Synthesis and photochemical reactivity of phthalimidoadamantane–tyrosine conjugates

Article abstract of DOI:10.1007/s11164-017-2927-2

Abstract: Dipeptide 3, tetrapeptide 4 and pentapeptide 5, containing adamantylphthalimide and tyrosine, were synthesized and their photochemical reactivity investigated. Upon excitation to the triplet excited state, 3 does not give any photoproduct, although the photoinduced electron transfer (PET) should take place based on the thermodynamic properties. Tetrapeptide 4 and pentapeptide 5 are photochemically reactive, undergoing decomposition upon excitation. The lack of anticipated photodecarboxylation reactivity is explained by PET between the tyrosine and the phthalimide. However, deprotonation of the phenoxyl radical-cation giving phenoxyl radicals or back electron transfer giving starting material are probably faster than intrastrand single electron transfer which would lead to carboxyl radical and decarboxylation. The results indicate the importance of fine-tuning the molecular structure to attain the desired photoreactivity by the right choice of the reactants redox potential, as well as their acid/base properties.

Full text of DOI:10.1007/s11164-017-2927-2

Res Chem Intermed
DOI 10.1007/s11164-017-2927-2
Synthesis and photochemical reactivity
of phthalimidoadamantane–tyrosine conjugates
1
Margareta Sohora1 Nikolina Vidovic
•
•
´
Kata Mlinaric-Majerski Nikola Basaric
1
1
•
´
´
Received: 15 November 2016 / Accepted: 27 February 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract Dipeptide 3, tetrapeptide 4 and pentapeptide 5, containing adamantylph-
thalimide and tyrosine, were synthesized and their photochemical reactivity investigated.
Upon excitation to the triplet excited state, 3 does not give any photoproduct, although
the photoinduced electron transfer (PET) should take place based on the thermodynamic
properties. Tetrapeptide 4 and pentapeptide 5 are photochemically reactive, undergoing
decomposition upon excitation. The lack of anticipated photodecarboxylation reactivity
is explained by PET between the tyrosine and the phthalimide. However, deprotonation
of the phenoxyl radical-cation giving phenoxyl radicals or back electron transfer giving
starting material are probably faster than intrastrand single electron transfer which would
lead to carboxyl radical and decarboxylation. The results indicate the importance of fine-
tuning the molecular structure to attain the desired photoreactivity by the right choice of
the reactants redox potential, as well as their acid/base properties.
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-2927-2)
contains supplementary material, which is available to authorized users.
´
Nikola Basaric
nbasaric@irb.hr
&
1
ˇ ´
Department of Organic Chemistry and Biochemistry, Ruder Boskovic Institute,
¯
ˇ
Bijenicka cesta 54, 10000 Zagreb, Croatia
123

M. Sohora et al.
Graphical Abstract
O
O
N
H
N
OH
O
O
ν
h
PET process
photodecarboxylation
acetone
3
OH
ν
h
acetone
O
O
O
H
N
H
N
N
OH
N
H
O
O
O
n
4
n = 1
5 b = 2
OH
Keywords Phthalimide Á Tyrosine Á Peptides Á Photodecarboxylation Á
Photoinduced electron transfer
Introduction
Phthalimide is a versatile chromophore utilized in different photochemical reactions
[1], and is particularly useful in organic synthesis [2, 3]. Photoinduced reactions of
phthalimides include H-abstractions [4], cycloadditions [5] or photoinduced electron
transfer (PET) [6, 7]. PET reactions of phthalimides can initiate decarboxylation [8],
or elimination of silyl ethers [9, 10]. Thus, PET-promoted decarboxylation has been
applied in the synthesis of macrocylic ethers [11–15] and cyclic peptides [16, 17].
Furthermore, intermolecular photodecarboxylations have also been developed [18]
and used in photoinduced acetate [19, 20], benzyl [21, 22], and a-amino acid addition
to phthalimides [23], or for the formation of cyclic aryl ethers [24].
We have turned our attention to the photochemistry of phthalimides as a useful
synthetic method for the preparation of complex polycyclic molecules [25] with
antiproliferative [26] or antiviral activity [27]. We discovered that adamantylphthal-
imides undergo photoinduced H-abstractions [28], which can also take place in the
solid state [29] or in supramolecular complexes [30]. Moreover, the photochemical
reactivity of adamantyl amino acids activated by phthalimides has been investigated
[31], where radicals formed in the decarboxylation can be trapped with electron-
deficient alkenes giving adducts [32]. Furthermore, phthalimido-activated amino acids
have been incorporated into dipeptides which underwent photodecarboxylation
affording cyclic compounds with high enantioselectivity [33]. In contrast, N-
arylphthalimide derivatives gave only simple decarboxylation products [34].
Griesbeck et al. [35] have recently demonstrated that N-phthalimido tyrosine 1
underwent photodecarboxylation giving a tyramine derivative 2. Tyrosine is a good
123

Synthesis and photochemical reactivity…
electron donor in PET reactions with the redox potential of E° = 0.85 V vs FcFc? [36].
Thus, PET with phthalimide in the triplet excited state (ET = 293–300 kJmol-1) [37]
and the reduction potential of E° = -1.85 V
should be exergonic.
vs FcFc?
O
O
ν
h
OH
OH
(1)
acetone-H2O
K2CO3
N
N
COOH
O
O
2
1
Here, we describe the synthesis of di-, tetra-, and pentapeptides 3–5 containing
N-phthalimido adamantane amino acid at the N-terminus and tyrosine at the C-
peptide terminus. The molecular structures were designed to probe for selectivity in
the PET reactions between two electron donors, carboxylate or tyrosine, and the
dependence of the PET efficiency on the distance between the electron donor and
the acceptor (phthalimide).
O
O
O
O
H
N
O
H
N
H
N
OH
N
N
H
OH
N
O
O
O
O
O
O
4
3
OH
OH
OH
O
O
H
N
H
N
OH
N
N
H
N
H
O
O
O
O
5
Experimental
General
1H and 13C NMR spectra were recorded on a Bruker Avance Spectrometer at 300 or
600 MHz. All NMR spectra were measured in CDCl3, DMSO-d6, CD3CN or
CD3OD using tetramethylsilane as a reference. High-resolution mass spectra
(HRMS) were measured on an Applied Biosystems 4800 Plus ESI TOF/TOF
instrument. IR spectra were recorded on a FT-IR ABB Bonem MB 102
¨
spectrophotometer. Melting points were obtained using an Original Kofler
Mikroheitztisch apparatus (Reichert, Wien) and are uncorrected. Silica gel or
alumina was used for the chromatographic purifications. Solvents were purified by
123

M. Sohora et al.
distillation. The chemicals for the synthesis were obtained from the usual
commercial sources and used as received. Photochemical reactions were carried
in a Luzchem reactor in quartz cuvettes or quartz Erlenmeyer flasks. The CH3CN
used in the irradiation experiments was of HPLC purity, whereas the p.a. acetone
was additionally purified by refluxing over KMnO4 and distillation. The synthesis of
all known precursors is given in the supporting information.
Phth-Ad-Tyr(OH)-OBn (3OBn)
A flask was charged with 3-(N-phthalimidoadamantane)-1-carboxylic acid 6
(175 mg, 0.54 mmol), HBTU (224 mg, 0.59 mmol), HOBT (80 mg, 0.59 mmol),
triethylamine (TEA; 157 lL, 1.13 mmol) and CH2Cl2 (dried over molecular sieves
˚
4A). After stirring for 10 min at rt under inert N2-atmosphere, L-tyrosine benzyl
ester (228 mg, 0.59 mmol) was added and the reaction was stirred for 3 days. When
the reaction was completed, brine (30 mL) was added to the reaction mixture. The
product was extracted with ethyl acetate (3 9 20 mL), and the extracts were washed
with HCl (1 M, 15 mL), H2O (15 mL), saturated aqueous NaHCO3 (15 mL) and
H2O (15 mL). The organic extracts were dried over anhydrous Na2SO4 and filtered,
and the solvent was removed on a rotary evaporator, furnishing the product
(270 mg, 87%) which was purified by column chromatography on silica gel using
CH2Cl2/MeOH (0–10%) as eluent.
(S)-2-{[3-(N-Phthalimido)a-1-yl]carboxamido}-3-(4-hydroxyphenyl)propanoic acid
:
benzyl ester (3OBn) Colorless solid; m.p. 190–192 °C; IR (KBr) m~max/cm-1
1
3371, 2912, 2856, 1741, 1706, 1636, 1614, 1513, 1456, 1374, 1315, 841, 721; H
NMR (CD3OD, 300 MHz) d/ppm: 7.80–7.70 (m, 4H), 7.47 (d, J = 7.6 Hz, 1H),
7.34–7.18 (m, 5H), 6.96 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 5.12 (d,
J = 12.2 Hz, 1H), 5.10 (d, J = 12.2 Hz, 1H), 4.65–4.54 (m, 1H), 3.09 (dd, J = 5.6,
13.9 Hz, 1H), 2.95 (dd, J = 8.8, 13.9 Hz, 1H), 2.59-2.37 (m, 6H), 2.22 (s, 2H),
1.86–1.58 (m, 6H); 13C NMR (150 MHz, CD3OD) d/ppm: 179.1 (s, 1C), 173.1 (s,
1C), 170.9 (s, 2C), 157.3 (s, 1C), 137.0 (s, 2C), 135.3 (d, 2C), 133.1 (s, 1C), 131.4
(d, 2C), 129.5 (d, 2C), 129.3 (d, 1C), 128.9 (s, 1C), 123.6 (d, 2C), 116.2 (d, 2C),
68.0 (t, 1C), 61.3 (s, 1C), 55.5 (d, 1C), 43.9 (s, 1C), 42.2 (t, 1C), 43.30 (t, 1C), 43.29
(t, 1C), 38.7 (t, 2C), 37.0 (t, 1C), 36.2 (t, 1C), 31.0 (d, 2C); HRMS (ESI-qTOF) m/z:
[M ? H]?Calcd. for C35H34N2O6 579.2495, Found 579.2504.
Phth-Ad-Tyr(OH)-OMe (3Me)
This compound was prepared according to the procedure for the preparation of
3OBn from 6 (477 mg, 1.47 mmol), HBTU (612 mg, 1.61 mmol), HOBT (217 mg,
1.61 mmol), TEA (430 lL, 3.09 mmol) L-tyrosine methyl ester (498 mg,
1.61 mmol). The crude product was purified by column chromatography on silica
gel using hexane/CH2Cl2 (0–10%) and CH2Cl2/MeOH (0–10%). The pure product
was isolated in the form of a colorless solid (71%, 523 mg).
(S)-2-{[3-(N-Phthalimido)adamantan-1-yl]carboxamido}-3-(4-hydroxyphenyl)propanoic
acid methyl ester (3Me) Colorless solid; m.p.[350 °C; IR (KBr) mmax/cm-1: 3489,
~
123

Synthesis and photochemical reactivity…
1
1725, 1635, 1378, 1080, 876; H NMR (CD3CN, 600 MHz) d/ppm: 7.73 (s, 4H),
7.03 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 6.37 (d, J = 7.5 Hz, 1H), 4.55-
4.45 (m, 1H), 3.65 (s, 3H), 3.08 (dd, J = 5.1, 14.0 Hz, 1H), 2.92 (dd, J = 8.3,
14.0 Hz, 1H), 2.52–2.38 (m, 6H), 2.23 (br.s, 2H), 1.82–1.59 (m, 6H); 13C NMR
(CD3CN, 75 MHz) d/ppm: 177.0 (s, 1C), 173.2 (s, 1C), 170.5 (s, 2C), 156.7 (s, 1C),
134.9 (d, 2C), 132.9 (s, 2C), 131.4 (d, 2C), 128.9 (s, 1C), 123.2 (d, 2C), 116.1 (d,
2C), 60.9 (s, 1C), 54.5 (d/q, 1C), 52.7 (d/q, 1C), 43.5 (s, 1C), 42.0 (t, 1C), 40.0 (t,
2C), 38.6 (t, 2C), 37.0 (t, 1C), 35.8 (t, 1C), 30.5 (d, 2C); HRMS (ESI-qTOF) m/z:
[M ? H]? Calcd. for C29H30N2O6 503.2182; Found 503.2190.
Phth-Ad-Tyr(OH)-OH (3)
A flask was charged with benzyl ester 3OBn (270 mg, 0.47 mmol), 10% Pd/C
(*70 mg) and abs. MeOH (15 mL). The flask was closed with a septum and purged
with nitrogen in order to remove air. Et3SiH (0.75 ml, 4.7 mmol) was added to the
suspension in the flask during 1 h. The reaction was monitored on TLC. When the
reaction was completed, Pd/C was removed by filtration through filter paper (blue
ribbon) and the solvent was removed on a rotary evaporator. The pure product
(173 mg, 76%) was isolated after purification by column chromatography on silica
gel using CH2Cl2/MeOH (0–10%) as eluent.
(S)-2-{[3-(N-Phthalimido)adamantan-1-yl]carboxamido}-3-(4-hydroxyphenyl)propanoic
acid (3) Colorless solid; m.p. [350 °C; IR (KBr) mmax/cm-1: 3363, 1701, 1631,
~
1374, 1086, 886; 1H NMR (CD3CN, 300 MHz) d/ppm: 7.74 (s, 4H), 7.03 (d,
J = 8.5 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 6.37 (d, J = 7.5 Hz, 1H), 4.55-4.45 (m,
1H), 3.08 (dd, J = 5.1, 14.0 Hz, 1H), 2.92 (dd, J = 8.3, 14.0 Hz, 1H), 2.52–2.38
(m, 6H), 2.23 (br.s, 2H), 1.82–1.59 (m, 6H); 13C NMR (CD3CN, 75 MHz) d/ppm:
177.4 (s, 1C), 173.2 (s, 1C), 170.5 (s, 2C), 156.7 (s, 1C), 135.0 (d, 2C), 132.9 (s,
2C), 131.5 (d, 2C), 129.1 (s, 1C), 123.2 (d, 2C), 116.1 (d, 2C), 60.9 (s, 1C), 54.5 (d,
1C), 43.5 (s, 1C), 42.0 (t, 1C), 39.9 (t, 2C), 38.6 (t, 2C), 36.6 (t, 1C), 35.8 (t, 1C),
30.5 (d, 2C); HRMS (ESI-qTOF) m/z: [M ? H]? Calcd. for C28H28N2O6 489.2026;
Found 489.2038.
General procedure for the activation of carboxylic acid by DCC-NHS
procedure [40]
A flask was filled with Boc-protected aminoacid (10 mmol), DCC (11 mmol), NHS
˚
(11 mmol) and CH2Cl2 (25 mL, dried over molecular sieves 4A). The reaction
mixture was stirred at -5 °C for 5 h, and left in a refrigerator overnight. The next
day, the precipitate was filtered off and the solvent was removed on a rotary
evaporator. The residue was dissolved in ethyl acetate and the remaining precipitate
was filtered off. The solution was washed with 0.5 M NaHCO3 (30 mL), H2O
(30 mL), 0.5 M HCl (30 mL), and H2O (30 mL), dried over anhydrous MgSO4,
filtered, and the solvent was removed on a rotary evaporator. The crude
succinimido-activated amino acid was used in the coupling step without additional
purification.
123

M. Sohora et al.
Phth-Ad-Gly-OSu (8)
This compound was prepared according to the general procedure from dipeptide 7
(0.32 g, 0.8 mmol), NHS (0.11 g, 0.9 mmol) and DCC (0.19 g, 0.9 mmol). The
product was isolated in the form of a colorless amorphous solid (0.37 g, 91%)
which, without purification, was used in the next step.
1
Colorless amorphous solid; H NMR (CD3OD, 300 MHz) d/ppm: 7.75 (s, 4H),
3.52–3.36 (m, 2H), 2.82 (s, 4H), 2.65–2.45 (m, 6H), 2.29 (br.s, 2H), 1.98–1.67 (m,
6H).
General procedure for the peptide coupling via succinimide-activated amino
acid [40]
A round-bottom flask was charged with amino acid (2.5 mmol), NaHCO3 (5 mmol,
or 7.5 mmol in the case of using TFA salt of amino acid) and THF-H2O (1:1,
20 mL). A solution of succinimide-activated amino acid (2.75 mmol) in THF
(15 mL) was added dropwise to the mixture, and the reaction was stirred at rt for
1–2 days. THF was removed on a rotary evaporator, the reaction mixture was
acidified with 0.5 M HCl to pH 2, and the product was extracted with ethyl acetate
(3 9 30 mL). The organic layers were washed with water and dried over anhydrous
Na2SO4. After filtration and evaporation of the solvent, the product was purified by
column chromatography on silica gel.
PhthAd-Gly-Phe-Tyr(OH)-OH (4)
This compound was prepared according to the general procedure from dipeptide
H-PheTyr-OH (0.70 g, 1.6 mmol) and 8 (0.83 g, 1.7 mmol). The product was
isolated by column chromatography on silica gel with MeOH/CH2Cl2 (5-10%) as
eluent in the form of a colorless solid (0.85 g, 78%).
N-[3-(N0-phthalimido)-1-adamantanecarbonyl]glycyl-L-phenylalanyl-L-tyrosine
(4) Colorless solid; m.p. 256–258 °C; IR (KBr) mmax/cm-1: 3563, 2937, 2875,
2375, 2354, 1729, 1708, 1687, 1646, 1563, 1542, 1500, 1458, 1354, 1083, 833,
~
1
625, 604; H NMR (CD3OD, 300 MHz) d/ppm: 7.78 (s, 4H), 7.26–7.15 (m, 5H),
7.06 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 4.55–4.51 (m, 1H),
4.43–4.39 (m, 1H), 3.91 (d, J = 16.4 Hz, 1H), 3.74 (d, J = 16.4 Hz, 1H), 3.16-
3.07 (m, 2H), 2.94-2.84 (m, 2H), 2.60-2.42 (m, 6H), 2.29 (s, 2H), 1.88-1.75 (m,
2H), 1.69 (d, J = 12.5 Hz, 1H); 13C NMR (CD3OD, 150 MHz) d/ppm: 180.5 (s,
1C), 172.9 (s, 1C), 172.0 (s, 1C), 170.9 (s, 1C), 157.0 (s, 2C), 138.2 (s, 1C/2C),
135.3 (d, 2C), 133.1 (s, 1C/2C), 131.5 (d, 2C), 130.2 (d, 2C), 130.0 (s, 1C),
129.6 (d, 2C), 127.8 (d, 1C), 123.6 (d, 2C), 116.1 (d, 2C), 61.4 (s, 1C), 57.4 (d,
1C), 56.4 (d, 1C), 44.1 (s, 1C), 43.8 (t, 1C), 42.1 (t, 1C), 40.3 (t, 2C), 38.8 (t,
2C), 38.2 (t, 1C), 37.9 (t, 1C), 36.2 (t, 1C), 31.0 (d, 2C), one singlet was not
seen; HRMS (ESI-qTOF) m/z: [M ? H]? Calcd. for C39H40N4O8 693.2924;
Found 693.2932.
123

Synthesis and photochemical reactivity…
PhthAd-Gly-Phe-Phe-Tyr(OH)-OBn (5OBn)
A flask was charged with PhthAd-Gly-OSu 8 (0.59 g, 1.54 mmol), HBTU (0.64 g,
1.70 mmol), HOBt (0.23 g, 1.70 mmol), TEA (450 lL, 3.23 mmol) and dry DMF
(20 mL). The reaction mixture was stired at rt under N2 for 10 min and then
TFA 3 H-Phe-Phe-Tyr-OBn (1.13 g, 1.7 mmol) was added. The reaction was
conducted for 3 days. When the reaction finished, DMF was removed on a rotary
evaporator and CH3CN (10 mL) and brine (70 mL) were added. The mixture was
extracted with ethyl acetate (3 9 30 mL). The combined organic layers were
washed with 5% HCl (15 mL), H2O (15 mL), 5% NaHCO3 (15 mL), H2O (15 mL),
dried over anhydrous MgSO4 and filtered. The solvent was removed on a rotary
evaporator and the residue chromatographed on a column of silica gel with 0–10%
MeOH/CH2Cl2. The product (0.60 g, 42%) was isolated in the form of a colorless
solid.
N-[3-(N0-phthalimido)-1-adamantanecarbonyl]glycyl-L-phenylalanyl-L-phenylalanyl-
~
L-tyrosine benzyl ester (5OBn) Colorless solid; m.p. 115–117 °C; IR (KBr) mmax
/
cm-1: 3403, 3072, 3039, 2942, 2885, 2789, 2462, 2404, 1712, 1635, 1519, 1462,
1366, 1308, 1192, 1135, 1077, 750, 731, 519; 1H NMR (CD3OD, 300 MHz) d/ppm:
7.33 (s, 4H), 7.36-7.08 (m, 15H), 6.94 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 8.5 Hz,
2H), 5.04 (s, 2H), 4.63–4.47 (m, 3H), 3.79 (d, J = 16.2 Hz, 1H), 3.67 (d,
J = 16.2 Hz, 1H), 3.15–2.73 (m, 6H), 2.62–2.39 (m, 6H), 2.25 (br.s, 2H), 1.93–1.63
(m, 6H); 1H NMR (DMSO-d6, 300 MHz) d/ppm: 9.23 (br.s, 1H), 8.75-8.67 (m, 1H),
8.41 (d, J = 7.2 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.00–7.93 (m, 1H), 7.85–7.74
(m, 4H), 7.37–7.08 (m, 15H), 6.98 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H),
5.06 (d, J = 12.0 Hz, 1H), 5.04 (d, J = 12.0 Hz, 1H), 4.60-4.40 (m, 3H), 3.74–3.62
(m, 2H), 3.00–2.64 (m, 6H), 2.47-2.32 (m, 6H), 2.19 (br.s, 2H), 1.75–1.56 (m, 6H);
13C NMR (CD3OD, 150 MHz) d/ppm: 173.1 (s, 1C), 172.5 (s, 1C), 138.1 (s, 1C),
131.4 (d, 2C), 130.3 (d, 2C), 130.2 (d, 2C), 129.6 (d, 2C), 129.5 (d, 2C), 129.4 (d,
4C), 129.3 (d, 1C),129.2 (s, 1C), 128.4 (s, 1C), 127.8 (d, 1C), 127.7 (d, 1C), 123.6
(d, 2C), 116,3 (d, 2C), 67,9 (t, 1C), 61.3 (s, 1C), 55.9 (d, 3C), 44.1 (s, 1C), 42.3 (t,
2C), 40.4 (t, 2C), 38.9 (t, 2C), 38.5 (t, 1C), 38.3 (t, 1C), 37.8 (t, 1C), 36.3 (t, 1C),
31.0 (d, 2C).
PhthAd-Gly-Phe-Phe-Tyr(OH)-OH (5)
A flask (20 mL) was charged with ester 5OBn (0.15 g, 0.2 mmol), 10% Pd/C
(0.03 g) and dry methanol (5 mL). The reaction mixture was purged with nitrogen
for 15 min. Et3SiH (0.32 ml, 2.0 mmol) was added dropwise and the stirring was
continued over 1 h. The progress of the reaction was monitored on TLC with 5%
MeOH/CH2Cl2 as an eluent. When the reaction was completed, Pd/C was filtered
off through filter paper (blue ribbon), and the solvent was removed on a rotary
evaporator. The pure product was obtained in the form of a colorless solid (0.13 g,
quantitatively).
N-[3-(N0-phthalimido)-1-adamantanecarbonyl]glycyl-L-phenylalanyl-L-phenylalanyl-
L-tyrosine (5) Colorless solid; m.p. 124–126 °C; IR (KBr) mmax /cm-1: 3383, 2907,
~
123

M. Sohora et al.
1
1704, 1646, 1502, 1200, 720; H NMR (DMSO-d6, 300 MHz) d/ppm: 12.39 (br.s,
1H), 9.16 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 7.5 Hz, 1H), 7.85–7.73 (m,
4H), 7.73 (d, J = 8.5 H, 2H), 7.60 (t, J = 5.5 Hz, 1H), 7.27–7.07 (m, 10H), 7.01 (d,
J = 8.0 Hz, 2H), 6.65 (d, J = 8.0 Hz, 2H), 4.59–4.41 (m, 2H), 4.39–4.29 (m, 1H),
3.68 (dd, J = 16.0, 5.4 Hz, 1H), 3.51 (dd, J = 16.0, 5.4 Hz, 1H), 3.07–2.65 (m,
6H), 2.47–2.40 (m, 4H), 2.33 (d, J = 12.2 Hz, 2H), 2.19 (br.s, 2H), 1.76–1.63 (m,
5H), 1.57 (d, J = 12.2 Hz, 1H); 13C NMR (DMSO-d6, 75 MHz) d/ppm 176.0 (s,
1C), 172.7 (s, 1C), 170.8 (s, 1C), 170.5 (s, 2C), 169.0 (s, 2C), 168.7 (s, 1C), 155.9 (s,
2C), 137.6 (s, 1C), 137.4 (s, 1C), 134.3 (d, 2C), 131.2 (s, 1C), 130.0 (d, 2C), 129.2
(d, 2C), 129.2 (d, 2C), 128.0 (d, 2C), 127.9 (d, 2C), 127.8 (d, 1C), 126.2 (d, 1C),
126.1 (d, 1C), 122.4 (d, 2C), 114.9 (d, 2C), 59.7 (s, 1C), 53.9 (d, 1C), 53.7 (d, 1C),
53.4 (d, 1C), 42.2 (s, 1C), 42.1 (t, 1C), 42.0 (t, 2C), 40.8 (t, 1C), 38.8 (t, 2C), 37.5 (t,
1C), 37.4 (t, 1C), 36.0 (t, 1C), 34.8 (t, 1C), 28.9 (d, 2C); HRMS (ESI-qTOF) m/z:
[M ? H]? Calcd. for C48H49N5O9 840.3609; Found 840.3609.
Irradiation experiments
Solutions of peptides 3–5 (100 mg) were prepared in acetone–H2O (3:1 or 10:3,
100 mL) poured into a quartz Erlenmeyer flask to which K2CO3 was added (0, 0.5
or 1 equiv.). The solution was purged with N2 for 20 min, sealed and irradiated at
300 nm in a Luzchem reactor equipped with 8 lamps (1 lamp, 8 W). During the
irradiation, the solution was continuously stirred and cooled with a fan integrated in
the reactor. After the irradiation, the solvent was removed on a rotational evaporator
and the crude reaction mixture analyzed by NMR. For the product, isolation
preparative HPLC was performed on a Varian, using a Phenomenex Jupiter column
and eluting by CH3OH/H2O ? 0.1% TFA (0–50%) for 15 min and 100% MeOH for
10 min, followed by chromatography on preparative TLC on SiO2 using CH2Cl2/
MeOH 8% as eluent.
(S)-2-{[3-(N-Phthalmyl)adamantan-1-yl]carboxamido}-3-(4-hydroxyphenyl)propanoic
acid (9) Dipeptide 3 (5 mg, 0.01 mmol) and K2CO3 (1.4 mg, 0.010 mmol) were
dissolved in acetone (5 mL) and H2O (1.5 mL) and left for 3 days at rt in the dark.
The solvent was evaporated to afford the pure product 9 isolated in the form of a
colorless solid, 20 mg (44%); m.p. 144–146 °C; IR (KBr) mmax/cm-1: 3340, 2914,
~
2858, 1719, 1644, 1516, 1449, 1364, 1308, 1270, 1228, 1202, 1134, 835, 722, 710,
607; 1H NMR (CD3CN, 300 MHz) d/ppm: 7.78 (dd, J = 1.0, 7.5 Hz, 1H), 7.56 (dt,
J = 1.4, 7.4 Hz, 1H), 7.48 (dt, J = 1.5, 7.5 Hz, 1H), 7.42 (dd, J = 1.2, 7.4 Hz,
1H), 7.02 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 6.47–6.38 (m, 2H),
4.56–4.46 (m, 1H), 3.78 (s, 2H), 3.08 (dd, J = 5.1, 14.0 Hz, 1H), 2.92 (dd, J = 8.1,
14.0 Hz, 1H), 2.18 (br.s, 2H), 2.12-1.95 (m, 6H), 1.78–1.57 (m, 6H); 13C NMR
(CD3CN, 75 MHz) d/ppm: 177.6 (s, 1C), 173.6 (s, 1C), 169.5 (s, 1C), 168.4 (s, 1C),
156.8 (s, 1C), 140.2 (s, 1C), 132.6 (d, 1C), 131.5 (d, 2C), 130.4 (d, 1C), 130.3 (d,
1C), 129.1 (s, 2C), 128.6 (d, 1C), 116.1 (d, 2C), 54.6 (d, 1H), 53.6 (s, 1H), 52.9 (q,
1C), 43.3 (s, 1C), 43.1 (t, 1C), 41.1 (t, 2C), 38.84 (t, 1C), 38.79 (t, 1C), 36.7 (t, 1C),
36.0 (t, 1C), 30.3 (d, 2C); HRMS (ESI-qTOF) m/z: [M ? H]? Calcd. for
C29H32N2O7 521.2288; Found 521.2289.
123

Synthesis and photochemical reactivity…
(S)-2-{[3-(N-Phthalmyl)adamantan-1-yl]carboxamido}-3-(4-hydroxyphenyl)propanoic
acid methyl ester (9Me) Dipeptide ester 3Me (20 mg, 0.04 mmol) and K2CO3
(2.7 mg, 0.02 mmol) were dissolved in a mixture of acetone (20 mL) and H2O
(6 mL) and stirred for 2 h in the dark or irradiated. The solvent was removed on a
rotary evaporator to afford the pure product isolated in the form of a colorless solid,
30 mg (42%); m.p. 90–93 °C; IR (KBr) mmax /cm-1: 3353, 2912, 2856, 1729, 1644,
~
1511, 1442, 1311, 1270, 1225, 1085; 1H NMR (CD3CN, 600 MHz) d/ppm: 7.78 (d,
J = 7.7 Hz, 1H), 7.56 (dt, J = 1.2, 7.5 Hz, 1H), 7.48 (dt, J = 1.2, 7.7 Hz, 1H),
7.42 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 6.42
(s, 1H), 6.38 (d, J = 7.5 Hz, 1H), 4.58–4.53 (m, 1H), 3.79 (s, 1H), 3.66 (s, 2H), 3.04
(dd, J = 5.3, 14.0 Hz, 1H), 2.92 (dd, J = 8.0, 14.0 Hz, 1H), 2.18 (br.s, 2H),
2.11–2.05 (m, 4H), 2.01–1.97 (m, 2), 1.76–1.66 (m, 5H), 1.63 (d, J = 12.6 Hz, 1H);
13C NMR (CD3CN, 150 MHz) d/ppm: 177.2 (s, 1C), 173.3 (s, 1C), 169.5 (s, 1C),
168.5 (s, 1C), 156.8 (s, 1C), 140.2 (s, 1C), 132.7 (d, 1C), 131.4 (d, 2C), 130.4 (d,
1C), 130.2 (d, 1C), 129.0 (s, 2C), 128.6 (d, 1C), 116.2 (d, 2C), 54.6 (d, 1H), 53.6 (s,
1H), 52.9 (q, 1C), 52.7 (q, 1C), 43.3 (s, 1C), 43.2 (t, 1C), 41.11 (t, 1C), 41.10 (t, 1C),
38.9 (t, 1C), 38.85 (t, 1C), 37.1 (t, 1C), 36.1 (t, 1C), 30.3 (d, 2C); HRMS (ESI-
qTOF) m/z: [M ? H]? Calcd. for C30H34N2O7 535.2444; Found 535.2448.
Results and discussion
Synthesis
Dipeptide esters 3OBn and 3Me were prepared from N-protected tyrosine and
phthalimido amino acid 6 [32] using N,N,N0,N0-tetramethyl-O-(1H-benzotriazol-1-
yl)uronium hexafluorophosphate (HBTU) and 1-hydroxybenzotriazole (HOBT)
activation protocol [38]. The benzyl deprotection from 3OBn by use of triethyl-
silane and Pd/C, according to the modification of the known procedure [39],
afforded dipeptide with the free carboxylic acid 3 (Scheme 1).
The synthesis strategy for the preparation of tetra- and pentapeptides was based
on the coupling of adamantyl glycine dipeptide 7 with a Phe-Tyr or Phe-Phe-Tyr
fragment, respectively. Dipeptide 7 [33, 34] was prepared from 6 and unprotected
glycine by use of N-hydroxysuccinimide (NHS) and N,N’-Dicyclohexylcarbodi-
imide (DCC) activation [40]. The synthesis of H-Phe-Tyr-OH and H-Phe-Phe-Tyr-
OH fragments is shown in Scheme S1 in the supporting information. N-Boc-
protected phenylalanine reacted with unprotected tyrosine using the NHS and DCC
coupling protocol, and afforded dipeptide from which the N-Boc group was
removed by trifluoroacetic acid (TFA) giving TFA 9 H-Phe-Tyr-OH. The same
coupling protocol was applied to prepare N-Boc-Phe-Phe-OH. The introduction of
Tyr as the third amino acid was performed in the same manner using unprotected
amino acid. In addition, succinimide ester N-Boc-Phe-Phe-OSu was coupled with
benzyl-protected L-Tyr, giving benzyl-protected tripeptide N-Boc-Phe-Phe-Tyr-
OBn. Alternatively, the coupling with L-Tyr(OH)-OBn was also performed by use
of a stronger activation reagent, HBTU and HOBT, yielding N-Boc-Phe-Phe-Tyr-
123

M. Sohora et al.
OH
O
O
O
H
N
O
-TFA+H3N
N
O
O
O
O
N
COOH
HBTU, HOBT, TEA
OH
3OBn
O
OH
6
Et3SiH, 10% Pd/C
MeOH
HBTU
HOBT
TEA
O
-TFA+H3N
CH3
O
O
O
H
N
O
OH
N
O
H
N
O
OCH3
N
O
O
O
3
OH
3Me
OH
Scheme 1 Synthesis of 3 and 3Me
OBn. The Boc deprotection by TFA gave tripetide TFA 9 H-Phe-Phe-Tyr-OBn
which was used in the synthesis of pentapeptide.
To prepare tetrapeptide, adamantylglycine 7 was activated by NHS and DCC to
the succinimide derivative 8 and coupled with dipeptide H-Phe-Tyr-OH to afford 4
in 78% yield. Attempts to prepare pentapeptide using the same strategy, from 8 and
tripeptide H-Phe-Phe-Tyr-OH, gave very low yields on the desired pentapeptide 5
which was very difficult to purify due to the formation of gel. Therefore, we
prepared benzyl C-protected pentatpeptide derivative 5OBn. Since we used
protected tripeptide H-Phe-Phe-Tyr-OBn, a stronger coupling reagent HBTU and
HOBT could be employed, giving higher yields on the peptide 5OBn. Benzyl
deprotection to free carboxylic acid pentapeptide 5 was achieved by in situ-formed
H-radicals using Et3SiH and Pd/C (Scheme 2).
Peptides 3–5 were fully characterized by spectroscopic methods, and, for 4 and 5,
CD spectra were recorded (see Fig S1 in the supporting information). It is
interesting that the CD spectra of 4 and 5 have significantly different patterns,
indicating different structure. Probably, the introduction of an additional Phe into
the backbone introduces peptide turns, resulting in a helicoidal structure.
Photochemistry
Based on a literature precedent [35], it is anticipated that irradiation of 3–5 in the
presence of a base, needed to deprotonate the carboxylic acid, would give rise to
photodecarboylation and cyclization products [33]. Irradiation was performed in
CH3CN under direct excitation conditions (kex = 300 nm) or in acetone which acts
as a triplet sensitizer (ET = 332 kJ/mol) [41]. The results are summarized in
Table 1.
123

Synthesis and photochemical reactivity…
O
O
O
O
O
H
N
O
H
N
NHS
DCC
H-Phe-Tyr-OH
N
OH
N
N
4
NaHCO3
O
O
O
O
O
7
8
HBTU
HOBT
TEA
H-Phe-Phe-Tyr-OBn
OH
O
O
Et3SiH, Pd/C
MeOH
O
H
N
H
5
N
O
N
H
N
H
N
O
O
O
O
5OBn
Scheme 2 Synthesis of 4 and 5
Irradiation of dipeptide 3 performed in acetone is expected to selectively excite
phthalimide by energy transfer from acetone. Since the triplet state energy of
tyrosine (ET = 340–350 kJ/mol) [42, 43] is higher than the ET of acetone, only
phthalimide sensitization is exergonic. On excitation of the phthalimde to the triplet
excited state, the photodecarboxylation reaction should be feasible when the
carboxylic acid is deprotonated, and in principle only one-half of the K2CO3
equivalent is needed. However, in the presence of 0.5 equiv. of K2CO3, dipeptide 3
upon irradiation showed unexpected photochemical stability. Irradiation of 3 in the
presence of a higher K2CO3 concentration led to almost complete conversion of 3,
but the transformation was shown to take place in a thermal rather than a
photochemical reaction. Products 9 and 9Me were formed in a base-catalyzed
phthalimide ring opening in the presence of 2.2 mM K2CO3 (Scheme 3); they were
isolated and characterized by spectroscopic methods. Interestingly, base concen-
tration of 1 mM did not catalyze the imide ring opening (Table 1).
Based on phthalimide and tyrosine redox potential, PET should take place
between the tyrosine as electron donor and the triplet excited state of phthalimide as
electron acceptor. Furthermore, Mariano et al. suggested that primary PET is
followed by intrachain single ET (ISET), giving equilibrated ET states that
eventually give rise to stable products if there is a reversible process such as
decarboxylation or desilylation [44, 45]. Mariano’s hypothesis is in accord with the
photodecarboxylation of 1, demonstrated by Griesbeck et al. [35]. Consequently, it
is surprising that 3 is photochemically stable. The presumed reason for the observed
photostability may be a very fast back electron transfer (BET) so that ISET cannot
compete with it. The other plausible reason for the lack of ISET may be a very fast
deprotonation of phenoxyl radical-cation 3CT which gives phenoxyl radical 3PhO.
Acidity of phenoxyl radical-cations and fast deprotonation in aqueous solution is
well known [46]. Furthermore, the lack of reactivity of tyrosine-containing peptides
in the photocatalytic decarboxylation reactions initiated by phenanthrene and
123

M. Sohora et al.
Table 1 Irradiation conditions and conversions of peptides 3–5a
Comp. Phthalimide conc./ K2CO3 conc./ Solvent
mM
Irradiation
time
Conversion %b
(isolated %)
mM
3
2.20
0
Acetone–H2O
10:3
3 h
\5
3
1.90
2.20
4.75
4.75
1.40
1.40
1.20
1.20
0.95
2.20
0
Acetone–H2O
10:3
2 h
\5
3
Acetone–H2O
10:3
3 h
98 (83)c
\5
3Me
Acetone–H2O
10:3
3 h
3Me
2.38
0.70
0.70
0.60
0.60
Acetone–H2O
10:3
3 h
91 (86)c
30 (–)d
0
4
4
5
5
Acetone–H2O
3:1
40 min
40 min
20 min
20 min
CH3CN–H2O
3:1
Acetone–H2O
3:1
20 (–)d
15 (–)d
CH3CN–H2O
3:1
5
5
0.79
0.79
0
Acetone
2 h
2 h
42 (–)d
93 (–)d
2.37
Acetone–H2O
3:1
5
0.79
0
CH3CN
2 h
30 (–)d
a
Irradiation was performed in quartz test tubes (13–15 mL) in a Luzchem reactor by use of 8 lamps with
the output at 300 nm (1 lamp, 8 W). Prior to irradiation, the solutions were purged for 30 min with N2
b
From NMR spectra
c
Formed in a thermal reaction
d
Only high molecular weight products
O
HO
O
O
H
N
O
O
H
N
K2CO3
H2O
N
OR
N
H
OR
O
O
O
OH
3
R = H
9
R = H, R' = H
OH
3Me R = CH3
9Me R = CH3, R' = H
Scheme 3 Thermal base-catalyzed reaction of 3 and 3Me
dicyanonabenzene has been demonstrated by Yoshimi et al. [47]. In contrast,
tyrosine-containing peptides that were substituted at the tyrosine phenolic oxygen
underwent decarboxylation and radical addition to electron-deficient alkenes [47].
Therefore, ISET probably does not take place due to 3CT deprotonation. 3RAD1
and 3RAD2 are never populated, so decarboxyltion of 3 giving the anticipated
123

Synthesis and photochemical reactivity…
products 10 and 11 does not take place (Scheme 4). It is interesting that 3PhO also
does not lead to any stable photoproduct. The presumed reason is depopulation by
BET and protonation back to 3. If the cyclization to strained 12 took place, the
hemiaminal would not be stable, so it would revert back to 3. The other plausible
lack of reactivity for 3 may be due to the quenching of the phthalimide triplet state
by intermolecular H-transfer from phenol OH. However, H-transfer reactions
usually take place several orders of magnitude slower compared to SET, so this
pathway is less probable, although it cannot be fully disregarded.
Contrary to dipeptide 3, tetrapeptide 4 and pentapeptide 5 were photochemically
reactive. Thus, 40 min of irradiation of an acetone–H2O solution of 4 resulted in
30% conversion of the starting material (Table 1). However, NMR and HPLC
analysis of the photolysis mixture indicated the formation of numerous products.
The anticipated decarboxylation product 13 or cyclization product 14 were not
detected. Contrary to the acetone solution, 4 in CH3CN–H2O was photochemically
stable, indicating that photodecomposition was initiated only upon excitation of
phthalimide to the triplet state by energy transfer from acetone.
Pentapeptide 5 was photochemically reactive in both acetone–H2O and CH3CN–
H2O solution. A short 20 min of irradiation resulted in a similar 15–20% conversion
for both solutions. Similar to the photodecomposition of 4, decarboxylation product
15 or cyclization product 16 were not detected. Instead, decomposition of the
material took place, giving high molecular weight products. Thus, at the high
K2CO3 concentration of 2.4 mM, almost a complete conversion of the peptide was
achieved. However, photodecomposition of the peptide in CH3CN and acetone, in
the same concentration (0.79 mM), was also feasible without the base, although the
process was less efficient (Table 1). This finding indicates that the decomposition is
not connected to the reactivity of the carboxylic functional group or the thermal
ν
h
O
O
O
O
ISET
O
H
N
acetone
H
N
O
H
N
O-
O
O-
N
N
PET
N
O
O
O
O
O
O
BET
OH
3
3RAD1
3CT
H2O
OH
OH
+H+ H2O
-H+
O
O
H
N
O
H
O
O
H
N
BET
N
O-
N
N
O-
N
O
O
O
O
O
O
O-
3-
OH
3RAD2
O
3PhO
OH
-OOC
HN
O
H
N
O
N
O
HN
O
O
O
3
O
OH
11
N
OH
N
H
O
O
10
12
Scheme 4 Plausible mechanism for photochemical reaction of 3
123

M. Sohora et al.
imide ring opening, as seen with 3. Most probably, photodecomposition is caused by
PET between the phthalimide and the tyrosine, giving a long-lived phenoxyl radical
which initiates further radical reactions.
OH
O
H
O
N
O
O
NH
H
N
H
N
H
N
H
O
n
O
n
NH
HN
N
O
O
O
O
OH
13 n = 1
15
14 n = 1
n = 2
16
n = 2
Conclusion
Adamantylphthalimide tyrosine conjugates dipeptide 3, tetrapeptide 4 and pen-
tapeptide 5 were synthesized and their photochemical reactivity investigated. Upon
excitation to the triplet excited state, 3 probably undergoes PET between the
phthalimide and tyrosine, but not between the carboxylate and the phthalimide.
Therefore, decarboxylation does not take place and 3 does not lead to any
stable photochemical product. On the other hand, direct excitation, or acetone
sensitization of tetrapeptide 4 and pentapeptide 5, lead to photodecomposition.
Photodecomposition is similarly efficient, independent of the distance between the
electron donor (tyrosine) and the phthalimide. Simple decarboxylation or cycliza-
tion products were not obtained, presumably due to a faster formation of a phenoxyl
radical by PET followed by decomposition. Although PET probably takes place,
ISET cannot compete with BET and the deprotonation of phenol, which leads to no
product from 3, or material decomposition from 4 and 5. The results presented
indicate the importance of a thorough investigation of the photochemical reactivity
in diverse molecular structures for the rational design of molecules to attain high
reactivity in photocyclization reactions. The molecular structure of reactants
undergoing PET has to be wisely designed, not only by the right choice of the
reactants’ redox potential but also by their acid/base properties.
123

Synthesis and photochemical reactivity…
Supporting information
Supporting information contains synthetic procedures for the preparation of known
1
precursors, CD spectra of 4 and 5 and H and 13C NMR spectra of all known
compounds. It can be obtained free of charge at the web site.
Acknowledgements These materials are based on work financed by the Croatian Science Foundation
(HrZZ grant no. IP-2014-09-6312). The authors declare that they have no conflict of interest.
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