A photochemical route for efficient cyclopeptide formation with a minimum of protection and activation chemistry

Article abstract of DOI:10.1021/ja025804o

An elaborated protocol is described which allows the efficient transformation of di-, tri-, and tetrapeptides into cyclopeptides with a minimum of protection and activation chemistry using the photoinduced electron transfer initiated decarboxylation of N-phthaloyl peptides resulting in C-C coupling between the initially formed carbon radicals. Copyright

Full text of DOI:10.1021/ja025804o

Published on Web 08/23/2002
A Photochemical Route for Efficient Cyclopeptide Formation with a Minimum
of Protection and Activation Chemistry
Axel G. Griesbeck,* Thomas Heinrich, Michael Oelgemo¨ller, Johann Lex, and Arne Molis
Institute of Organic Chemistry, UniVersity of Cologne, Greinstrasse 4, D-50939 Ko¨ln, Germany
Received February 4, 2002
Scheme 2
Synthetic cyclic oligopeptides can depict reactive conformational
motifs of bioactive oligopeptides1 and are thus intensively inves-
tigated as peptidomimetica,2 as pharmaceutically active low-
molecular weight analogues3 or as artificial arrays with defined
nanostructures.4 Synthetic routes to these target structures are
numerous, taking advantage of the highly developed techniques in
peptide synthesis.5 Due to the fact that these compounds are
macrocyclic polylactams, the fundamental restrictions in (thermal)
macrocyclization chemistry have to be considered.6 Photochemical
Scheme 3
macrocyclizations constitute an alternative class of reactions which
often are controlled by the excited-state rather than ground-state
properties.7 Following our studies on the intramolecular photo-
decarboxylation of ω-phthalimido alkyl carboxylates8 and its
intermolecular version9 in aqueous media, this concept was also
investigated as a general route to macrocyclic products (Scheme
1).10 In fact, the synthesis of medium- and macrocyclic amines,11
lactones,12 polyethers,11 thioethers,13 as well as cycloalkynes14 was
acid (Auda). The photolyses (λ ) 300 nm) were performed in water/
realized.15
acetone mixtures at initial pHinit values of 6-7. Analogous to that
in the Ala-Pro derivative,16 protection of the primary amide group
Scheme 1. Photoinduced Electron Transfer Decarboxylation/
Cyclization Reaction of ω-Phthalimido Alkylcarboxylates with
Divergent Linker Chains (L1, L2) And Spacer Functional Groups X
restored the cyclization activity, and already the sarcosine substrate
Gly-Sar gave the six-membered lactam in 53% yield. From these
first trials we suspected that a secondary amide is not applicable
as primary functional group in the peptide tether due to the
hydrogen-bonding hypothesis.11,17 Photochemical reactivity was,
however, recovered by using longer secondary spacer chains
(Scheme 3); the Gly-âAla couple gave solely the decarboxylation/
hydrogen transfer product, but longer amino acids as second
components also restored the cyclization activity. For example, the
Gly-ꢀAca substrate gave the 10-membered product in 69% yield.
Thus, hydrogen-bonding deactivation can be overwritten by using
the appropriate substitution pattern.
Another way to improve the photocyclization efficiency is to
increase of the chain lengths of the primary amino acid tether;
whereas the âAla-Gly substrate gave only 24% of the corresponding
seven-membered lactam, the âAla-âAla couple gave the eight-
membered lactam already in 32% yield, and the ꢀAca-âAla substrate
resulted in the 11-membered lactam in 55% yield.18
The lactams 1a,b were characterized by X-ray structure analyses
(Figure 1). The product 1a from the âAla/γ-aminobutyric acid pair
(ring size: 9) has the E-amide configuration; in the larger ring 1b
(ring size: 10) from the Gly-ꢀAca pair the amide configuration
switched to Z.19
To further explore the scope of this reaction and to develop a
flexible route to cyclopeptides using the photodecarboxylation/
cyclization protocol, we investigated a series of C-unprotected di-
and tripeptides activated by the N-terminal phthalimide functional-
ity. The basic concept is shown schematically for a cyclic peptide
incorporating a tripeptide motif in Scheme 2: a chromo-/electro-
phore which is N-terminal AA1-linked to an oligopeptide chain
serves as excited-state electron acceptor and oxidizes the C-terminal
carboxylate group with subsequent extrusion of CO2 and cyclization.
In preliminary studies we, however, did not succeed in cyclizing
the phthalimide substrate of the Gly-Gly dipeptide,11 indicating that
hydrogen bonding between the imido carbonyl groups and a
proximate amide NH might deactivate the electron-transfer reactiv-
ity and interfere with the cyclization step. When this hydrogen
bond was inhibited, as for example in N-phthaloyl Ala-Pro, photo-
cyclization occurred in moderate yields.16
As primary spacers AA1, unbranched ω-amino acids were applied
with increasing (CH2)n spacer lengths of n ) 1, 2, 3, 5, 10, and 11.
As the C-terminal amino acid we used glycine, sarcosine (Sar),
â-alanine (âAla), ꢀ-aminocaproic (ꢀAca), and 11-aminoundecanoic
* To whom correspondence should be addressed. E-mail: griesbeck@uni-
koeln.de.
Figure 1. Structures of the products 1a,b in the crystal.
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J. AM. CHEM. SOC. 2002, 124, 10972-10973
10.1021/ja025804o CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Scheme 4
and is applied for more complex structures in ongoing work. These
preliminary results suffer from medium chemical yields due to
substantial hydrolysis at high pH, a competing process which can
be suppressed using buffered aqueous conditions.18
Acknowledgment. This research was supported by the Deutsche
Forschungsgemeinschaft.
Supporting Information Available: Details of the photocyclization
reactions, NMR-spectroscopic data of selected photocyclization prod-
ucts, pH reaction profiles, and X-ray crystallographic data of 1a and
1b (PDF). An X-ray crystallographic file of 1a (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 5
References
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Scheme 6
(3) For example, the RGD-containing cyclopeptides: (a) Haubner, R.; Gratias,
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The chain elongation concept proved to be also successful for
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tripeptide substrates; the photocyclization path was still active when
longer amino acid spacers were used as the first (i.e., AA1-Gly-
Gly, Scheme 4) or third (i.e., Gly-Gly-AA3, Scheme 5) component.
The triglycine derivative20 resulted in decarboxylation and unse-
lective photodecomposition. Elongating the primary linker chain
stepwise increased the cyclization efficiacy: from âAla (m ) 2,
24%), to ꢀAca (m ) 5, 42%) and Auda (m ) 10, 57%). All
experiments were conducted under the same substrate concentration
conditions (10 mM), and thus dilution effects cannot be responsible
for the high yields of photocyclization products. Likewise, the
diglycine-linked tripeptides PhtdGlyGlyAA3 became reactive for
chain-elongated amino acids as the internal tethers. In this series,
the âAla substrate resulted solely in photosolvolysis. Photocycliza-
tion was observed with AA3 ) γ-aminobutyric acid (n ) 3, 36%),
ꢀAca (n ) 5, 51%), and Auda (m ) 10, 69%). Diglycine-containing
cyclopeptides are thus available in flexible chain modifications
which appear important for the design of new â-turn mimetica.21
One step further in this protocol, the N-phthaloyl derivative of
the tetrapeptide Gly-Pro-Gly-Gly (2) was synthesized by standard
coupling and deprotection procedures from N-phthaloyl glycine,
proline, and diglycine in 68% yield. The irradiation of this substrate
was performed in a 4:1 water/acetone mixture with 0.5 equivalents
of potassium carbonate and resulted in the 12-membered cyclo-
peptide 3 in 34% yield (Scheme 6). A control (dark) experiment
showed that the pH is constant over the reaction time, whereas
photolysis led to a substantial increase in pH. Consequently,
continuous pH control served as a useful analytic tool to follow
the progress and to identify the chemoselectivity of the reaction.22
Whereas photosolvolysis or solvolysis in general resulted in a slight
decrease in pH (due to the formation of a phthalamide acid),
photocyclization went parallel with a strong increase in pH. The
latter effect is due to the charge shift from the carboxylate anion
to give an alkoxide which leads to an increase in OH- concentra-
tion.23
(9) (a) Griesbeck, A. G.; Oelgemo¨ller, M. Synlett 1999, 492-494. (b)
Griesbeck, A. G.; Oelgemo¨ller, M. Synlett 2000, 71-72. (c) Griesbeck,
A. G.; Oelgemo¨ller, M.; Lex, J. Synlett 2000, 1455-1457.
(10) Griesbeck, A. G.; Kramer, W.; Oelgemo¨ller, M. Synlett 1999, 1169-
1178.
(11) Griesbeck, A. G.; Henz, A.; Kramer, W.; Lex, J.; Nerowski, F.;
Oelgemo¨ller, M.; Peters, K.; Peters, E.-M. HelV. Chim. Acta 1997, 80,
912-933.
(12) Griesbeck, A. G.; Nerowski, F.; Lex, J. J. Org. Chem. 1999, 64, 5213-
5217.
(13) Griesbeck, A. G.; Oelgemo¨ller, M.; Lex, J.; Haeuseler, A. Schmittel, M.
Eur. J. Org. Chem. 2001, 1831-1843.
(14) Yoo, D. J.; Kim, E. Y.; Oelgemo¨ller, M.; Shim, S. C. Heterocycles 2001,
54, 1049-1055.
(15) A highly efficient alternative photochemical route to macrocycles uses
the PET-desilylation of R-trialkylsilylmethyl ethers and -thioethers: (a)
Yoon, U. C.; Oh, S. W.; Lee, J. H.; Park, J. H.; Kang, K. T.; Mariano, P.
S. J. Org. Chem. 2001, 66, 939-943. (b) Yoon, U. C.; Mariano, P. S.
Acc. Chem. Res. 2001, 34, 523-533.
(16) Griesbeck, A. G.; Kramer, W.; Bartoschek, A.; Schmickler, H. Org. Lett.
2001, 3, 537-539.
(17) Oelgemo¨ller, M.; Griesbeck, A. G.; Lex, J.; Haeuseler, A.; Schmittel, M.;
Niki, M.; Hesek, D.; Inoue, Y. Org. Lett. 2001, 3, 1593-1596.
(18) Griesbeck, A. G.; Heinrich, M.; Lex, J.; Oelgemo¨ller, M.; Molis, A.;
Heidtmann, A. HelV. Chim. Acta 2002. In print.
(19) Typical for the transition in lactam ring size: Endo, Y.; Ohno, M.; Hirano,
M.; Itai, A.; Shudo, K. J. Am. Chem. Soc. 1996, 118, 1841-1855.
(20) Prepared by the Nefkens procedure (Nefkens, G. H. L. Nature 1960, 185,
309) using strongly reduced reaction times (complete conversion for Phtd
glyglygly after 15 min at room temperature).
(21) See, for example, the Gly-Gly-Aca cyclotripeptides: MacDonald, M.;
Velde, D. V.; Aube´, J. Org. Lett. 2000, 2, 1653-1655.
(22) Griesbeck, A. G.; Kramer, W.; Oelgemo¨ller, M. Green Chem. 1999, 1,
205-207.
(23) Go¨rner, H.; Oelgemo¨ller, M.; Griesbeck, A. G. J. Phys. Chem. A 2002,
106, 1458-1464.
In summary, this protocol represents a new route for cyclopeptide
formation with a minimum of protection and activation chemistry
JA025804O
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