Chiral isocyanoazides: Efficient bifunctional reagents for bioconjugation

Article abstract of DOI:10.1002/ejoc.200901326

Chiral scaffolds combining isocyanide and azide groups can be effectively synthesized to permit the efficient construction of both amino (hydroxy) acids and triazole derivatives, which enables the preparation of hybrid peptide molecules by Ugi/ click or click/Ugi strategies.

Full text of DOI:10.1002/ejoc.200901326

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901326
Chiral Isocyanoazides: Efficient Bifunctional Reagents for Bioconjugation
Valentine G. Nenajdenko,*[a] Anton V. Gulevich,[a] Nadezhda V. Sokolova,[a]
Andrey V. Mironov,[a] and Elizabeth S. Balenkova[a]
Keywords: Isocyanides / Azides / Multicomponent reactions / Click chemistry / Bioconjugation
Chiral scaffolds combining isocyanide and azide groups can
be effectively synthesized to permit the efficient construction
of both amino (hydroxy) acids and triazole derivatives, which
enables the preparation of hybrid peptide molecules by Ugi/
click or click/Ugi strategies.
Introduction
The unusual valence structure of the isocyanide group
and the unique reactivity of isocyanides[1] lend themselves
for the development of multicomponent reactions
(MCRs),[2] such as the Ugi and Passerini reactions, which
are especially effective for synthesis of amino and hydroxy
acids, peptides, and depsipeptides.[3,4] The azide functional
group is also highly reactive and has found many synthetic
applications. In particular, organic azides serve as valuable
intermediates in combinatorial chemistry and in the synthe-
sis of peptides and other nitrogen-containing hetero- and
alicyclic compounds.[5] The discovery of the “click” CuI-
catalyzed Huisgen 1,3-dipolar cycloaddition reaction be-
tween acetylenes and azides opens a very simple and effec-
tive route to the regioselective synthesis of 1,2,3-triazoles.[6]
Click chemistry was demonstrated to be useful for the as-
sembly of functional units into one molecule by using the
1,2,3-triazole moiety as a fastening knot.[7]
The simultaneous incorporation of isocyanide and azide
functionalities into one substrate permits one to combine
the transformation of the isocyanide group into a peptide
fragment with connection by an azide group to another
valuable fragment (Scheme 1). Moreover, the 1,2,3-triazolyl
moiety, readily available by the click chemistry protocol,
was found to be an effective amide bond surrogate that can
mimic peptides.[8] Therefore, triazolo-modified peptides can
serve as efficient peptidomimetics with improved medicinal
properties such as solubilization, hydro(lipo)philicity, en-
zyme binding, and transport of biomolecules in living sys-
tems (modified lipids, sugars, etc).[9]
Scheme 1. Isocyanoazides
“clickable” peptides.
– precursors for the synthesis of
Natural proteins such as glycoproteins, lipoproteins, and
protein–porphyrin complexes (myoglobin, hemoglobin)
often function as complex aggregates that incorporate other
fragments. Artificial conjugated biopolymers consisting of
a protein part connected with other biomolecules by a tri-
azole moiety can be used as blood components,[10] antican-
cer medications,[11] and HIV protease inhibitors.[12] There-
fore, a facile approach to the ligation of proteins, peptides,
or their mimics with biologically important molecules or
polymers is extremely desirable.[13]
Another prospective application of isocyanoazides is in
supramolecular chemistry and related fields. Such common
functional units as fullerenes, porphyrins, phthalocyanines,
calixarenes, crown ethers, polyaromatics, carboranes, and
ferrocene can be equipped with a chiral peptide backbone.
These hybrid molecules would offer interesting possibilities
for advanced structural design, such as self-assembly to chi-
ral helices.
[a] Department of Chemistry, Moscow State University,
Leninskije Gory, 199991 Moscow, Russia
Fax: +7-495-9328846
Isocyanides[14] and azides[15] also play important roles in
coordination chemistry. Therefore, isocyanoazides can be
used as efficient ligands for the synthesis of new promising
E-mail: nen@acylium.chem.msu.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901326.
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V. G. Nenajdenko et al.
SHORT COMMUNICATION
complexes. Moreover, polymerization of isocyanoazides op- Passerini reactions were performed with different substrates
ens broad possibilities for preparation of azido-modified to demonstrate the high efficiency and synthetic utility of
polymeric materials.[16]
isocyanoazides 5a–e. In all cases, the corresponding prod-
Several examples of azido-substituted amino acids[17] ucts 6 and 8 were obtained in good yields (Table 1,
and azido acids[18] appeared recently in the literature as pro- Scheme 3).
spective building blocks for the synthesis of peptides. How-
ever, use of isocyanoazides opens the way to a more diverse
approach owing to the possibility of constructing modified
peptide molecules with both natural and unnatural amino
acids in one step by divergent synthesis. Currently, there
are only two literature examples of a molecule having both
isocyano and azide groups. Zhu et al. developed a molecule
in which isocyanide and azide groups are connected by an
eight-atom chain.[19] Michelin et al. used 2-(azidomethyl)-
phenyl isocyanide as a ligand for transition metals.[20]
In this paper, we report the synthesis of chiral scaffolds
with isocyanide and azide groups in one molecule as a new
type of linker permitting the construction of both amino
(hydroxy) acids and triazole derivatives and the preparation
of peptide-modified molecules by Ugi/click or click/Ugi
strategies.
The presence of an azido group in the products 6 of the
Ugi reaction allows subsequent triazole formation affording
1,2,3-triazolyl-substituted peptides 7. The click reaction
proceeds regioselectively in high yields with a model acetyl-
ene (phenyl propargyl ether). The best yield was obtained
with CuI·P(OEt)3 as a catalyst. Consequently, we have de-
veloped an “Ugi/click” strategy for the synthesis of tri-
azolo-modified peptide molecules 7. It is noteworthy that
the Ugi reaction and subsequent cycloaddition can be per-
formed in a “one-pot” tandem reaction sequence without
decreasing the yields (as an example, 7a can be obtained in
50% yield).
Isocyanoazides 5 themselves are promising compounds
for the preparation of chiral isocyanotriazoles by click
chemistry. However, we found that it is impossible to in-
volve 5 in a click reaction directly (triazole 11 is not
formed): apparently, formation of stable CuI complexes 9
takes place under these reaction conditions. To confirm this
suggestion, we have synthesized complexes 9a,b in excellent
yields. This observation demonstrates the bidentate nature
of 5 as a new type of chiral ligand (Scheme 4).
According to the X-ray data, 9a packs as a coordination
polymer in which copper is coordinated strongly to both
the isocyanide carbon and the α-nitrogen of the azide group
(Figure 1). It is noteworthy that azides usually coordinate
CuI through a terminal γ-nitrogen with a bond angle of
approximately 180°,[15] whereas, in the case of 9a, coordina-
tion by α-nitrogen takes place. This can be attributed to the
effect of chelation with a second isocyanoazide molecule via
a 16-membered cycle. Therefore, due to their bifunctional
nature, isocyanoazides 5 are promising ligands for transi-
tion metals.
Results and Discussion
The starting point of the work was to develop an ef-
ficient, universal, and atom-economic strategy for synthesis
of isocyanoazides from commercially available -amino
alcohols 1 (Scheme 2). The key transformation is a “one-
pot” sequence in which the formation of mesylates is fol-
lowed by dehydration of the formamide moiety to give iso-
cyanides 4 in excellent yields. Isocyanides 4 containing a
good leaving group undergo facile nucleophilic substitution
with sodium azide to afford target isocyanoazides 5 in good
yields.
It is noteworthy that, despite their high nitrogen content
(for 5a: C3H4N4, N 58.3%), isocyanoazides are quite stable
compounds at the room temperature and can be distilled in
vacuo below 50 °C.[21] NMR spectroscopic and GC analy-
Copper complexes 9 by themselves are not effective self-
ses of isocyanide 5d prepared from -isoleucinole (contain- catalysts for the Huisgen 1,3-dipolar cycloaddition. How-
ing an additional stereocenter) showed a stereochemical pu- ever, formation of isocyanotriazoles 10 from azide com-
rity higher than 99% de, indicating that no racemization plexes 9 readily occurs under standard conditions with ex-
had occurred during the steps of the synthesis.
ternal CuI catalysis. Triazoles 10 can be isolated quantita-
The optical purity of the isocyanoazides was further con- tively as copper complexes. Deprotected isocyanotriazoles
firmed by Ugi reactions with -α-phenylethylamine 11 are obtained by treatment with a strong CuI complex-
1
(Table 1). Presence of a single set of signals in H and 13C ation agent. We found Na2S2O3 to be a very practical new
NMR spectra of products 6b–e (Table 1, entries 2–5) indi- reagent for the deprotection, which is superior to the highly
cates the formation of a single diastereomer. The Ugi and toxic cyanides used in the literature. Consequently, com-
Scheme 2. Synthesis of isocyanoazides.
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Chiral Isocyanoazides: Efficient Bifunctional Bioconjugation Reagents
Table 1. Synthesis of modified amides.
[a] de Ͼ 99%. [b] dr ≈ 1:1.
plexation of isocyanide with CuI can be used as a protection
strategy for the isocyanide residue. A number of triazole-
containing isocyanides 11 was obtained in good yields by
this simple “one-pot” procedure (Table 2).
Table 2. Synthesis of modified amides.
Scheme 3. Passerini reaction with isocyanoazides.
Scheme 4. Synthesis of Cu isocyanoazide complexes.
The Ugi reaction with Boc-glycine allows one to obtain
“clickable” peptide 12 containing the azide “fastener”. Sub-
sequent cycloaddition leads to triazole-containing peptide
13 in a good yield (Scheme 5). It should be noted that isocy-
anides 11 also can undergo multicomponent reactions to
afford triazolo-modified peptide molecules like 13.
Figure 1. X-ray analysis of complex 9a.[22]
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V. G. Nenajdenko et al.
SHORT COMMUNICATION
was demonstrated to be an efficient protection/deprotection
protocol for this valuable functionality. The chemistry de-
scribed in this work opens access to “clickable” peptides
equipped with the azide “fastener”. We also demonstrated
that azidoisocyanides are effective for the divergent synthe-
sis of hybrid peptide molecules.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details and copies of NMR spectra.
Acknowledgments
This work was financially supported by Russian Federal Agency of
Education, Grant P2063. We thank Dr. B. V. Lokshin for the op-
tical rotation measurements.
Scheme 5. Synthesis of “clickable” and triazolo-modified peptides.
Furthermore, this strategy is effective for the conjugation
of a peptide fragment with other biomolecules. As an
example, we synthesized cholesterol derivative 15, con-
sisting of peptide and cholesterol, connected by a triazole
linker, by cycloaddition of clickable peptide 12 to propargyl
cholesterol 14.[23] Binding of this peptide fragment to
cholesterol changed the properties of this extremely impor-
tant biomolecule dramatically, which can be useful for the
creation of new potent drugs (Scheme 6).[24]
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In summary, we have suggested an efficient route to chi-
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Chiral Isocyanoazides: Efficient Bifunctional Bioconjugation Reagents
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Published Online: February 1, 2010
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