Molecular diversity approach to the synthesis of peptide-derived ruthenium complexes and their evaluation as oxidation catalysts

Article abstract of DOI:10.1016/S0040-4039(00)00851-0

This paper reports the synthesis of a small library of peptide-derived ruthenium complexes as potential oxidation catalysts. Evaluation of the solid-supported complexes identified several potentially promising epoxidation catalysts. Liberation of the prom

Full text of DOI:10.1016/S0040-4039(00)00851-0

Tetrahedron Letters 41 (2000) 5789±5793
Molecular diversity approach to the synthesis of
peptide-derived ruthenium complexes and their evaluation as
oxidation catalysts
Amarnath Natarajan and Jose S. Madalengoitia*
Department of Chemistry, University of Vermont, Burlington, VT 05405, USA
Received 24 March 2000; accepted 25 May 2000
Abstract
This paper reports the synthesis of a small library of peptide-derived ruthenium complexes as potential
oxidation catalysts. Evaluation of the solid-supported complexes identi®ed several potentially promising
epoxidation catalysts. Liberation of the promising catalysts from the solid-support resulted in catalysts
with improved activity. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: supported reagents/reactions.
The search for new oxidation catalysts with improved eciency and selectivity is a continuing
source of interest in the organic chemistry community. Among these catalysts, the metallo-
porphyrins have been the focus of much attention as alkene oxidants.1 A number of contributions
in this ®eld have shown that the regioselectivity and stereoselectivity2 of these reactions can be
a€ected by the ligand architecture and donor properties around the metal.3 However, the intro-
duction of the structural diversity and varying donor properties necessary for catalyst optimiza-
tion is not easily achieved in porphyrin systems.4 Interestingly, the existence of non-heme-based
biological metal-oxo catalysts5 indicates that the synthesis of a peptide-derived ligand library
could allow the generation of the necessary diversity for the discovery and optimization of novel
oxidation catalysts.6 This work describes the solid-phase synthesis of a small library of solid-
supported peptide-derived ligands (dipeptides) and the evaluation of the corresponding ruthenium
complexes using optimized conditions developed in our laboratories.
Diversity at the C-terminus was generated from elements Fmoc-Asn-OH, Fmoc-Lys(Boc)-OH,
Fmoc-His(Trt)-OH, while diversity at the N-terminus was generated from 9a±c (Scheme 1),
phenanthroic acid and Fmoc-Asn-OH. Fig. 1 summarizes the structures generated. Fragments
1C±3C were chosen because of the availability, simplicity and diverse donor properties of the
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00851-0

5790
side-chain functionality (-NH2, -CONH2 and 4-imidazolyl). Fragments 1N±3N were chosen as
potential tridentate systems possessing a similar structure but signi®cant variations in one of the
donor groups. Fragments 4N and 5N are systems which are easily accessible and are structurally
quite di€erent from the other N fragments. Altogether, the small library generated thus possesses
a number of signi®cantly diverse structures. The synthesis of the diversity elements 9a±c was
accomplished from the known aldehyde 7 (Scheme 1).5 First, the aldehyde was allowed to react
with the appropriate amine and the resultant imine was reduced (H2, Pd±C) a€ording the corre-
sponding secondary amine. Boc protection (Boc2O, CH2Cl2) of the secondary amine and hydro-
lysis of the ester group (NaOH, 1:1 MeOH:H2O) gave the respective acids 9a±c.
Scheme 1. Synthesis of diversity elements 9a±9c and 10
Figure 1. Ligand library composition
A library of 15 ligands was synthesized in a parallel fashion on aminomethylpolystyrene
(AMP) resin using a combination of Fmoc/Boc chemistries and standard peptide coupling pro-
7
.
cedures. The library was then incubated with 1 equiv. of RuCl3 H2O for 72 h at rt under nitrogen
in degassed DMF to generate the ruthenium catalysts. The complexes were evaluated for their
ability to catalyze the oxidation of cis-stilbene (10 equiv.) with PhIO (40 equiv.) in CH2Cl2. The

5791
results from the these reactions are graphically shown in Fig. 2. All ruthenium complexes cata-
lyzed the formation of benzaldehyde and cis-stilbeneoxide (in all cases trans-stilbene oxide was
formed in quantities (ꢀ4%) comparable to the control (PhIO+cis-stilbene)). Some trends in the
product distribution are apparent. More epoxide is formed by complexes possessing a histidine
(3C) at the C-terminus. For example, Ru-3C1N generates more epoxide than Ru-1C1N and Ru-
2C1N; Ru-3C2N generates more epoxide than Ru-1C2N and Ru-2C2N, etc. This trend is also
apparent in the Ru-xC4N and Ru-xC5N series. Of the ligands possessing the fragments 1N, 2N
and 3N, epoxide formation increases as the variable donor changes from amine to amide to aro-
matic nitrogen with Ru-3C3N producing more epoxide than Ru-3C1N and Ru-3C2N; Ru-2C3N
producing more epoxide than Ru-2C1N and Ru-2C2N, etc. The trend that begins to emerge is
that aromatic nitrogen donors in¯uence the character of the catalyst to favor epoxidation over
oxidative cleavage. This trend is further supported by the activity of Ru-3C4N (possessing the
phenanthroline group) and Ru-His-His which forms almost as much cis-stilbene oxide as the
most active complex Ru-3C3N (39%). These data indicate that metal complexes can be ®ne-tuned
to perform better by altering the donor groups and the ligand architecture around the metal
center.
Figure 2. Product distribution in the oxidation reaction of cis-stilbene catalyzed by ruthenium complexes
We also wished to address the performance of some of these catalysts in solution. To this end,
ligands 1C4N, 3C3N, 1C4N and His-His were synthesized on chlorotrityl resin and the respective
Ru complexes were formed as described. Since we have shown that the catalytic activity of AMP-
His-His-Ru is not a€ected by chlorotrityl resin cleavage conditions (1% TFA) we expected that
liberation of the complexes from chlorotrityl resin with 1% TFA would not result in catalyst
decomposition. Accordingly, the complexes Ru-1C4N, Ru-3C3N, Ru-3C4N and Ru-His-His
were synthesized, liberated and evaluated as before [cis-stilbene oxide (10 equiv.) and PhIO (40
equiv.)]. Much to our surprise these performed much better as epoxidation catalysts in solution
(Table 1) with Ru-His-His exhibiting no oxidative cleavage. The origin of these results is not clear

5792
Table 1
Epoxidation activity of resin liberated ruthenium complexes
at this juncture. However, it is apparent that the catalysts Ru-3C3N, Ru-3C4N and Ru-His-His
performed better than Ru-1C4N both in solution and in the solid-phase indicating that it is
appropriate to screen the solid-supported complexes for lead structures.
In conclusion, we have synthesized a small library of peptide-derived ligands with diverse
functionalities. `On bead' evaluation of the corresponding complexes enabled the facile identi®-
cation of active, novel and simple oxidation catalysts. Furthermore, liberation of the catalysts
from the solid-support a€orded superior epoxidation catalysts. Interestingly, a solid-supported
catalyst which quite cleanly a€ords oxidative cleavage has also been identi®ed (Ru-1C1N). This
result is tantalizing in that it suggests the possibility of developing oxidative cleavage catalysts to
carry out kinetic resolutions. These studies have also identi®ed a trend that catalysts possessing
aromatic nitrogen donors increase epoxidation over oxidative cleavage. As a quick test of this
.
hypothesis we have synthesized a new complex (11+RuCl3 H2O) possessing an additional aromatic
nitrogen donor which a€ords more epoxide (52%) than the original lead structures included in
this study. Encouraged by these results, we have begun the synthesis of the next series of ligands
based on a design strategy which uses di€erent ligand architectures and incorporates aromatic
nitrogen donors.
General Procedure for the generation of the library: The ligands were synthesized on AMP resin
(100-200 mesh; 0.5 mmol/g loading, Advanced Chem Tech). All coupling reactions were carried
out in a fritted 10 mL glass-stoppered vial with agitation from a rotary shaker. The resin was
allowed to swell in CH2Cl2 (2Â15 min), washed with 10% Et3N in DMF (2Â5 min) and the ®rst
residue (Fmoc-Asn-OH, Fmoc-Lys(Boc)-OH, Fmoc-His(Trt)-OH) (4 equiv.) was coupled with
DIC/HOBt (4 equiv.) in DMF. The couplings were monitored by the Kaiser test. The resin was
washed with DMF (4Â1 min) and CH2Cl2 (4Â1 min). Fmoc deprotection was accomplished with
20% piperidine in DMF (2Â20 min). The resin was again washed with DMF (4Â1 min) and
CH2Cl2 (4Â1 min). The resulting free amine was coupled with a second residue (1N±5N) as before
except 4N which required HOAt and longer coupling times (8 h). The acid labile protecting
groups were removed using 50% TFA in CH2Cl2 (2Â15 min). The ligands were washed with 10%
Et3N in DMF (2Â5 min) before metal incubation.
General procedure for the synthesis of ClTrt-resin bound ligands: H2N-Xxx-ClTrt (100±200
mesh; 1.0 mmol/g loading) was coupled with the corresponding amino acid (4 equiv. 10, or

5793
phenanthroic acid) using HOAt/DIPC (4 equiv.) in DMF over 90±120 min. Fmoc deprotection
was accomplished with 20% piperidine in DMF (2Â20 min).
Acknowledgements
This work was supported by the American Chemical Society petroleum research fund PRF
5-26407. The amino acids and resins were purchased from Advanced Chemtech.
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