Organometallic peptide NHC complexes of CpRh(III) and arene Ru(II) moieties from l-thiazolylalanine

Article abstract of DOI:10.1016/j.jorganchem.2010.12.044

The 3-ethyl thiazolium peptide salts Boc-Thia-Leu-OMe and Boc-Thia-Leu-Phe-OMe based on the unnatural amino acid thiazolylalanine (Thia) have been prepared. After deprotonation, they reacted rapidly via the silver carbene transfer reaction with [RhCpCl₂]₂ and [Ru(p-cymene)Cl₂]₂ to yield the corresponding thiazole-based carbene complexes 7-10 in acceptable yield. All new compounds were characterized by multinuclear NMR spectroscopy, mass spectrometry, and elemental analysis. These complexes constitute the first examples of thiazolylalanine-2-ylidene metal bioconjugates.

Full text of DOI:10.1016/j.jorganchem.2010.12.044

Journal of Organometallic Chemistry 696 (2011) 1018e1022
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Communication
Organometallic peptide NHC complexes of Cp*Rh(III) and arene Ru(II) moieties
from -thiazolylalanine
L
*
Jessica Lemke, Nils Metzler-Nolte
Lehrstuhl für Anorganische Chemie I e Bioanorganische Chemie, Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstraße 150, 44801 Bochum, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The 3-ethyl thiazolium peptide salts Boc-Thia-Leu-OMe and Boc-Thia-Leu-Phe-OMe based on the
unnatural amino acid thiazolylalanine (Thia) have been prepared. After deprotonation, they reacted
rapidly via the silver carbene transfer reaction with [RhCp*Cl2]2 and [Ru(p-cymene)Cl2]2 to yield
the corresponding thiazole-based carbene complexes 7e10 in acceptable yield. All new compounds were
characterized by multinuclear NMR spectroscopy, mass spectrometry, and elemental analysis. These
complexes constitute the first examples of thiazolylalanine-2-ylidene metal bioconjugates.
Ó 2011 Elsevier B.V. All rights reserved.
Received 31 October 2010
Received in revised form
28 December 2010
Accepted 29 December 2010
Keywords:
Bioorganometallic chemistry
NHC complexes
Peptide bioconjugates
Rhodium compounds
Ruthenium compounds
Thiamine
Thiazolylalanine
Thiamine (vitamin B1) belongs to the water-soluble B complex
vitamins. It consists of a pyrimidine and a substituted thiazole ring.
In particular its diphosphate salts are vital in the metabolism of
sugars. Thiamine is not naturally produced in humans and thus
needs to be supplied by our diet. Its deficiency leads to diseases like
Beriberi, with fatal outcome if thiamine is not supplemented by
a suitable diet. Metal coordination (Zn2þ, Cd2þ, Hg2þ) to thiamine
diphosphate occurs via the pyrimidine nitrogen atom and phos-
phate groups [1,2].
Although it is accepted that thiamine forms a free carbene as an
intermediate during benzoin condensation, [3] no carbene-type
metal complexes of thiamine itself or its derivatives are known. As
much simpler compounds, thiazolyl-2-ylidene complexes mainly
from thiazole itself were reported [4e6]. They were usually
prepared from N-alkyl functionalised thiazolium salts as ligand
precursors which were transformed to the lithium carbene and
then reacted with metal carbonyls to form the desired complexes.
Compared to the much better investigated N-heterocyclic carbene
(NHC) complexes derived from imidazole, thiazolyl-2-ylidene
complexes only have one substituent at the nitrogen atom of
the heterocycle, whereas the imidazole-based NHC complexes may
have two different substituents on both nitrogen atoms. As
bioorganic derivatives of thiazole, amino acids such as thiazolyla-
lanine (Thia) [7], have been described, but again no metal
complexes of such compounds were reported. In view of this, we
set out to prepare thiazolium peptides and the first carbene-type
metal complexes thereof via the Ag2O transmetallation route [8].
Biomolecules conjugated to metal complexes have been used in
several biochemical and medicinal applications, ranging from
biosensors to radioimaging and drugs [9,10]. A special interest lies
in the field of organometallic bionconjugates, where the metal
complex is covalently bound to a biomolecule, e.g. DNA, PNA and
peptides [11e13]. Our group has reported covalent organometallic
bioconjugates based on ferrocene-peptide and PNA conjugates [14],
as well as cobaltcarbonyl-alkyne peptides [15] and scorpionate
derivatives [16]. Recently, the syntheses of NHC-metal peptide
conjugates have been published [17e19], as well as the syntheses of
NHC-sugar conjugates [20] and NHC-gold amino acid conjugates
[20,21].
To form the di- and tripeptide derivatives, Boc-l-thiazolylalanine
was activated with N-methylmorpholine and isobutyl chloro-
formate in THF to which solutions of the deprotonated l-leucine
methylester or the deprotonated dipeptide Leu-Phe-OMe (2) in THF
were added [22]. After filtration and extraction, the thiazolylala-
nine peptides 3 and 4 were obtained as white-yellow powders in
excellent yields. The dipeptide 3 and the tripeptide 4 were trans-
formed into the 3-ethyl thiazolium salts using literature conditions
(Scheme 1) [23].
* Corresponding author. Tel.: þ49 (0)234 32 28152; fax: þ49 (0)234 32 14378.
E-mail address: nils.metzler-nolte@rub.de (N. Metzler-Nolte).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.12.044

J. Lemke, N. Metzler-Nolte / Journal of Organometallic Chemistry 696 (2011) 1018e1022
1019
S
O
HCl
N
Br
Boc
HN
O
Boc NH NH
*
i)
N
Rh
Ru
+
H2N
Cl
Cl
S
Cl
Cl
S
N
OCH3
CO2CH3
HO2C
S
S
N
N
O
iii)
3
O
O
Boc NH NH
CO2CH3
Boc
Boc
NH
S
NH
NH
NH
CO2CH3
O
N
CO2CH3
O
Boc NH NH
Boc
HN
i)
H3N
OCH3
N
N
+
S
O
5
7
9
H
O
HO2C
HN
O
H3CO2C
Br
N
F3C
O
S
Ru
Rh
Cl
Cl
N
iii)
Cl
Cl
O
S
S
N
2
4
NH
NH
Boc
O
O
Scheme 1. Synthesis of the thiazolylalanine peptides. i) N-methylmorpholine, isobutyl
chloroformiate, NEt3, THF, 1 h.
O
Boc
Boc
HN
NH
NH
NH
NH
H3CO2C
O
O
HN
H3CO2C
HN
H3CO2C
The crude thiazolium salts were purified via flash column
chromatography. Thiazolium peptide salts 5 and 6 were obtained as
white powders after lyophilisation from water-acetonitrile
mixtures in moderate yields (Scheme 2).
The NHC-rhodium(III) and -ruthenium(II) complexes were
synthesised by addition of Ag2O to the thiazolium salts in
dichloromethane, containing molecular sieves to absorb the
formed water. After shaking the mixture overnight, the chloro-
bridged metal dimers (dichloro(Cp*)rhodium(III) and dichloro
(p-cymene)ruthenium(II) dimer) were added. Almost instantly, the
carbene transfer reaction started, indicated by the precipitation of
a white solid, likely to be silver bromide. After 24 h, the mixtures
were filtered through celite and the crude products were purified
by flash column chromatography. Complexes 7e10 were obtained
as orange powders in moderate yields after recrystallization from
dichloromethane/pentane (Scheme 3). In all cases, the reaction did
not give full conversion. This is likely due to the ligand precursors
losing reactivity upon elongation of the peptide chain.
6
8
10
Scheme 3. Synthesis of the rhodium and ruthenium carbene complexes. iii) 2 eq.
thiazolium salt, 1 eq. Ag2O, 1 eq. [(p-cymene)RuCl2]2 or [Cp*RhCl2]2, CH2Cl2, molecular
sieve, N2.
All products were comprehensively characterized by mass
spectrometry, NMR spectroscopy and elemental analysis. A char-
acteristic feature of the thiazolium peptides 5 and 6 is the down-
field-shifted signal of the acidic N¼CH-S proton at 10.61 ppm (5)
and 10.20 ppm (6) with a 4J coupling of about 2 Hz in the 1H NMR
spectra. In the 13C NMR spectra, the signals around 145e152 ppm
(N¼CH-S) of the thiazolium salts are downfield shifted as well,
compared to the signal for the C¼CH-S carbon atom around
120 ppm. Upon metal complexation, the downfield-shifted proton
signal disappears and the C¼CH-S proton signal becomes a singlet.
In the 13C NMR spectra, the metal-carbene carbon signals are
observed at 170 ppm for the rhodium carbenes and at 172 ppm for
the ruthenium carbenes. All spectroscopic data are well in agree-
ment with values reported for other NHC complexes of Ru(arene) or
Rh(Cp*) fragments, respectively. In electrospray ionisation mass
spectrometry (ESI-MS pos.), the metal complexes, as well as the
thiaozolium salts, show the [M-halide]þ peak as the base peak.
Further, for the rhodium conjugates 9 and 10, a second peak occurs,
which was identified as the [M ꢀ Et ꢀ H þ K]þ peak (Fig. 1).
In summary, we have demonstrated that thiazolyl-2-ylidene
rhodium(III) and ruthenium(II) complexes, where the ligand
precursors themselves are peptide conjugates, are easily accessible
via the silver carbene transfer reaction. Such compounds are of
fundamental interest as they constitute the first metal thiazolyl-2-
ylidene bioconjugates. Based on the rich chemistry of imidazole-
based NHC complexes especially in catalysis, related applications of
functional thiazolyl carbenes may be envisaged. In bio-
organometallic chemistry in particular, Ru(arene) complexes were
extensively studied for their antiproliferative activity [24e27].
While the aqueous chemistryof the Rh(Cp*) fragment and bindingto
amino acids and nucleobases has been extensively investigated
[28,29], the thiazolylalanine complexes described herein are the first
peptide bioconjugates of this metal fragment [30]. Gilbertson et al.
have demonstrated how carefully designed peptides may serve as
Br
S
S
N
O
N
ii)
+
O
Boc NH NH
CO2CH3
Br
Boc NH NH
CO2CH3
3
5
Br
N
S
S
O
N
O
ii)
Boc NH NH
+
Br
NH
NH
Boc
O
O
HN
HN
H3CO2C
H3CO2C
4
6
Scheme 2. Synthesis of the 3-ethyl thiazolylalanine peptide salts. ii) 1 eq. peptide,
1 mL ethylbromide/100 mg peptide, acetonitrile, N2, 90 ꢁC, 60 h.

1020
J. Lemke, N. Metzler-Nolte / Journal of Organometallic Chemistry 696 (2011) 1018e1022
3100. Electrospray ionisation mass spectra (ESI) were recorded
with a Bruker Esquire 6000.
1.2. Syntheses of new compounds
1.2.1. 1
To a stirred solution of Boc-leucine monohydrate (2.49 g,
10 mmol) in THF (50 mL) was added N-methylmorpholine (1.12 mL,
10 mmol) followed by the addition of isobutyl chloroformiate
(1.32 mL, 10 mmol), resulting in a precipitation of a white solid. In
a second flask, phenylalanine methylester hydrochloride (2.15 g,
10 mmol) was suspended in THF (50 mL) containing triethylamine
(1.38 mL,10 mmol). Both suspensions were mixed and stirred for 1 h
at room temperature. After removal of the white precipitates by
filtration, the solvent was removed under reduced pressure and the
residual oil dissolved in CHCl3 (100 mL). The solution was washed
with water (50 mL) and the aqueous solution was back-extracted
with CHCl3 (3 ꢂ 50 mL). The combined CHCl3 solutions were
dried over Na2SO4. Evaporation of the solvent under reduced pres-
sureyielded the product asawhite solid (3.76 g, 96%).1H NMR (CDCl3,
250 MHz, 25 ꢁC):
d
¼ 7.29e7.07 (6H, m, CAr,PheH, NHLeu),6.47 (1H, d,
3JH,H ¼ 7.6 Hz, NHPhe), 4.84e4.67 (1H, m, Ca,PheH), 4.12e3.90 (1H, m,
Ca,LeuH), 3.63 (3H, s, CO2CH3), 3.19e3.00 (2H, m, Cb,PheH), 2.17e1.93
(1H, m, Cg,LeuH),1.60e1.47(2H, m, Cb,LeuH),1.41(9H, s, NH-CO2(CH3)3),
0.89 (6H, dd, 3JH,H ¼ 6.1 Hz, 4JH,H ¼ 2.4 Hz, Cd,LeuH). e C21H32N2O5 calc.
C, 64.26; H, 8.22; N, 7.14; found C, 63.43; H, 8.46; N, 6.76.
1.2.2. 2
To a solution of 1 (3.6 g, 9.18 mmol) in CH2Cl2 (30 mL) was added
TFA (20 mL) at 0 ꢁC. The solution was stirred for 1 h. The solvent was
removed under reduced pressure and the residue was taken up in
diethylether and stirred for 30 min to yield a white precipitate
which was then dried in vaccuo (2.98 g, 80%). 1H NMR (CDCl3,
3
250 MHz, 25 ꢁC):
(6H, m, C
d
¼ 7.34 (1H, d, JH,H ¼ 7.2 Hz, NHLeu), 7.29e7.00
Ar,PheH, NHPhe), 4.78e4.62 (1H, m, Ca,PheH), 4.10e3.95 (1H,
m, Ca,LeuH), 3.69 (3H, s, CO2CH3), 3.07 (2H, d, 3JH,H ¼ 6.7 Hz, Cb,PheH),
1.72e1.46 (3H, m, Cb,LeuH, Cg,LeuH), 0.94e0.76 (6H, m, Cd,LeuH). e MS
(ESIþ): 293.15 [M-TFA]þ. e C18H25F3N2O5 calc. C, 53.20; H, 6.20;
N, 6.89; found C, 53.02; H, 6.50; N, 6.72.
Fig. 1. Comparison of the ESI-MS (pos.) of the thiazolium peptide salt 6 and the cor-
responding ruthenium and rhodium complexes. (a) 6 [M ꢀ Br]þ, (b) 8 [M ꢀ Cl]þ and (c)
10 [M ꢀ Cl]þ and [M ꢀ Et ꢀ H þ K]þ
.
ligands for metal-catalyzed transformation with high enantiose-
lectivity [31e34]. In their work, amino acids with phosphine side
chains were used. These amino acids are not commercially available
and required careful control of the reaction conditions due to
oxidation of the phosphine groups. In principle, the present paper
suggests that thiazolylalanine may be a more convenient alternative
for such applications, in addition to the above mentioned use in
medicinal inorganic chemistry [35]. Further work along these lines
of thought is in progress in our laboratory.
1.2.3. 3
To a stirred solution of Boc-thiazolylalanine (0.2 g, 0.74 mmol) in
THF (10 mL) was added N-methylmorpholine (83
followed by the addition of isobutyl chloroformiate (98
0.74 mmol), resulting in a precipitation of a white solid. In a second
flask leucine hydrochloride (134 mg, 0.74 mmol) was dissolved in
THF (10 mL), containing triethylamine (102 mL, 0.74 mmol). Both
m
L, 0.74 mmol)
mL,
suspensions were mixed and stirred for 1 h at r.t.. After removal of
the precipitation by filtration, the solvent was removed under
reduced pressure and the residual oil was dissolved in CHCl3
(50 mL). The solution was washed with water (50 mL) and the
aqueous solution was back-extracted with CHCl3 (3 ꢂ 50 mL). The
combined organic solutions were dried over Na2SO4. Evaporation of
the solved and lyophilisation from a mixture of acetonitrile/water
yielded 3 as a yellow-white powder (228 mg, 77%). 1H NMR (CDCl3,
1. Experimental
1.1. General
All reagents were purchased from commercial sources and used
as received. l-amino acids were purchased from Novabiochem and
IRIS Biotech. Although the final products are stable to air and
moisture, all reactions were carried out under an inert N2 gas
atmosphere in dry solvents. Solvents were distilled over CaCl2
(CH2Cl2) and CaH2 (acetonitrile). Glassware was used oven dry.
NMR spectra were recorded on either Bruker DPX 250 (250 MHz) or
on Bruker DRX 400 (400 MHz) spectrometers. The NMR chemical
250 MHz, 25 ꢁC):
d
¼ 8.69 (1H, d, 3JH,H ¼ 2.0 Hz, N¼CH-S), 7.04 (1H,
3
d, JH,H
¼
2.0 Hz, C¼CH-S), 6.69 (1H, br.s, NHLeu
) 6.12
(d, 3JH,H ¼ 6.5 Hz, NHThia), 4.51e4.31 (2H, m, Ca,LeuH, Ca,ThiaH), 3.59
(3H, s, CO2CH3), 3.21 (2H, dq, 3JH,H ¼ 5.7 Hz, 2JH,H ¼ 14.7 Hz, Cb,ThiaH),
1.45e1.34 (3H, m, Cb,LeuH, Cg,LeuH), 1.36 (9H, s, Boc), 0.75 (6H, dd,
3JH,H ¼ 6.3 Hz, JH,H ¼ 2.4 Hz, Cd,LeuH). e 13C NMR (CDCl3, 63 MHz,
4
25 ꢁC):
d
¼ 173.0 (COThia), 171.1 (CO2CH3), 155.6 (Cq,Thia), 153.1
shifts (
d
) are reported in ppm relative to the residual proton
(COBoc), 153.0 (N¼CH-S), 115.5 (N-C¼CH-S), 80.1 (Cq,Boc), 54.2
(Ca,Thia), 52.2 (CO2CH3), 50.6 (Ca,Leu), 41.4 (Cb,Leu), 33.2 (Cb,Thia), 28.3
(CBoc), 24.5, 23.0 (Cd,Leu), 21.8 (Cg,Leu). e MS (ESIþ): 400.17 [M þ H]þ,
chemical shifts of the deuterated solvent set relative to external
TMS. Microanalysis was performed on an Analytik Jena multi EA

J. Lemke, N. Metzler-Nolte / Journal of Organometallic Chemistry 696 (2011) 1018e1022
1021
422.18 [M þ Na]þ. e C18H29N3O5S calc. C, 54.12; H; 7.32, N; 10.52,
7.31e7.09 (5H, m, HAr,Phe), 6.14 (d, 3JH,H ¼ 7.7 Hz, NHThia), 4.85e4.64
(4H, m, Ca,PheH, Ca,LeuH, N-CH2-CH3), 4.37e4.26 (1H, m, Ca,ThiaH), 3.39
(3H, s, CO2CH3), 3.34e3.26 (2H, m, Cb,PheH), 3.12 (2H, d, 3JH,H ¼ 7.2 Hz,
S; 8.03; found C, 51.61, H, 7.25; N, 10.02; S, 7.2.
3
1.2.4. 4
Cb,ThiaH), 1.60 (3H, t, JH,H ¼ 7.2 Hz, N-CH2-CH3), 1.49e1.34 (3H, m,
3
To a stirred solution of Boc-thiazolylalanine (0.2 g, 0.74 mmol) in
Cb,LeuH, Cg,LeuH), 1.30 (9H, s, Boc), 0.78 (6H, dd, JH,H ¼ 5.7 Hz,
THF (10 mL) was added N-methylmorpholine (83
mL, 0.74 mmol)
2JH,H ¼ 16.3 Hz, Cd,LeuH). e13C NMR (CDCl3, 63 MHz, 25 ꢁC):
¼ 173.1
d
followed by the addition of isobutyl chloroformiate (98
mL,
(COThia), 172.8 (CO2CH3), 170.0 (COLeu), 157.8 (Cq,Thia), 155.5 (COBoc),
146.1 (N¼CH-S), 136.8 (Cq,Ar,Phe), 129.6 (CAr,Phe), 128.6 (CAr,Phe), 127.0
(CAr,Phe), 124.4 (N-C¼CH-S), 80.3 (Cq,Boc), 54.1(Ca,Thia, N-CH2-CH3),
52.4 (Ca,Phe), 50.6 (CO2CH3), 49.5 (Ca,Leu), 40.8 (Cb,Leu), 37.6 (Cb,Phe),
31.0 (Cb,Thia), 28.4(CBoc), 24.8 22.7 (Cd,Leu), 22.0 Cg,Leu), 15.7 (N-CH2-
CH3). e (ESIþ): 575.29 [M ꢀ Br]þ. e C29H43BrN4O6S calc. C, 53.12; H,
6.61; N, 8.5; S, 4.89; found C, 50.21; H, 6.74; N, 7.83; S, 4.56.
0.74 mmol), resulting in a precipitation of a white solid. In a second
flask 2 (0.3 g, 0.74 mmol) was dissolved in THF (10 mL), containing
triethylamine (102 mL, 0.74 mmol). Both suspensions were mixed
and stirred for 1 h at r.t.. After removal of the precipitation by
filtration, the solvent was removed under reduced pressure and the
residual oil was dissolved in CHCl3 (50 mL). The solutionwas washed
with water (50 mL) and the aqueous solution was back-extracted
with CHCl3 (3 ꢂ 50 mL). The combined organic solutions were dried
over Na2SO4. Evaporation of the solved and recrystallization from
THF/hexane at 4 ꢁC yielded 4 as a yellow-white powder (245 mg,
1.2.7. 7
To a dried Schlenktubecharged withmolecular sieves (4Å, 50mg)
were added 5 (97 mg, 0.19 mmol) and Ag2O (22 mg, 0.10 mmol). The
mixture was flushed three times with N2 and then dry CH2Cl2 was
added (15 mL). The flask was closed and shaken overnight in the dark.
[Ru(p-cymene)Cl2]2 (59 mg, 0.10 mmol) was added and the reaction
was allowed to shake for another 24 h. The solution was filtered
through celite and the solvent was removed under reduced pressure.
The orange residue was purified by flash column chromatography
(SiO2, CH2Cl2/MeOH, 9:1) and was then recrystallized from CH2Cl2/
pentane (10 mL/30 mL) at ꢀ20 ꢁC to yield 7 as an orange powder
61%).1H NMR (CDCl3, 250 MHz, 25 ꢁC):
d
¼ 8.72 (1H, d, 3JH,H ¼ 1.9 Hz,
N¼CH-S), 7.32e6.99 (8H, m, CAr PheH, NHPhe, NHLeu, C¼CH-S), 6.16 (d,
,
3JH,H ¼ 7.4 Hz, NHThia), 4.80 (1H, dd, 3JH,H ¼ 6.5 Hz, 14.0 Hz, Ca,PheH),
4.63e4.39 (2H, m, Ca,LeuH, Ca,ThiaH), 3.68 (3H, s, CO2CH3), 3.40e3.18
(2H, d, m, Cb,ThiaH), 3.15e2.99 (2H, m, Cb,PheH),1.64e1.43 (3H, m,
3
Cb,LeuH, Cg,LeuH), 1.43 (9H, s, Boc), 0.82 (6H, dd, JH,H ¼ 6.2 Hz,
2JH,H ¼ 9.3 Hz, Cd,LeuH). e 13C NMR (CDCl3, 63 MHz, 25 ꢁC):
¼ 171.9
d
(COThia), 171.6 (CO2CH3), 171.2 (COLeu), 155.6 (Cq,Thia), 153.2 (COBoc),
152.8 (N¼CH-S), 136.1 (Cq,Ar,Phe), 129.3 (CAr,Phe), 128.6 (CAr,Phe), 127.1
(CAr,Phe), 125.5 (N-C¼CH-S), 80.1 (Cq,Boc), 54.3 (Ca,Thia), 53.5 (Ca,Phe),
52.3 (CO2CH3), 51.6 (Ca,Leu), 40.8 (Cb,Leu), 37.7 (Cb,Phe), 33.2 (Cb,Thia),
28.3 (CBoc), 24.5, 23.0 (Cd,Leu), 21.8 (Cg,Leu). e MS (ESIþ): 547.28
[M þ H]þ, 569.29 [M þ Na]þ. e C27H38N4O6S calc. C, 59.32; H, 7.01; N,
10.25; S, 5.87; found C, 57.6; H, 7.14; N, 9.7; S, 5.44.
(40 mg, 28%).1H NMR (acetonitrile-d3, 250 MHz, 25 ꢁC)
d
¼ 7.38 (1H, s,
C¼CH-S), 6.00 (1H, d, 3JH,H ¼ 8.1 Hz, NHLeu), 5.66e5.45(1H, m, NHThia),
5.42 (2H, dd, AA0XX0, N ¼ 8.0 Hz, 6.0 Hz, HAr,pꢀcymene), 5.23 (2H, dd,
AA0XX0, N ¼ 13.1 Hz, 5.9 Hz, HAr,pꢀcymene), 4.83e4.64(2H, m, Ca,LeuH, N-
CH2-CH3), 4.50e4.31 (2H, m, Ca,ThiaH, N-CH2-CH3), 3.66 (3H, s,
CO2CH3), 3.51e3.30 (1H, m, Cb,ThiaH), 3.26e3.06 (1H, m, Cb,ThiaH),
2.82e2.63 (1H, m, CH(CH3)2-Arpꢀcymene),1.98 (3H, s, HMethyl,pꢀcymene),
1.76e1.46 (6H, m, Cb,LeuH, Cg,LeuH, N-CH2-CH3), 1.39 (9H, s, Boc), 1.21
(6H, dd, 3JH,H ¼ 6.9 Hz, 2JH,H ¼ 2.7 Hz, (CH(CH3)2-Arpꢀcymene), 0.92 (6H,
dd, 3JH,H ¼ 8.0 Hz, 2JH,H ¼ 6.4 Hz, Cd,LeuH). e 13C NMR (acetonitrile-d3,
1.2.5. 5
To a screw-top Schlenk tube was given 3 (228 mg, 0.57 mmol),
dissolved in dry acetonitrile (2 mL) and excess ethylbromide (4 mL).
The tube was sealed and the mixturewas stirred for 60 h at 90 ꢁC and
was then directly loaded to a flash chromatography column (SiO2,
EtOAc/pentane 1:1 / ethylbromide, CH2Cl2/MeOH 9:1 / educt and
product (Rf (CH2Cl2/MeOH, 9:1) ¼ 0.10). 5 was received as an oil
which was lyophilised from acetonitrile/water to yield a yellow-
63 MHz, 25 ꢁC):
d
¼ 174.2 (COThia), 171.9 (CO2CH3), 171.9 (NCS), 156.8
(Cq,Thia), 147.2 (COBoc), 124.3 (C¼CH-S), 107.6, 101.5 (Cq,Ar,pꢀcymene),
87.9, 87.5, 86.7, 85.7 (CAr,pꢀcymene), 80.8 (Cq,Boc), 54.7 (Ca,Thia), 53.2 (N-
CH2-CH3), 52.2 (CO2CH3), 50.8 (Ca,Leu), 41.4 (Cb,Leu), 31.8 (Cb,Thia), 28.7
(CBoc), 25.5 (CMethyl,pꢀcymene), 22.8, 22.0 (Cd,Leu), 21.8 (Cg,Leu), 18.9, 18.7
(CH(CH3)2-Arpꢀcymene), 17.1 (CH(CH3)2-Arpꢀcymene),15.8 (N-CH2-CH3).
e MS (ESIþ): 698.14 [M ꢀ Cl]þ.e C30H47Cl2N3O5RuS calc. C, 49.11; H,
6.46; N, 5.73; S, 4.37; found C, 46.43; H, 5.84; N, 5.65; S, 3.90.
white solid (97 mg, 33%). 1H NMR (CDCl3, 250 MHz, 25 ꢁC):
d
¼ 10.61
(1H, d, 3JH,H ¼ 2.3 Hz, N¼CH-S), 8.84 (1H, d, 3JH,H ¼ 6.6 Hz, NHLeu), 8.16
3
3
(1H, d, JH,H ¼ 2.3 Hz, C¼CH-S) 5.91 (d, JH,H ¼ 6.7 Hz, NHThia),
4.90e4.72 (3H, m, Ca,LeuH, N-CH2-CH3), 4.48e4.28 (Ca,ThiaH), 3.68
(3H, s, CO2CH3), 3.39e3.25 (2H, m, Cb,ThiaH), 1.83e1.45 (6 H, m,
Cb,LeuH, Cg,LeuH, N-CH2-CH3), 1.35 (9H, s, Boc), 0.75 (6H, pseudo-tr,
1.2.8. 8
To a dried Schlenk tube charged with molecular sieves (4 Å,
50 mg) were added 6 (95 mg, 0.14 mmol) and Ag2O (17 mg,
0.07 mmol). The mixture was flushed three times with N2 and then
dry CH2Cl2 was added (15 mL). The flask was closed and shaken
overnight in the dark. [Ru(p-cymene)Cl2]2 (44.4 mg, 0.07 mmol) was
added and the reaction was allowed to shake for another 24 h. The
solution was filtered through celite and the solvent was removed
under reduced pressure. The orange residue was purified by flash
column chromatography (SiO2, CH2Cl2/MeOH, 9:1) and was then
recrystallized from CH2Cl2/pentane (10 mL/30 mL) at ꢀ20 ꢁC to yield
8 as an orange powder (30 mg, 24%). 1H NMR (acetonitrile-d3,
3JH,H ¼ 5.9 Hz, Cd,LeuH). e 13C NMR (CDCl3, 63 MHz, 25 ꢁC):
¼ 173.6
d
(COThia), 170.1 (CO2CH3), 159.0 (Cq,Thia), 155.3 (COBoc), 145.7 (N¼CH-
S),124.2 (C¼CH-S), 80.4 (Cq,Boc), 52.4 (Ca,Thia), 51.9 (N-CH2-CH3), 50.7
(CO2CH3), 49.5 (Ca,Leu), 39.8 (Cb,Leu), 31.2 (Cb,Thia), 28.5 (CBoc), 25.0,
22.9 (Cd,Leu), 21.5 (Cg,Leu), 15.8 (N-CH2-CH3). e MS (ESIþ): 428.21
[M ꢀ Br]þ. e C20H34BrN3O5S calc. C, 47.24; H, 6.74; N, 8.26; S, 6.31;
found C, 45.99; H, 6.55; N, 7.94; S, 6.07.
1.2.6. 6
To a screw-top Schlenk tube was given 4 (245 mg, 0.45 mmol),
dissolved in dry acetonitrile (2 mL) and excess ethylbromide (4 mL).
The tube was sealed and the mixturewas stirred for 60 h at 90 ꢁC and
was then directly loaded to a flash chromatography column (SiO2,
EtOAc/pentane 1:1 / ethylbromide, CH2Cl2/MeOH 9:1 / educt and
product (Rf (CH2Cl2/MeOH, 9:1) ¼ 0.13). 6 was received as an oil
which was lyophilised from acetonitrile/water to yield a yellow-
250 MHz, 25 ꢁC)
d
¼ 7.53 (1H, s, C¼CH-S), 7.43 (1H, d, 3JH,H ¼ 7.1 Hz,
NHLeu), 7.41e7.16 (6H, m, HAr,Phe, NHPhe), 5.96e5.87 (1H, m, NHThia),
5.42 (2H, pseudo-tr, AA’XX’, N ¼ 6.5 Hz, HAr,pꢀcymene), 5.23 (2H, dd,
AA’XX’, N ¼ 11.7 Hz, 6.0 Hz, HAr,pꢀcymene), 4.86e4.53 (4H, m, Ca,LeuH,
Ca,PheH, N-CH2-CH3), 4.34e4.24 (1H, m, Ca,ThiaH), 3.64 (3H, s,
CO2CH3), 3.24e2.94 (4H, m, Cb,ThiaH, Cb,PheH), 2.83e2.61 (1H, m, CH
(CH3)2-Arpꢀcymene), 1.98 (3H, s, HMethyl,pꢀcymene), 1.76e1.40 (6H, m,
Cb,LeuH, Cg,LeuH, N-CH2-CH3), 1.39 (9H, s, Boc), 1.26e1.19 (6H, m, CH
white solid (95 mg, 31%).1H NMR (CDCl3, 250 MHz, 25 ꢁC):
d
¼ 10.20
3
(1H, d, 3JH,H ¼ 2.5 Hz, N¼CH-S), 8.66 (1H, d, JH,H ¼ 7.7 Hz, NHPhe),
8.00 (1H, d, 3JH,H ¼ 2.5 Hz, C¼CH-S) 7.77 (1H, 3JH,H ¼ 7.7 Hz, NHLeu),
(CH3)2-Arpꢀcymene), 0.88 (6H, dd, JH,H ¼ 6.4 Hz, JH,H ¼ 10.8 Hz,
3
2

1022
J. Lemke, N. Metzler-Nolte / Journal of Organometallic Chemistry 696 (2011) 1018e1022
Cd,LeuH). e 13C NMR (acetonitrile-d3, 63 MHz, 25 ꢁC):
d
¼ 173.6
1.76e1.42 (21H, m, Cb,LeuH, Cg,LeuH, N-CH2-CH3, Cp(CH3)5),1.34 (9H, s,
Boc), 0.86 (6H, dd, 3JH,H ¼ 6.5 Hz, 2JH,H ¼ 14.0 Hz, Cd,LeuH). e13C NMR
(COThia), 173.3 (CO2CH3), 171.9 (COLeu), 171.7 (NCS), 156.9 (Cq,Thia),
148.4 (COBoc), 138.7 (Cq,Ar,Phe), 130.7 (CAr,Phe), 129.7 (CAr,Phe), 128.0
(CAr,Phe), 124.2 (C¼CH-S), 107.6, 101.5 (Cq,Ar,pꢀcymene), 90.0, 87.8, 87.3,
85.9 (C,Ar,pꢀcymene), 80.9 (Cq,Boc), 55.2 (Ca,Thia), 55.0 (N-CH2-CH3), 53.4
(CO2CH3), 53.2 (Ca,Phe), 50.9 (Ca,Leu), 42.2 (Cb,Leu), 38.4 (Cb,Phe), 32.2
(Cb,Thia), 28.9 (CBoc), 25.7 (CMethyl,pꢀcymene), 23.6, 22.8 (Cd,Leu), 22.3
(Cg,Leu), 18.9, 18.7 (CH(CH3)2-Arpꢀcymene), 18.2 (CH(CH3)2-
Arpꢀcymene), 17.8 (N-CH2-CH3). e MS (ESIþ): 845.17 [M ꢀ Cl]þ. e
(DMSO-d6, 100 MHz, 25 ꢁC):
d
¼ 171.9 (COThia), 171.8 (CO2CH3), 171.7
(COLeu), 170.0 (NCS), 155.4 (Cq,Thia), 146.5 (COBoc), 137.0 (Cq,Ar,Phe),
129.0 (CAr,Phe), 128.1 (CAr,Phe), 126.5 (C¼CH-S), 96.8, 96.5, 96.3 (“td”,
JRh,H ¼ 6.4 Hz, Cq,Cp
*
), 78.4 (Cq,Boc), 53.5 (Ca,Thia), 51.8 (CO2CH3, NCH3),
53.2 (Ca,Phe), 50.8 (Ca,Leu), 41.2 (Cb,Leu), 36.5 (Cb,Phe), 29.7 (Cb,Thia), 28.0
(CBoc), 23.9 (Cg,Leu), 22.9, 21.6 (Cd,Leu), 17.0 (N-CH2-CH3), 8.5 (“t”,
JRh,C ¼ 22.6 Hz, CCp,Me). e MS (ESIþ): 847.29 [M ꢀ Cl]þ, 891.20, 893.17
[M-Et-HþK]þ. e C39H57Cl2N4O6RhS calc. C, 53.00; H, 6.50; N, 6.34; S,
3.63; found C, 53.64; H, 7.31; N, 7.31; S, 3.97.
C
39H56Cl2N4O6RuS calc. C, 53.17; H, 6.41; N, 6.36; S, 3.64; found C,
50.33; H, 5.94; N, 6.33; S, 3.25.
1.2.9. 9
Acknowledgments
To a dried Schlenk tube charged with molecular sieves (4 Å,
50 mg) were added 5 (62 mg, 0.12 mmol) and Ag2O (14 mg,
0.06 mmol). The mixture was flushed three times with N2 and then
dry CH2Cl2 was added (15 mL). The flask was closed and shaken
overnight in the dark. [RhCp*Cl2]2 (37.2 mg, 0.06 mmol) was added
and the reaction was allowed to shake for another 24 h. The solution
was filtered through celite and the solvent was removed under
reduced pressure. The orange residue was purified by flash column
chromatography (SiO2, CH2Cl2/MeOH, 9:1) and was then recrystal-
lized from CH2Cl2/pentane (10 mL/30 mL) at ꢀ20 ꢁC to yield 9 as an
orange powder (25 mg, 28%). 1H NMR (DMSO-d6, 400 MHz, 25 ꢁC)
We thank the Ruhr-University Research School and the German
Science Foundation DFG (FOR 630) for funding.
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d
¼ 8.36 (1H, d, 3JH,H ¼ 7.9 Hz, NHLeu), 7.63 (1H, s, C¼CH-S), 4.6e4.57
3
(1H, m, Ca,LeuH), 7.20 (d, JH,H ¼ 8.7 Hz, NHThia), 4.52e4.43 (2H,
Ca,LeuH, N-CH2-CH3), 4.40e4.28 (1H, m, N-CH2-CH3, Ca,ThiaH), 3.61
(3H, s, CO2CH3), 3.17e2.99 (2H, m, Cb,ThiaH),1.71e1.44 (21, m, Cb,LeuH,
Cg,LeuH, N-CH2-CH3, Cp(CH3)5), 1.35 (9H, s, Boc), 0.88 (6H, dd,
2
3JH,H ¼ 6.4 Hz, JH,H ¼ 20.7 Hz, Cd,LeuH). e 13C NMR (DMSO-d6,
100 MHz) :
d
¼ 172.7 (COThia), 171.0 (CO2CH3), 170.7 (NCS), 155.2
(Cq,Thia), 147.7 (COBoc), 124.2 (C¼CH-S), 96.3 (“d”, JRh,H ¼ 6.8 Hz,
Cq,Cp ), 78.3 (Cq,Boc), 52.8 (Ca,Thia), 51.9 (CO2CH3), 51.8 (N-CH2-CH3),
*
50.2 (Ca,Leu), omitted bysolvent (Cb,Leu), 29.8 (Cb,Thia), 28.0 (CBoc), 24.1
(Cg,Leu), 22.7, 21.1 (Cd,Leu),17.0 (N-CH2-CH3), 8.3 (CCp,Me). e MS (ESIþ):
700.21 [M ꢀ Cl]þ, 744.0, 746.10 [M-Et-HþK]þ. e C30H48Cl2N3O5RhS
calc. C, 48.92; H, 6.57; N, 5.70; S, 4.35; found C, 46.3; H, 6.53; N, 5.63;
S, 4.66.
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1.2.10. 10
To a dried Schlenk tube charged with molecular sieves (4 Å,
50 mg) were added 6 (83 mg, 0.13 mmol) and Ag2O (15 mg,
0.06 mmol). The mixture was flushed three times with N2 and then
dry CH2Cl2 was added (15 mL). The flask was closed and shaken
overnight in the dark. [RhCp*Cl2]2 (38.7 mg, 0.06 mmol) was added
and the reaction was allowed to shake for another 24 h. The solution
was filtered through celite and the solvent was removed under
reduced pressure. The orange residue was purified by flash column
chromatography (SiO2, CH2Cl2/MeOH, 9:1) and was then recrystal-
lized from CH2Cl2/pentane (10 mL/30 mL) at ꢀ20 ꢁC to yield 10 as an
orange powder (30 mg, 27%). 1H NMR (DMSO-d6, 400 MHz, 25 ꢁC)
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d
¼ 8.40 (1H, d, 3JH,H ¼ 7.6 Hz, NHLeu), 7.94 (d, 3JH,H ¼ 8.4 Hz, NHPhe),
7.58 (1H, s, C¼CH-S), 7.28e7.16 (6H, m, HAr,Phe, NHThia), 4.6e4.57 (1H,
m, Ca,LeuH),4.52e4.43 (3H, m, Ca,PheH, N-CH2-CH3), 4.40e4.28 (1H,
m, Ca,ThiaH), 3.58 (3H, s, CO2CH3), 3.13e2.88 (4H, m, Cb,ThiaH, Cb,PheH),