Tetrahedron Letters
Photochemical synthesis of cyclic peptide models from phthalimido
acetamides and phthaloyl dipeptide esters
a
a
a
a
a
b
Katrin Krüger , Virginia Lübke , Jonathan Pettinger , Luke Ashton , Laetitia Bonnet , Cherie A. Motti ,
c,1
a,
⇑
Johann Lex , Michael Oelgemöller
a
James Cook University, College of Science and Engineering, Townsville, Queensland 4811, Australia
Australian Institute of Marine Science (AIMS), Biomolecular Analysis Facility, Townsville, Queensland, Australia
University of Cologne, Institute of Organic Chemistry, Greinstrasse 4, D-50939 Cologne, Germany
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
The photochemistry of several phthalimido acetamides and phthaloyl dipeptide esters has been investi-
gated. Their photocyclization ability strongly depended on the substitution pattern of the amide linker
group. While secondary amide-derived starting materials were largely unreactive, the corresponding ter-
tiary amide-linked derivatives furnished the desired cyclic peptide model compounds in acceptable to
good yields (41–80%). The structurally related ester-linked model derivatives also remained unreactive
upon irradiation. Preferential hydrogen-abstraction from the E-cis-substituent is suggested to explain
the observed differences in cyclization ability.
Received 6 January 2018
Revised 21 February 2018
Accepted 26 February 2018
Available online xxxx
Keywords:
Phthalimide
Photochemistry
Photocyclization
Hydrogen-abstraction
Cyclic peptide models
Ó 2018 Elsevier Ltd. All rights reserved.
Due to their biological importance, the photochemistry of
amino acids and peptides has been intensively studied over the
past decades. Photoinduced electron transfer cyclization reactions
increased solubility of the starting material and product in acetone
and the reduced toxicity of this co-solvent, all subsequent irradi-
ations were performed in a 1:1 acetone/water mixture.
7
1
of their related N-protected phthaloyl derivatives have likewise
The secondary amide linked phthalimido acetamides 4a and
4b underwent partial photodecomposition and remaining starting
materials were recovered in 88% and 85% yield, respectively, after
exhaustive irradiation for 48 h (Scheme 2). The rigid Z-trans-con-
formation and the likely formation of a solvent shell around the
secondary amide linker in the starting materials 4a and 4b, in
combination with the required E-cis-conformation in the prospec-
tive products 5a and 5b prevent successful cyclization.8
Compound 5a is also known to be unstable and decomposes by
2
been widely explored. In contrast, the photocyclization of phthal-
3
imido acetamides by hydrogen-abstraction are rather rare. The
photochemistry of a series of phthalimido acetamides and phtha-
loyl dipeptide esters, both readily accessible by standard peptide
4
coupling, was thus explored.
To find the most suitable solvent system, the photocyclization
of phthaloyl dipeptide ester 1a was selected as a model reaction
–10
(Scheme 1; Table 1). Photoirradiation for 3 h with 300 nm light fur-
5
a,11
nished regioisomer 2a as the sole product. The presence of water
had a significant impact on the conversion rates, which increased
with increasing amounts of water. Previous studies have shown
that the presence of water alters the photophysical properties
through hydrogen-bonding and subsequently enhances photo-
polymerization.
In contrast, tertiary phthalimido acetamides underwent suc-
cessful cyclization reactions. A similar conformationally controlled
photocyclization of secondary vs. tertiary aryl enamides has been
1
2
reported by Rigby and co-workers. Irradiation times varied sig-
nificantly depending on the N, N-disubstitution pattern and amino
acid linker (Scheme 3; Table 2).
5
chemical reactivity. No significant differences between acetone
and acetonitrile mixtures were found in terms of conversion rates,
although acetone is known to function as a triplet-sensitizer, while
The symmetrical glycine-derived tertiary phthalimido aceta-
mides 6a-e furnished the desired cyclic peptide models 7a-e in
6
irradiation in acetonitrile operates via direct excitation. Due to the
1
3
moderate to good yields (51–75%). The phthalimides 6b, 6d, 6e
and 6i furthermore resulted in the formation of diastereoisomeric
⇑
Deceased.
mixtures. Likewise, the branched
a-amino acid containing starting
materials 6f and 6g yielded the corresponding cyclization products
1
040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
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