π-Ligands for generating transition metal-peptide complexes: Coordination of amino acid derivatives to tungsten utilizing alkyne ligands

Article abstract of DOI:10.1021/ol026298a

(figure presented) Amino acid derivatives bearing an alkyne (AA-CCH) at either the N- or C-terminus readily react with W(CO)₃(S₂CNMe₂)₂ to replace the carbon monoxides and form the novel bis-alkyne complexes W(A

Full text of DOI:10.1021/ol026298a

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2917-2920
π-Ligands for Generating Transition
Metal−Peptide Complexes: Coordination
of Amino Acid Derivatives to Tungsten
Utilizing Alkyne Ligands
Timothy P. Curran,*,†,‡ Arlicia L. Grant,† Rebecca A. Lucht,† Joi C. Carter,‡ and
Jesse Affonso‡
Department of Chemistry, Trinity College, Hartford, Connecticut 06106-3100, and
Department of Chemistry, College of the Holy Cross,
Worcester, Massachusetts 01610-2395
timothy.curran@trincoll.edu
Received June 4, 2002
ABSTRACT
Amino acid derivatives bearing an alkyne (AA-CCH) at either the N- or C-terminus readily react with W(CO)3(S CNMe2)2 to replace the carbon
2
monoxides and form the novel bis-alkyne complexes W(AA-CCH)2(S CNMe2)2; the solution behavior of these complexes shows that only the
2
alkyne, and not the other functional groups on the amino acid, bonds to the tungsten.
Most short peptides do not adopt well-defined conformations
because the energy differences between the possible con-
formations open to them are not substantial.1 The tendency
of short peptides to assume a myriad of conformations can
be overcome by adding constraints that limit the conforma-
tional freedom of the peptide. The addition of covalent
constraints has been successfully employed for maintaining
peptides in helix, turn, and sheet conformations.2 In other
cases helices and sheets have been generated by coordination
of a transition metal to ligands located on the peptide.2,3
The use of metal-ligand interactions for controlling
peptide conformation is attractive for a number of reasons.
First, the generation of a metal-ligand complex can usually
be achieved in fewer steps than the somewhat lengthy and
complicated syntheses that have been described for co-
valently constrained peptides. Second, there are a wide
variety of transition metal-ligand combinations that might
be employed. Third, the transition metal provides an easy
spectroscopic handle for assessing the behavior and reactivity
of the ordered peptide. Fourth, the presence of a transition
metal in the peptide can greatly facilitate the determination
of an X-ray crystal structure.
We are seeking to uncover new approaches for controlling
peptide conformation through the use of transition metal-
peptide interactions. In particular, we are seeking to identify
ligands that (1) can be easily introduced anywhere (N-
terminus, C-terminus, or side chain) onto a peptide, (2) are
unreactive under the normal conditions of peptide synthesis,
(3) would readily react with a transition metal complex under
† Trinity College.
‡ College of the Holy Cross.
(1) Dill, K. A. Biochemistry 1990, 29, 7133.
(2) Schneider, J. P.; Kelly, J. W. Chem. ReV. 1995, 95, 2169.
(3) DeGrado, W. F.; Summa, C. M.; Pavone, V.; Nastri, F.; Lombardi,
A. Annu. ReV. Biochem. 1999, 68, 779.
10.1021/ol026298a CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/27/2002

conditions that maintain the structural integrity of the peptide,
and (4) could maintain two or more peptides around the
transition metal.
of an N-protected amino acid active ester (6a,b) (either
nitrophenyl or hydroxysuccinimidyl esters) with propargyl-
amine hydrochloride (7) to yield the derivatives 8a,b.
Two molar equivalents of these alkynyl amino acids (AA-
CCH ) 4a, 5a,b, 8a,b) were subsequently reacted with one
molar equivalent of W(CO)3(S2CNMe2)2 [W(CO)3(dmtc)2]8
in refluxing methanol under an inert atmosphere (Scheme
2). Upon addition of the alkynyl amino acid to the rust orange
To date, most investigations of peptide-ligand chemistry
have focused on the use of basic ligands (both natural and
unnatural) on the peptide for metal binding.4 In contrast the
ability of π-ligands on the peptide for metal binding has
received very little study.5,6 As an entry into such investiga-
tions, we were drawn to the capacity of tungsten and
molybdenum dithiocarbamate complexes to form air-stable,
d4 mono- or bis-alkyne complexes.7 From the literature on
these complexes we reasoned that an alkyne met the four
criteria for the type of ligand we were seeking.
Scheme 2. Preparation of Bis-Alkyne Complexesa
To probe the feasibility of this ligand, the alkynyl amino
acid derivatives shown in Scheme 1 were prepared. The
a Reagents and conditions: (a) MeOH, reflux, 2-24 h.
Scheme 1. Preparation of Alkynyl Amino Acidsa
solution of W(CO)3(dmtc)2 the color quickly changed to a
deep green, which indicated that the tungsten complex had
coordinated the first alkyne ligand.9 After a period of 2-24
h the solution color eventually changed from deep green to
a pale, lemon yellow, which indicated that the tungsten had
coordinated the second alkyne ligand.10,11 Once the solutions
had become pale yellow reflux was halted. The methanol
was removed by rotary evaporation and the crude tungsten
bis-alkynyl amino acid was purified to homogeneity by flash
chromatography. Product purity was assessed by thin-layer
chromatography.
The products isolated from these reactions were identified
as the bis-alkyne complexes W(AA-CCH)2(dmtc)2 (AA-CCH
) 4a, 5a,b, 8a,b) with several methods of analysis. First,
each purified complex yielded a combustion analysis for
carbon, hydrogen, and nitrogen that was consistent with the
expected structure of the product.
Second, three of the complexes (W(AA-CCH)2(dmtc)2,
AA-CCH ) 5a,b, 8b) were analyzed by electrospray mass
spectrometry (ESMS). Until recently it was thought that, in
general, organometallic species were too fragile for analysis
by mass spectrometry. However, the advent of ESMS has
allowed for the analysis of organometallics by mass spec-
trometry.12 Methanol solutions of these tungsten bis-alkynyl-
amino acids yield signals for M + H, M + Na, and M +
2Na ions. Owing to the presence of the four major tungsten
isotopes, these ions appear in unique and distinctive patterns.
Thus, correlation of the actual ion pattern to the theoretical
pattern can serve as confirmation of the structure. Shown in
Figure 1 are the theoretical13 and actual isotope patterns for
the M + H ion derived from the complex W(5b)2(dmtc)2.
a Reagents and conditions: (a) EDC or DCC, DIEA, CH2Cl2;
(b) DIEA, CH2Cl2.
alkyne ligand was readily introduced at the N-terminus via
acylation of an amino acid ester hydrochloride (3a,b) with
either 4-pentynoic acid (1) or 5-hexynoic acid (2), using a
carbodiimide mediated coupling reaction to yield the deriva-
tives 4a and 5a,b, respectively. Alternatively, the alkyne
ligand was readily introduced at the C-terminus by reaction
(8) Burgmayer, S. J. N.; Templeton, J. L. Inorg. Chem. 1985, 24, 2224.
(9) Templeton, J. L.; Herrick, R. S.; Morrow, J. R. Organometallics 1984,
3, 535.
(10) Herrick, R. S.; Templeton, J. L. Organometallics 1982, 1, 842.
(11) Morrow, J. R.; Tonker, T. L.; Templeton, J. L. J. Am. Chem. Soc.
1985, 107, 5004.
(12) (a) Henderson, W.; Nicholson, B. K.; McCaffrey, L. J. Polyhedron
1998, 17, 4291. (b) Traeger, J. C. Int. J. Mass Spectrom. 2000, 200, 387.
(13) Theoretical isotope patterns were calculated with a program available
at a website provided by the University of Sheffield: http://www.shef.ac.uk/
chemistry/chemputer/.
(4) Severin, K.; Bergs, R.; Beck, W. Angew. Chem., Int. Ed. Engl. 1998,
37, 1634.
(5) (a) Zahn, I.; Polborn, K.; Wagner, B.; Beck, W. Chem. Ber. 1991,
124, 1065. (b) Steiner, N.; Nagel, U.; Beck, W. Chem. Ber. 1988, 121,
1759.
(6) Sewald, N.; Gaa, K.; Burger, K. Heteroat. Chem. 1993, 4, 253.
(7) Templeton, J. L. AdV. Organomet. Chem. 1989, 29, 1.
2918
Org. Lett., Vol. 4, No. 17, 2002

1
Figure 2. The H NMR spectrum of W(5b)2(dmtc)2 dissolved in
CDCl3 in the region between 10.8 and 11.2 ppm. The resonances
that appear here arise from the terminal alkyne hydrogens in the
tungsten bis-alkyne complexes. Four separate resonances (labeled
a-d) for terminal alkyne hydrogen are seen. Resonances b and c
are derived from the cis isomer, while resonances a and d are
derived from the trans′ and trans′′ isomers.
Figure 1. (a) The theoretical isotope pattern expected for the M
+ H ion in the ESMS spectrum of W(5b)2(dmtc)2. (b) The ESMS
of the lysine bis-alkyne complex, W(5b)2(dmtc)2. The spectrum
shows the M + H ions in the region from m/z 1128 to 1142.
plexes. When two terminal alkynes coordinate to tungsten
or molybdenum to form bis complexes, there are several
possible arrangements of the alkynes relative to each other
(see Scheme 3). The two alkynes can be cis to each other,
That the theoretical and actual isotope patterns form a nearly
identical match confirms the structure of W(5g)2(dmtc)2.
To confirm that only the alkynes, and not the other
functional groups associated with the amino acid derivatives,
were bonding to the tungsten, the UV-visible spectra of each
complex was recorded. Each complex was colored yellow,
both in the solid state and in solution, and each complex
displayed nearly identical absorption spectra that are char-
acterized by a shoulder peak located around 330 nm. Both
the yellow color of the complexes and the nearly identical
UV-visible spectra indicate that only the alkyne, and not
the other functional groups associated with the amino acid
derivative, bonds to the tungsten.
Scheme 3. Conformational Isomers
The structure and bonding in these complexes was further
confirmed by their 1H NMR spectra. Resonances from both
the alkynylamino acid and the dithiocarbamate were present
and possessed area integrations consistent with the bis-alkyne
1
structure. Further, the H NMR spectra all showed a set of
resonances located around 11.1 ppm that possessed a relative
integration equal to two hydrogens. These resonances in the
1H NMR spectrum of W(5b)2(dmtc)2 are shown in Figure
2. As noted in previous work with bis-alkyne complexes
derived from simple, terminal alkynes, the alkyne hydrogen
resonates around 11.0 ppm.10 The similar location of the
alkyne hydrogen in these alkynylamino acid complexes
indicates again that only the alkyne is involved in the bonding
to the tungsten.
or they can be trans to each other. Owing to the presence of
the dithiocarbamate ligands there are two different trans
orientations (trans′ and trans′′ in Scheme 3). The trans′ and
trans′′ conformations are differentiated by the magnetic
environments of the terminal alkyne hydrogens. Although
the two terminal alkyne hydrogens in the trans′ conformation
As seen in Figure 2, the terminal alkyne hydrogens in these
complexes do not appear as a simple singlet; rather, they
appear as a complex pattern of resonances. This complex
pattern for the terminal alkyne hydrogens serves as a window
on the conformational behavior of these bis-alkyne com-
Org. Lett., Vol. 4, No. 17, 2002
2919

are identical with each other, they are distinctly different
from the two terminal alkyne hydrogens in the trans′′
conformation. In the 1H NMR spectrum each of the two trans
conformers should give rise to one signal arising from the
terminal alkyne hydrogens. In contrast, in the cis arrange-
ment, the two terminal alkyne hydrogens are in different
magnetic environments so this conformer should give rise
to two separate signals in the 1H NMR spectrum. This pattern
of resonances can then be further complicated by long-range
coupling and/or the presence of conformational isomers
associated with the amino acid.
The results presented here demonstrate that the alkyne
meets the four criteria needed for coordination of peptides
to a transition metal. The alkyne is unreactive during normal
peptide synthesis. It is easily appended to the N- or C-termini
(or by extension, to acid or amine side chain groups) of
amino acid derivatives with use of standard amide bond
forming reactions. The alkyne readily reacts with W(CO)3-
(dmtc)2 to form novel bis-alkyne complexes, and the peptide
backbone of these amino acid derivatives does not inhibit
or interfere with the transition metal-ligand chemistry. That
these complexes also can adopt a cis arrangement of the two
alkyne ligands, even with an attached amino acid, demon-
strates that these species have the potential to order the
conformation of larger alkynylpeptides through interstrand
hydrogen bonding. Studies to explore this possibility are in
progress.
As seen in Figure 2, four signals are visible for the terminal
alkyne hydrogens in W(5b)2(dmtc)2. The other bis-alkyne
complexes derived from the alkynylamino acids shown in
Scheme 1 also display similar patterns with their terminal
alkyne hydrogens. The appearance of these signals indicates
that these complexes adopt all three conformations about the
metal: cis, trans′, and trans′′ (Scheme 3). This behavior is
similar to that of bis-alkyne complexes derived from simple,
terminal alkynes; they also adopt all three conformations in
solution.10 This conformational isomerism is manifested in
other parts of the 1H NMR spectra of these complexes, where,
for example, multiple peaks are seen for the amide NH
protons and the dithiocarbamate methyl groups. The overall
Acknowledgment. Financial support was provided by the
National Science Foundation (NSF-RUI grant CHE94-17783
to T.P.C.) and the Camille and Henry Dreyfus Foundation
(Henry Dreyfus Teacher-Scholar Award to T.P.C.). Fruitful
conversations with Professor Richard Herrick (College of
the Holy Cross) and Professor David Henderson (Trinity
College) are gratefully acknowledged.
1
appearance of the H NMR spectra is consistent with a
dynamic system in which there is an equilibrium between
the three conformers. For our purposes, the observation that
these alkynylamino acid complexes can adopt the cis
conformation is encouraging, because this is the orientation
that would permit hydrogen bonding (or other intermolecular
attractions) between two adjacent peptides linked to the
tungsten via an alkyne appendage.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026298A
2920
Org. Lett., Vol. 4, No. 17, 2002