (s, 1 H, CH), 8.55 [d, J(H,H) =
2(CF3COO)– (8a): After repetition of the procedure for the Fmoc-
Gly-OH coupling described above (compound 6), the free amino
group was obtained by double treatment with 20% piperidine in
DMF (2 and 18 min). The free amino group was coupled to Fmoc-
Pro-OH by the standard coupling procedure. Usual washing and
subsequent Fmoc removal with 20% piperidine in DMF were car-
ried out. 1-(2-Azido-3-phenylpropyl)-3-(carboxymethyl)-3H-imid-
azol-1-ium trifluoroacetate (3a) was treated with the free amino
group by the standard coupling procedure. The azido group on the
resin was reduced to the amino group by swelling of the resin in
a DMF solution of dithiothreitol (DTT, 0.25 ) and subsequent
addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 2 equiv.). Af-
ter 16 h at 50 °C, the resin was cooled to 20 °C and washed with
DMF (6ϫ) and DCM (6ϫ). Four Fmoc amino acids (Fmoc-Val-
9.0 Hz, 1 H, CH], 8.40 [d, 3J(H,H) = 5.9 Hz, 1 H, CH], 8.20 [t,
3
3J(H,H) = 5.9 Hz, 1 H, CH], 8.03 [d, J(H,H) = 7.5 Hz, 1 H, CH],
3
7.99 (m, 3 H, CH), 7.90 [d, J(H,H) = 6.9 Hz, 1 H, CH], 7.86 [d,
3J(H,H) = 7.40 Hz, 1 H, CH], 7.75–7.47 (m, 10 H, CH), 7.30–7.05
(m, 15 H, CH), 5.20–5.00 (m, 5 H, CH, CH2), 4.48 (m, 2 H, CH),
4.41 (m, 2 H, CH), 4.27 (m, 3 H, CH, CH2), 4.16 (m, 2 H, CH),
3.92 (m, 1 H, CH), 3.75 (m, 1 H, CH), 3.69 [dd, 3J(H,H) = 6.3,
3J(H,H) = 16.6 Hz, 1 H, CH], 3.62 (m, 1 H, CH), 3.50 (m, 1 H,
3
3
CH), 3.40 [dd, J(H,H) = 4.5, J(H,H) = 16.3 Hz, 1 H, CH], 3.03
[dd, 3J(H,H) = 4.5, 3J(H,H) = 14.5 Hz, 1 H, CH], 2.91 (m, 2 H,
3
3
CH2), 2.84 [dd, J(H,H) = 4.6, J(H,H) = 13.9 Hz, 1 H, CH], 2.77
[dd, 3J(H,H) = 9.4, 3J(H,H) = 13.7 Hz, 1 H, CH], 2.68 [dd, 3J(H,H)
3
= 9.0, J(H,H) = 13.6 Hz, 1 H, CH], 2.20 (m, 1 H, CH), 2.10–1.93
(m, 3 H, CH, CH2), 1.80 (m, 2 H, CH), 1.20 [d, 3J(H,H) = 7.3 Hz,
3
3
OH, Fmoc-Phe-OH, Fmoc-Ala-OH, Fmoc-Val-OH) were sub- 3 H, CH3], 1.02 [d, J(H,H) = 5.4 Hz, 3 H, CH3], 1.01 [d, J(H,H)
3
sequently coupled to the resin according to the standard TBTU
coupling and deprotection (piperidine) procedure. The last amino
acid was (Fmoc-) deprotected and capped with 2-naphthoic acid
by the standard TBTU coupling procedure. The final product was
released from the resin by treatment with 95 % TFA (aq) (2 h).
Crude purity ca. 80%. Purity Ͼ95% after prep. HPLC; 16.6 mg
(26%) was obtained from 360 mg of PEGA800 resin (loading =
= 5.4 Hz, 3 H, CH3], 0.97 [d, J(H,H) = 6.9 Hz, 3 H, CH3], 0.94
3
3
[d, J(H,H) = 6.7 Hz, 3 H, CH3], 0.91 [d, J(H,H) = 6.4 Hz, 3 H,
CH3], 0.88 [d, 3J(H,H) = 6.9 Hz, 3 H, CH3], 0.88 [d, 3J(H,H) =
6.4 Hz, 3 H, CH3] ppm. 13C NMR (150.9 MHz, [D6]DMSO): δ =
173.31, 172.22, 171.99, 172.90, 171.79, 172.10, 170.02, 168.66,
167.40, 164.92, 164.77, 158.32, 158.09, 156.64, 137.70, 137.24,
137.23 2 ϫ (N+=CN), 134.16, 131.95, 131.21, 129.10, 128.97,
128.93, 128.77, 128.70, 128.10, 128.07, 128.00, 127.91, 127.89,
0.194 mmol/g resin). 1H NMR (600 MHz, [D6]DMSO): δ = 8.92 (s,
1 H, N+CHN), 8.90 (s, 1 H, N+CHN), 8.67 [d, J(H,H) = 6.5 Hz, 127.88, 127.66, 127.52, 126.65, 126.30, 126.25, 126.22, 126.21,
1 H, CH], 8.59 (s, 1 H, CH), 8.51 [d, J(H,H) = 8.8 Hz, 1 H, CH], 124.42, 123.56, 122.28, 122.05, 116.49, 114.55, 69.67, 60.23, 59.96,
8.47 [d, J(H,H) = 5.7 Hz, 1 H, CH], 8.26 [t, J(H,H) = 5.9 Hz, 1 57.81, 56.21, 54.64, 52.04, 52.00, 51.95, 50.52, 50.34, 50.33, 50.18,
3
3
3
3
3
H, CH], 8.04–7.96 (m, 6 H, CH3), 7.87 [d, J(H,H) = 7.3 Hz, 1 H,
CH], 7.72–7.53 (m, 7 H, CH), 7.54 (br. s, 1 H, NH), 7.48 (br. s, 1
49.31, 49.09, 47.40, 42.08, 37.41, 37.17, 36.55, 36.46, 30.35, 30.23,
29.67, 28.99, 19.12, 18.70, 18.47, 17.63, 17.21 ppm. HRMS (ESI):
H, NH), 7.29–7.07 (m, 15 H, CH, NH), 5.26 (s, 2 H, CH2), 5.10 calcd. for C76H97N15O11 [M – 2 CF3COO–]2+/2 697.8746; found
[d, 3J(H,H) = 16.5 Hz, 1 H, CH], 5.02 [d, J(H,H) = 16.5 Hz, 1 H,
697.8742. MS (ESI): calcd. for C82H97F9N15O17 [M + CF3COO–]–
3
CH], 4.48 (m, 1 H, CH), 4.40 (m, 3 H, CH, CH2), 4.27 (m, 4 H, 1734.7; found 1735.5.
3794
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3785–3797

Optically Active (Peptido-carbene)palladium Complexes
(2-Naphthylcarbonyl-Val-Ala-Leu-Gly-{1-[(S)-2-amino-3-phenylpro-
was added in air into a vial containing swollen resin 6 (20.0 mg,
pyl]-3-(2-oxoethyl)-3H-imidazol-1-ium}-Leu-Gly-{1-[(S)-2-amino-3- 0.229 mmol/g resin), THF (2 mL) and DMSO (0.25 mL). The final
phenylpropyl]-3-(2-oxoethyl)-3H-imidazol-1-ium}-Val- reaction mixture was heated to 75 °C for 4 h and then cooled to
NH2)2+2(CF3COO)– (8c): Crude purity ca. 70% after TFA cleav-
age. HRMS (ESI): calcd. for C68H92N14O10 [M – 2 CF3COO–]2+/2
632.3561; found 632.3555; [M + CF3COO–]– not observed.
20 °C. The final complex 7 was obtained from the resin by treat-
ment with TFA (aq., 95%) (2 h). The solution of the complex was
concentrated in vacuo and directly analysed by MS (ESI) as the
crude product. MS (ESI): calcd. for C36H39N6O5Pd [M –
CF3COO–]+ 741.2; found 741.2. b) In Solution. [(Fmoc-NH-Gly-{1-
[(S)-2-amino-3-phenylpropyl]-3-(eth-1-en-2-olato)-3H-imidazolin-2-
ylidene}-Val-NH2)palladium(II)]+(CF3COO)– (7): A dry 100 mL
Schlenk tube was charged under argon with imidazolium salt 6
(35.0 mg, 0.045 mmol), a solvent mixture of THF (4 mL)/DMSO
(0.5 mL) and finally Pd(OAc)2 (1.5 equiv., 15.1 mg). The final reac-
tion mixture was heated to 80 °C and stirred for 16 h, followed by
concentration in vacuo to afford a brown oil. The crude product
was purified by prep. HPLC (0.1% aq. TFA/acetonitrile) to yield 7
General Procedure for On-Resin Synthesis of (N-Heterocyclic car-
bene enolato)palladium Complexes. [(2-Naphthylcarbonyl-Gly-{1-
[(S)-2-amino-3-phenylpropyl]-3-(eth-1-en-2-olato)-3H-imidazolin-2-
ylidene}-Val-NH2)palladium(II)]+(CF3COO)– (5a): 2-(tert-Bu-
tylimino)-2-(diethylamino)-1,3-dimethylperhydro-1,3,2-diazaphos-
phorin (BEMP, 2.5 equiv., 33.0 µL, 0.115 mmol) was added at
20 °C into a dry (under argon) Schlenk flask containing a shaken
mixture of swollen resin 4a (200 mg, 0.046 mmol) and DMF
(5.0 mL). After complete addition, the reaction mixture was shaken
for 15 min and then treated with PdCl2COD (1.5 equiv., 19.7 mg,
0.069 mmol) in one portion. The final yellow reaction mixture was
shaken for 1 h and filtered. The resin was purified by the usual
washing procedure with DMF (5ϫ2 mL) and DCM (5ϫ2 mL).
The final complex (5a) was cleaved from the resin by treatment
with TFA (aq., 95%) (2 h) and concentrated in vacuo. Purification
by HPLC and lyophilisation yielded the title compound as a white
solid. Yield: 12.0 mg (33%). NMR spectroscopic data are given in
Table 1. HRMS (ESI): calcd. for C32H35N6O4Pd [M – CF3COO–]
1
(17.0 mg) as a brown solid. H NMR (250 MHz, [D6]DMSO): δ =
7.95–7.04 (m, 20 H, CH), 7.93 (s, 1 H, CH), 4.40–3.40 (m, 12 H,
CH, CH2), 0.80 (m, 6 H, CH3) ppm. 13C NMR (150.9 MHz, [D6]-
DMSO): δ = 185.67 (NCN), 168.95, 167.84, 165.03, 157.90, 156.40,
145.10, 143.70, 140.62, 137.50, 135.80, 128.93 (2 C), 128.15, 127.51,
127.01, 126.95 (2 C), 126.64, 126.26, 125.20, 122.34, 122.07, 120.00,
119.70, 69.66, 65.65, 63.66, 54.40, 49.98, 46.52, 43.25, 37.06, 33.64,
19.15, 17.73 ppm. HRMS (ESI): calcd. for C36H39N6O5Pd [M –
CF3COO–]+ 741.2017; found 741.2015.
+
673.1755; found 673.1762.
General Procedure for the Synthesis of Bis(N-heterocyclic carbene)-
palladium Complexes with Base on Resin. [(2-Naphthylcarbonyl-Val-
Ala-Phe-Val-{1-[(S)-2-amino-3-phenylpropyl]-3-(2-oxoethyl)-3H-imid-
azol-1-ium}-Pro-Gly-{1-[(S)-2-amino-3-phenylpropyl]-3-(2-oxoethyl)-
3H-imidazol-1-ium}-Val-NH2)palladium(II)]2+(2CF3COO)2– (9a): A
dry 10 mL Schlenk tube was charged under argon with resin-bound
bis(imidazolium) salt 8a (20 mg, loading = 0.191 mmol/g resin,
0.004 mmol), a solvent mixture of THF (1 mL)/DMF (0.16 mL)
and finally BEMP (2.5 equiv., 2.7 mg). The mixture was deproton-
ated by shaking for 15 min and then treated with PdCl2COD
(1.5 equiv., 1.6 mg) in one portion. After an additional 1 h of shak-
ing at 20 °C, the resin was filtered and washed with DMF
(5ϫ1 mL) and DCM (5ϫ1 mL). The final complex 9a was ob-
tained from the resin by treatment with TFA (95%, aq.) (2 h). The
solution of the complex was concentrated in vacuo and directly
analysed by HRMS (ESI) as the crude product. HRMS (ESI):
calcd. for C73H90N14O10Pd [PdIIM – 2 CF3COO–]2+/2 714.3000;
found 714.3004.
[(2-Naphthylcarbonyl-Gly-{1-[(S)-2-amino-3-methylbutyl]-3-(eth-1-
en-2-olato)-3H-imidazolin-2-ylidene}-Val-NH2)palladium-
(II)]+(CF3COO)– (5b): The final complex 5b was cleaved from the
resin (20.0 mg) by treatment with TFA (aq., 95%) (2 h). The solu-
tion of the complex was concentrated in vacuo and directly ana-
lyzed by HRMS (ESI) as the crude product. HRMS (ESI): calcd.
for C28H35N6O4Pd [M – CF3COO–]+ 625.1755; found 625.1760.
[(2-Naphthylcarbonyl-Gly-{1-[(S)-2-amino-3-phenylpropyl]-3-(2-meth-
ylpent-4-en-5-olato)-3H-imidazolin-2-ylidene}-Val-NH2)palla-
dium(II)]+(CF3COO)– (5c): The final complex 5c was cleaved from
the resin (20.0 mg) by treatment with TFA (aq., 95%) (2 h). The
solution of the complex was concentrated in vacuo and directly
analyzed by HRMS (ESI) as the crude product. HRMS (ESI):
calcd. for C36H43N6O4Pd [M – CF3COO–]+ 729.2381; found
729.2377.
[(2-Naphthylcarbonyl-Val-Phe-Pro-Gly-{1-[(S)-2-amino-3-phenyl-
propyl]-3-(eth-1-en-2-olato)-3H-imidazolin-2-ylidene}-Val-NH2)-
palladium]+(CF3COO)– (5d): The final complex 5d was cleaved
from the resin (20.0 mg) by treatment with 95% TFA (aq) (2 h).
The solution of the complex was concentration in vacuo and di-
rectly analyzed by HRMS (ESI) as the crude product. HRMS
(ESI): calcd. for C51H60N9O7Pd [M – CF3COO–]+ 1016.3645;
found 1016.3695.
[(2-Naphthylcarbonyl-Val-Ala-Phe-Ala-{1-[(S)-2-amino-3-phenyl-
propyl]-3-(2-oxoethyl)-3H-imidazol-1-ium}-Val-Pro-Gly-{1-[(S)-2-
amino-3-phenylpropyl]-3-(2-oxoethyl)-3H-imidazol-1-ium}-Val-NH2)-
palladium(II)]2+(2CF3COO)2– (9b): The final complex 9b was
cleaved from the resin by treatment with TFA (aq., 95%) (2 h). The
solution of the complex was concentrated in vacuo and directly
analyzed by HRMS (ESI) as the crude product. HRMS (ESI):
calcd. for C82H95N15O17Pd [PdIIM – 2 CF3COO–]2+/2 749.8185;
found 749.8193.
[(2-Naphthylcarbonyl-Gly-{1-[(S)-2-amino-3-phenylpropyl]-3-(2-
ethen-3-olato)-3H-imidazolin-2-ylidene}-Val-NH2)palladium-
(II)]+(CF3COO)– (5e): The final complex 5e was obtained from the
resin (20.0 mg) by treatment with TFA (95%, aq.) (2 h). The solu-
tion of the complex was concentrated in vacuo and directly ana-
lyzed by HRMS (ESI) as the crude product. HRMS (ESI): calcd.
for C33H37N6O4Pd [M – CF3COO–]+ 687.1911; found 687.1884.
[(2-Naphthylcarbonyl-Val-Ala-Leu-Gly-{1-(2-amino-3-phenylpro-
pyl)-3-(2-oxoethyl)-3H-imidazol-1-ium}-Leu-Gly-{1-(2-amino-3-
phenylpropyl)-3-(2-oxoethyl)-3H-imidazol-1-ium}-Val-NH2)palla-
dium(II)]2+(2CF3COO)2– (9c): The final complex 9c was cleaved
from the resin by treatment with TFA (aq., 95%) (2 h). The solu-
tion of the complex was concentrated in vacuo and directly ana-
lyzed by HRMS (ESI) as the crude product. HRMS (ESI): calcd.
for C68H90N14O10Pd [PdIIM – 2 CF3COO–]2+/2 684.3000; found
684.2997.
General Procedure for the Synthesis of Palladium Complexes with
Pd(OAc)2. a) On Solid Phase. [(Fmoc-NH-Gly-{1-[(S)-2-amino-3-
phenylpropyl]-3-(eth-1-en-2-olato)-3H-imidazolin-2-ylidene}-Val-
NH2)palladium(II)]+(CF3COO)– (7): Pd(OAc)2 (5.0 equiv., 5.1 mg)
Eur. J. Org. Chem. 2008, 3785–3797
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3795

J. F. Jensen, K. Worm-Leonhard, M. Meldal
FULL PAPER
[14]
[15]
[16]
G. Nyce, T. Glauser, E. Connor, R. Waymouth, J. Hedrick, J.
Am. Chem. Soc. 2003, 125, 3046–3056.
K. Ding, H. Du, Y. Yuan, J. Long, Chem. Eur. J. 2004, 10,
2872–2884.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra for the synthesised compounds, RP-HPLC chro-
matograms and ESI-HRMS spectra for selected compounds.
For chiral carbene chelate systems, see: a) D. S. Clyne, J. Jin,
E. Genest, J. C. Gallucci, T. V. Rajanbabu, Org. Lett. 2000, 2,
1125–1128; b) V. César, S. Bellemin-Laponnaz, H. Wadepohl,
L. H. Gade, Chem. Eur. J. 2005, 11, 2862–2873; c) S. J. Rose-
blade, A. Ros, D. Monge, M. Alcarazo, E. Álvarez, J. M. Las-
saletta, R. Fernández, Organometallics 2007, 26, 2570–2578; d)
S. Nanchen, A. Pfaltz, Chem. Eur. J. 2006, 12, 4550–4558; e)
K.-S. Lee, M. K. Brown, A. W. Hird, A. H. Hoveyda, J. Am.
Chem. Soc. 2006, 128, 7182–7184; f) A. Ros, D. Monge, M.
Alcarazo, E. Álvarez, J. M. Lassaletta, R. Fernández, Organo-
metallics 2006, 25, 6039–6046.
a) S, R. Gilbertson, S. E. Collibee, A. Agarkov, J. Am. Chem.
Soc. 2000, 122, 6522–6523; b) S. J. Greenfield, A. Agarkov,
S. R. Gilbertson, Org. Lett. 2003, 5, 3069–3072.
S. J. Degrado, H. Mizutani, A. H. Hoveyda, J. Am. Chem. Soc.
2001, 123, 755–756.
Acknowledgments
The Danish National Research Foundation is gratefully acknowl-
edged for financial support.
[1] N. E. Leadbeater, M. Marco, Chem. Rev. 2002, 102, 3217–3274.
[2] Reviews: a) W. A. Herrmann, Angew. Chem. Int. Ed. 2002, 41,
1290–1309; b) reviews on N-heterocyclic carbene ligands in
asymmetric catalysis: M. C. Perry, K. Burgess, Tetrahedron:
Asymmetry 2003, 14, 951–961; c) T. Weskamp, V. P. W. Böhm,
W. A. Herrmann, J. Organomet. Chem. 2000, 600, 12–22; d) D.
Enders, H. Gielen, J. Organomet. Chem. 2001, 617–618, 70–80.
[3] For solid-supported bis(carbene) ligands, see: J. Schwartz,
V. P. W. B öhm, M. G. Gardiner, M. Grosche, W. A. Herrmann,
W. Hieringer, G. Raudaschl-Sieber, Chem. Eur. J. 2000, 6,
1773–1780.
[4] D. Bourissou, O. Guerret, F. P. Gabbaï, G. Bertrand, Chem.
Rev. 2000, 100, 39–91.
[5] a) K. Öfele, J. Organomet. Chem. 1968, 12, P42–P43; b) H. W.
Wanzlick, H. J. Schönherr, Angew. Chem. 1968, 80, 154; Angew.
Chem. Int. Ed. Engl. 1968, 7, 141–142.
[17]
[18]
[19]
[20]
C. A. Christensen, M. Meldal, Chem. Eur. J. 2005, 11, 4121–
4131.
I. M. Pastor, P. Västilä, H. Adolfsson, Chem. Eur. J. 2003, 9,
4031–4045.
[21]
[22]
[23]
[24]
C. Gennari, U. Piarulli, Chem. Rev. 2003, 103, 3071–3100.
A. J. Arduengo, III, US Patent 5,077,414, 1991.
W. Bao, Z. Wang, Y. Li, J. Org. Chem. 2003, 68, 591–593.
P. B. Alper, S.-C. Hung, C. H. Wong, Tetrahedron Lett. 1996,
37, 6029–6032.
M. F. M. Mustapa, R. Harris, N. Bulic-Subanovic, S. L. El-
liotts, S. Bregant, M. F. A. Groussier, J. Mould, D. Schultz,
N. A. L. Chubb, P. R. J. Gaffney, P. S. Driscoll, A. B. Tabor, J.
Org. Chem. 2003, 68, 8185–8192.
a) P. C. J. Kamer, P. W. N. M. Van Leeuwen, J. N. H. Reek,
Acc. Chem. Res. 2001, 34, 895–904; b) C. D. Casey, G. T. Whi-
teker, Isr. J. Chem. 1990, 30, 229–304.
M. Meldal, Tetrahedron Lett. 1992, 33, 3077–3080.
R. Knorr, A. Trzeciak, W. Bannwarth, D. Gillessen, Tetrahe-
dron Lett. 1989, 30, 1927–1930.
a) E. Meinjohanns, M. Meldal, T. Jensen, O. Werdelin, L.
Galli-Stampino, S. Mouritsen, K. Bock, J. Chem. Soc. Perkin
Trans. 1 1997, 871–884; b) M. Meldal, M. A. Juliano, A. M.
Jansson, Tetrahedron Lett. 1997, 38, 2531–2534.
C. P. Holmes, J. Org. Chem. 1997, 62, 2370–2380.
R. W. Alder, P. R. Allen, S. J. Williams, J. Chem. Soc., Chem.
Commun. 1995, 1267–1268.
W. A. Herrmann, L. J. Goossen, M. Spiegler, J. Organomet.
Chem. 1997, 547, 357–366.
A. J. Arduengo III, R. H. V. R. Dias, R. L. Harlow, M. Kline,
J. Am. Chem. Soc. 1992, 114, 5530–5534.
a) S. Grundemann, M. Albrecht, J. Loch, J. Faller, R. Crabtree,
Organometallics 2001, 20, 5485–5488; b) J. Van Veldhuizen, S.
Garber, J. Kingsbury, A. Hoveyda, J. Am. Chem. Soc. 2002,
124, 4954–4955; c) H. Aihara, T. Matsuo, H. Kawaguchi,
Chem. Commun. 2003, 2204–2205; d) P. Arnold, A. Scarisbrick,
A. Blake, C. Wilson, Chem. Commun. 2001, 2340–2341; e) D.
Sellmann, C. Allmann, F. Heinemann, F. Knoch, J. Sutter, J.
Organomet. Chem. 1997, 541, 291–305; f) E. Mas-Marza, M.
Poyatos, M. Sanau, E. Peris, Organometallics 2004, 23, 323–
325.
B. E. Ketz, A. P. Cole, R. M. Waymouth, Organometallics
2004, 23, 2835–2837.
D. S. McGuinness, K. J. Cavell, Organometallics 2000, 19, 741–
748.
[25]
[6] a) A. J. Arduengo III, R. L. Harlow, M. Kline, J. Am. Chem.
Soc. 1991, 113, 361–363; b) A. J. Arduengo III, M. Kline, J. C.
Calarese, F. Davidson, J. Am. Chem. Soc. 1991, 113, 9704–
9705; c) A. J. Arduengo III, Acc. Chem. Res. 1999, 32, 913–
921.
[26]
[7] a) W. A. Herrmann, M. Elison, J. Fischer, C. Kocher, G. Artus,
Angew. Chem. Int. Ed. Engl. 1995, 34, 2371–2374; b) A. Hillier,
G. Grasa, M. Viciu, H. Lee, C. Yang, S. Nolan, J. Organomet.
Chem. 2002, 653, 69–82; c) J. Loch, M. Albrecht, E. Peris, J.
Mata, J. Faller, R. Crabtree, Organometallics 2002, 21, 700–
706; d) C. Gstottmayr, V. Bohm, E. Herdtweck, M. Grosche,
W. A. Herrmann, Angew. Chem. Int. Ed. 2002, 41, 1363–1365;
e) S. Stauffer, S. Lee, J. Stambuli, S. Hauck, J. Hartwig, Org.
Lett. 2000, 2, 1423–1426; f) D. Mcguinness, K. Cavell, B. Skel-
ton, A. White, Organometallics 1999, 18, 1596–1605; g) D.
Mcguinness, K. Cavell, Organometallics 2000, 19, 741–748; h)
O. Navarro, H. Kaur, P. Mahjoor, S. P. Nolan, J. Org. Chem.
2004, 69, 3173–3180.
[8] a) C. W. Bielawski, R. H. Grubbs, Angew. Chem. Int. Ed. 2000,
39, 2903–2906; b) J. Louie, R. H. Grubbs, Angew. Chem. Int.
Ed. 2001, 40, 247–249; c) T. M. Trnka, J. P. Morgan, M. S. San-
ford, T. E. Wilhelm, M. Scholl, T.-L. Choi, S. Ding, M. W. Day,
R. H. Grubbs, J. Am. Chem. Soc. 2003, 125, 2546–2558; d) A.
Fürstner, Alkene Metathesis in Organic Synthesis, Springer,
Berlin, 1998.
[9] For immobilised olefin metathesis catalysts, see: S. C. Schürer,
S. Gessler, N. Buschmann, S. Blechert, Angew. Chem. Int. Ed.
2000, 39, 3898–3901.
[10] a) W. A. Herrmann, L. J. Goossen, C. Köcher, G. R. J. Artus,
Angew. Chem. Int. Ed. Engl. 1996, 35, 2805–2807; b) L. H.
Gade, V. César, S. Bellemin-Laponnaz, Angew. Chem. Int. Ed.
2004, 43, 1014–1017.
[11] a) R. Jackstell, M. Gómez Andreu, A. Frisch, K. Selvakumar,
A. Zapf, H. Klein, A. Spannenberg, D. Röttger, O. Briel, R.
Karch, M. Beller, Angew. Chem. Int. Ed. 2002, 41, 986–989; b)
M. Viciu, F. Zinn, E. Stevens, S. Nolan, Organometallics 2003,
22, 3175–3177.
[12] M. Perry, X. Cui, M. Powell, D. Hou, J. Reibenspies, K. Bur-
gess, J. Am. Chem. Soc. 2003, 125, 113–123.
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
a) H. M. J. Wang, I. J. B. Lin, Organometallics 1998, 17, 972–
975; b) R. S. Simons, P. Custer, C. A. Tessier, W. J. Youngs, Or-
ganometallics 2003, 22, 1979–1982; c) A. R. Chianese, X. W.
Li, M. C. Janzen, J. W. Faller, R. H. Crabtree, Organometallics
2003, 22, 1663–1667.
[13] M. Gardiner, W. A. Herrmann, C. Reisinger, J. Schwartz, M.
Spiegler, J. Organomet. Chem. 1999, 572, 239–247.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3785–3797

Optically Active (Peptido-carbene)palladium Complexes
[38] a) W. A. Herrmann, M. Elison, J. Fischer, C. Köcher, G. R. J.
Artus, Angew. Chem. Int. Ed. Engl. 1995, 34, 2371–2374; b)
W. A. Herrmann, J. Fischer, K. Öfele, G. R. J. Artus, J. Or-
ganomet. Chem. 1997, 538, 259–262; c) W. A. Herrmann, J.
Schwartz, M. G. Gardiner, Organometallics 1999, 18, 4082–
4089.
[39] a) A. M. Jansson, M. Grøtli, K. M. Halkes, M. Meldal, Org.
Lett. 2002, 4, 27–30; b) R. Akiyama, S. Kobayashi, J. Am.
Chem. Soc. 2003, 125, 3412–3413; c) R. Nakao, H. Rhee, Y.
Uozumi, Org. Lett. 2005, 7, 163–165.
Received: February 29, 2008
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