Direct modification of tripeptides using photoinduced decarboxylative radical reactions

Article abstract of DOI:10.1016/j.tet.2014.12.075

In order to explore the applicability of photoinduced electron transfer (PET) promoted decarboxylative reactions to the direct modification of peptides, a study was performed to assess the influence of amino acid side chains on photoreactions of N-terminal protected tripeptides. Photoinduced decarboxylation reactions of tripeptides, which are composed of central amino acids that possess alkyl, phenyl, thioether, hydroxy, and amide containing side chains, in the presence or absence of acrylonitrile and a thiol were found to proceed smoothly to give the corresponding radical addition, H-abstraction, and substitution products. Although photoreactions of tripeptides containing central amino acids with phenol and indole (Tyr and Trp) moieties do not take place efficiently, appropriate protection of these groups enables the substrates to undergo smooth photoinduced decarboxylative reactions.

Full text of DOI:10.1016/j.tet.2014.12.075

Tetrahedron 71 (2015) 1117e1123
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct modification of tripeptides using photoinduced
decarboxylative radical reactions
Kousuke Maeda, Hikaru Saito, Kazuyuki Osaka, Keisuke Nishikawa, Mai Sugie,
*
Toshio Morita, Ichiro Takahashi, Yasuharu Yoshimi
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, University of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to explore the applicability of photoinduced electron transfer (PET) promoted decarboxylative
reactions to the direct modification of peptides, a study was performed to assess the influence of amino
acid side chains on photoreactions of N-terminal protected tripeptides. Photoinduced decarboxylation
reactions of tripeptides, which are composed of central amino acids that possess alkyl, phenyl, thioether,
hydroxy, and amide containing side chains, in the presence or absence of acrylonitrile and a thiol were
found to proceed smoothly to give the corresponding radical addition, H-abstraction, and substitution
products. Although photoreactions of tripeptides containing central amino acids with phenol and indole
(Tyr and Trp) moieties do not take place efficiently, appropriate protection of these groups enables the
substrates to undergo smooth photoinduced decarboxylative reactions.
Received 26 November 2014
Received in revised form 19 December 2014
Accepted 20 December 2014
Available online 27 December 2014
Keywords:
Photoinduced decarboxylative radical
reaction
Modification of peptide
Tripeptide
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
phenanthrene (Phen), formed by single electron transfer (SET) from
the excited state of Phen (Phen ) to 1,4-dicyanobenzene (DCB)
*
Peptides continue to receive attention owing to their impor-
tance in the fields of biochemistry, organic chemistry, and material
science.1 A large effort in the past several decades has been given to
the study of peptide nanomaterials such as nanotubes.2 Although
a Click chemistry approach has been employed to modify peptides
via the formation of 1,2,3-triazole moieties,3 only a few other
methods for directly introducing functionality into peptides have
been uncovered. The main reason for this limitation is that a variety
of different functional groups that are present in the individual
amino acids, which mandates the use of highly specific and mild
reaction conditions.
(Scheme 1).7 The alkyl radicals, produced in this process by SET
from carboxylates to the Phen radical cation followed by de-
carboxylation of the intermediate carboxy radicals, react with
a variety of reagents such as electron-deficient alkenes, oxime
ethers, and thiols, to produce addition,7cee,gei reduction,7a,f and
substitution7b products in high yields. For example, alkyl radicals
formed by irradiation of a mixture of carboxylic acids containing
catalytic amounts of Phen and DCB undergo efficient addition to
electron-deficient alkenes.7i The results of this early effort dem-
onstrated that this photochemical process serves as an efficient
method for generating alkyl radicals from aliphatic carboxylic acids
under mild conditions.8
We believed that photoinduced electron transfer (PET) re-
actions, which take place in the absence of strong bases, heating,
and metal catalysts, could serve as efficient methods to modify
peptides. Of particular interest in this regard are studies carried out
This finding encouraged us to investigate PET promoted re-
actions of peptides that contain C-terminal carboxylic acid groups.
Below, the results of this effort, which led to the development of
a new method for modifying tripeptides, are described.
by Griesbeck4 and Mariano,5 which show that PET reactions of
u-
carboxylate and u-trialkylsilyl substituted N-phthalimido peptides
take place efficiently through radical pathways to generate cyclic
peptides containing 3-hydroxyphthalimidine group. Also, a photo-
induced thiol-ene click reaction has been used to modify peptides.6
Recently, we reported an interesting decarboxylation reaction of
carboxylic acids that is promoted by the radical cation of
2. Results and discussion
2.1. Photoinduced decarboxylation reactions of tripeptide:
influence of amino acid side chains on the efficiency of the
process
In the first phase of this study, PET induced decarboxylative
addition reactions of radicals, formed from N-Boc tripeptides 1 (N-
* Corresponding author. E-mail address: yyoshimi@u-fukui.ac.jp (Y. Yoshimi).
http://dx.doi.org/10.1016/j.tet.2014.12.075
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

1118
K. Maeda et al. / Tetrahedron 71 (2015) 1117e1123
Scheme 1. The mechanistic pathway for PET promoted decarboxylative radical addition of carboxylic acids to alkenes.
BocValXaaValOH), which contain a variety of central amino acids
(Xaa), to acrylonitrile 2 were examined in order to evaluate effect
of peptide side chain on efficiencies (Table 1). The protected
peptides are readily prepared starting with commercially available
protected amino acids using liquid phase peptide synthetic pro-
tocols. Photoreactions of the tripeptides 1 (20 mM) were carried
out by irradiating (100 W high-pressure mercury lamp through
Met, entry 3), hydroxy (1d, Ser, entry 4), and amide (1e, Gln, entry
5) side chains, undergo this addition reaction efficiently. In con-
trast, photoinduced decarboxylation of 1f and 1g, which possess
the respective internal amino acids Tyr and Trp that contain
electron rich phenol and indole moieties, do not take place (en-
tries 6 and 7).9 In these cases, starting materials are recovered
after irradiation. A plausible reason for this result is that electron-
donating arenes quench the photogenerated radical cation of Phen
thus preventing PET promoted decarboxylation. As anticipated,
introduction of Boc protecting groups on the phenolic hydroxy of
1f giving 1h and the indole nitrogen of 1g giving 1i enables the
tripeptides to undergo efficient PET promoted radical addition to 2
(entries 8 and 9), although in the case of 1i an uncharacterized
byproduct is also formed.
a Pyrex glass filter;
l >280 nm) aqueous acetonitrile solutions
(CH3CN/H2O¼9:1) containing Phen (20 mM), DCB (20 mM) and
acrylonitrile 2 (20 mM) under argon for 6 h at room temperature.
In each case, the corresponding radical addition product 3 is
produced as a 1:1 mixture of diastereomers. Interestingly, nearly
all of the N-Boc tripeptides, containing central amino acids with
alkyl (1a, Val, entry 1), phenyl (1b, Phe, entry 2), thioether (1c,
Table 1
Photoinduced decarboxylative radical addition of tripeptides N-BocValXaaValOH 1 to acrylonitrile 2a
Entry
1
Xaa
R
Yield of 3b (%)
Entry
8
Xaa
R
Yield of 3b (%)
>99
1a, Val
82
1h, Tyr(Boc)
2
3
1b, Phe
1c, Met
95
71
9
1i, Trp(Boc)
1j, His(Boc)
42
94
10
4
5
1d, Ser
1e, Gln
88
90
11
12
1k, Cys(Bn)
73
86
1l, Glu(OMe)
6
1f, Tyr
0
13
1m, Lys(Boc)
1n, Lys(Cbz)
82
7
1g, Trp
0
14
80
a
The photoreactions of 1 (20 mM) were carried out in the presence of Phen (20 mM), DCB (20 mM), and acrylonitrile 2 (20 mM) using 100-W high-pressure mercury lamp
under an argon atmosphere for 6 h.
b
Isolated yields.

K. Maeda et al. / Tetrahedron 71 (2015) 1117e1123
1119
Similarly, N-BocVal(N-BocHis)ValOH (1j) containing a protected
imidazole (entry 10), N-BocVal(BnCys)ValOH with an S-benzyl
protected thiol (1k, entry 11), N-BocVal(GluOMe)ValOH (1l, entry
12) with an O-methyl protected carboxylate, and N-BocVal(N-Boc-
Lys)ValOH (1m) and N-BocVal(N-CbzLys)ValOH (1n) with N-pro-
tected amines (entries 13 and 14) all participate in high yielding
radical addition reactions.
alkene leads to production of 6 (64%) as a 1:1 mixture of di-
astereomers, formed by addition of the intermediate radical to the
radical anion of DCB.7b
In the next phase of this investigation, the effect of varying the
amounts of the catalysts Phen and DCB on the efficiency of pho-
toinduced decarboxylative radical addition of 1b to 2 was explored
(Table 2).7i Photoreaction of 1b using catalytic amounts of Phen
(5 mM) and DCB (5 mM) was found to produce a high yield of 3b
over a longer irradiation time (12 h) (entry 1). Addition of 1 equiv of
NaOH to this photoreaction mixture leads to an acceleration (6 h) of
the photoreaction giving 3b in a similar high yield (entry 2). The
observation that when the amounts of Phen and DCB are decreased
to 1 mM a longer irradiation time is required to give a similar yield
of the photoadduct, demonstrates that these substances function as
a catalytic duo in the process. The results of additional studies show
that biphenyl and 1,4-dicyanonaphthalene also act as a catalytic
duo for the photoreaction of 1b and 2 (entry 4).
Scheme 2. Reduction and substitution of 1b via photoinduced decarboxylation.
2.2. Effect of phenol and indole on the photoinduced
decarboxylation
As mentioned above, tripeptides 1f and 1g, which contain
electron-donating arene groups, do not undergo this PET promoted
radical reaction. In order to better understand the reason for this
phenomenon, we investigated the photoreaction of N-BocValOH 7
in the presence of phenol (Table 3) and indole (Table 4). We ob-
served that Phen-DCB catalyzed photoreaction of 7 with 2 in the
presence of 1 equiv of NaOH also generates a high yield of adduct 8
as a racemic mixture (entry 1, Table 3).7c The use of a small amount
of phenol (2.5 mM) does not influence the efficiency of the pho-
toreaction (entry 2), and use of a higher concentration of phenol
(10 mM) leads to a significantly decrease in the yield of 8 (entry 3).
When 1 equiv of phenol is present in the reaction mixture, the yield
of 8 is markedly decreased (entry 4). On the other hand, the effi-
ciency of the photoreaction in the presence of 1 equiv of O-Boc-
phenol is not influenced (entry 5). An increase in the amount of
NaOH to 2 equiv in the reaction mixture containing phenol (gen-
erating phenolate ion) significantly retards the photoreaction (en-
try 6).
Table 2
Catalytic photoinduced decarboxylative radical addition of 1 to 2a
Entry Phen (mM) DCB (mM) NaOH (mM) Irradiation Yield of 3bb (%)
time (h)
1
2
5
5
1
1
5
5
1
1
0
20
20
20
12
6
24
24
94
93
74
50
3
4c
a
The photoreaction of 1b (20 mM) was carried out in the presence of catalytic
amounts of Phen and DCB.
b
Isolated yield.
c
Instead of Phen and DCB, biphenyl, and 1,4-dicyanonaphthalene were used.
A similar efficiency diminishing trend was observed when in-
dole is added to the mixture containing Phen-DCB, 7, and 2 (entries
1e4, Table 4). Also, the yield of 8 is not affected by the addition of
1 equiv of N-Boc-indole to the reaction mixture (entry 5). The
combined results indicate that phenol, phenolate ion, and indole
serve as quenchers of the PET promoted photoreaction. The re-
spective oxidation potentials of the respective electron rich arenes,
þ0.62 V (vs SCE in H2O, pH¼7),10 þ0.35 V (vs SCE in H2O,
pH¼12.5),11 and þ0.73 V (vs SCE in H2O, pH¼7)10 are all lower than
An investigation was carried out to determine if the new PET
promoted radical process could be used to promote reduction and
substitution reactions of tripeptides (Scheme 2). We observed that
photoreaction of tripeptide 1b (10 mM) in the presence of tert-
dodecanethiol (4) (30 mM) as a hydrogen atom source under
similar conditions to those described above leads to formation of
the reduction product 5 as a single stereoisomer in a moderate 60%
yield.7a,f Photoreaction of 1b conducted in the absence of a thiol and
Table 3
Influence of phenol and phenolate ion on the photoinduced decarboxylation
l
Entry
Phenol (mM)
NaOH (mM)
Yield of 8a (%)
Recovery of 7a (%)
1
2
3
0
2.5
10
20
20
20
20
20
20
20
20
40
85
88
20
11
91
0
0
4
71
85
0
4
5b
6
87
a
Isolated yields.
Instead of phenol, O-Boc-phenol was used.
b

1120
K. Maeda et al. / Tetrahedron 71 (2015) 1117e1123
Table 4
temperature, and concentrated in vacuo. The residues were dis-
Influence of indole on the photoinduced decarboxylation
solved in CH2Cl2, and washed with 4% NaHCO3, 1 M HCl, and water.
The organic layer was dried over Na2SO4 and concentrated in vacuo,
giving residues that were subjected to silica gel column chroma-
tography using hexane/AcOEt or CH2Cl2/AcOEt as eluents to give
the desired protected dipeptides N-BocValXaaOMe (75e90%).
The dipeptides were hydrolyzed by using 1 M NaOH in MeOH
until starting materials were consumed completely (by TLC moni-
toring). After each reaction is complete, 1 M H2SO4 was added until
pH¼3 and the solution was extracted with AcOEt or CH2Cl2. The
organic layer was washed with H2O and brine, and dried over with
Na2SO4, and concentrated in vacuo giving a residue that was sub-
jected to silica gel column chromatography using hexane/AcOEt or
CH2Cl2/AcOEt as eluents to give the desired dipeptide N-BocVal-
XaaOH (85e99%). Similarly, the repetitive couplingehydrolysis
sequences with hydrochloride salt of ValOMe gave tripeptides N-
BocValXaaValOH 1aed, feg, k (two steps, 72e89%).
Entry
Indole (mM)
Yield of 8a (%)
Recovery of 7a (%)
1
2
3
20
10
5
2.5
20
Trace
9
58
70
88
92
85
32
28
0
4
5b
a
Isolated yields.
Instead of indole, N-Boc-indole was used.
b
that of an aliphatic carboxylate ion such as hexanoate (þ1.16 V vs
SCE in CH3CN).12 Tyrosine and tryptophan both have oxidation
potentials that are similar to those phenol and indole, re-
spectively.10 As a result, the rates of SET from phenol, phenolate ion,
and indole to the radical cation of Phen (þ1.50 V vs SCE in CH3CN)13
could be faster than that from the carboxylate ion. In this event, the
presence of electron rich arenes would lead to reductive quenching
of the Phen radical cation. Thus, the observation that introduction
of Boc groups on the hydroxy and nitrogen of the respective phenol
and indole leads to less efficient quenching is in full accord with the
expected effects of these groups on arene oxidation potentials.
4.2.2. N-BocValValValOH 1a. White solid, mp 131 ꢀC; IR (KBr, cmꢁ1
)
3327, 2967, 1646, 1526; 1H NMR (500 MHz, CD3OD) dH 0.83e0.97
(m, 18H), 1.44 (s, 9H), 1.97e2.20 (m, 3H), 3.90 (d, J¼6.7 Hz, 1H),
4.24e4.35 (m, 2H); 13C NMR (125 MHz, CD3OD) dC 18.3, 18.6, 18.8,
19.6, 19.7, 19.8, 20.0, 28.7, 31.7, 31.8, 32.2, 58.9, 59.9, 61.7, 80.5, 157.9,
173.6, 174.4, 174.5; HRMS (FAB) calcd for (MþH)þ C20H38N3O6:
416.2761, found 416.2715.
4.2.3. N-BocValPheValOH 1b. White solid, mp 123e124 ꢀC; IR (KBr,
cmꢁ1) 3309, 3087, 1649; 1H NMR (500 MHz, CD3OD) dH 0.76e0.95 (m,
12H),1.43 (s, 9H),1.90e1.94 (m, 1H), 2.10e2.17 (m,1H), 2.91 (dd, J¼13.9,
8.6 Hz,1H), 3.12 (dd, J¼13.9, 5.8 Hz,1H), 3.83 (d, J¼6.7 Hz,1H), 4.29 (m,
1H), 4.75 (t, J¼6.4 Hz, 1H), 7.16e7.26 (m, 5H); 13C NMR (125 MHz,
CD3OD) dC 18.3,18.4,19.5,19.7, 28.7, 31.9, 32.1, 39.0, 55.5, 59.0, 61.6, 80.6,
127.7, 129.4, 129.5, 130.4, 138.2, 157.9, 173.3, 174.2, 174.3; HRMS (FAB)
calcd for (MþH)þ C24H38N3O6: 464.2760, found: 464.2777.
3. Conclusion
In the study described above, we found that the PET promoted
decarboxylation reactions can be utilized for direct modification of
appropriately protected peptides. The protected peptides are
readily prepared starting with commercially available protected
amino acids using solid or liquid phase peptide synthetic protocols.
Photoreactions of the tripeptides utilizing the PheneDCB dual
catalytic system proceed through a pathway involving decarbox-
ylative generation of radicals, which undergo addition, reduction,
and substitution reactions. Investigations of applications of this
photoreaction to peptide modification are currently in progress.
4.2.4. N-BocValMetValOH 1c. White solid, mp 101e102 ꢀC; IR (KBr,
cmꢁ1) 3310, 2967, 1648; 1H NMR (500 MHz, CD3OD) dH 0.91e1.02
(m, 12H), 1.44 (s, 9H), 1.90e2.21 (m, 7H), 2.49e2.60 (m, 2H), 3.87 (d,
J¼7.0 Hz, 1H), 4.32 (d, J¼5.5 Hz, 1H), 4.59 (t, J¼7.1 Hz, 1H); 13C NMR
(125 MHz, CD3OD) dC 15.2, 15.3, 18.3, 18.6, 18.7, 19.6, 19.8, 28.7, 30.7,
31.0, 31.6, 31.9, 33.1, 53.5, 53.6, 58.9, 59.0, 61.5, 80.5, 157.9, 173.6,
174.4; HRMS (FAB) calcd for (MþH)þ C20H38N3O6S: 448.2481,
found: 448.2520.
4. Experimental section
4.1. General experimental
4.2.5. N-BocValSerValOH 1d. White solid, mp 110e111 ꢀC; IR (KBr,
cmꢁ1) 3319, 2968, 1653; 1H NMR (500 MHz, CD3OD) dH 0.91e0.98
(m, 12H), 1.43 (s, 9H), 2.04e2.08 (m, 1H), 2.16e2.21 (m, 1H),
3.74e3.83 (m, 2H), 3.91e3.95 (m,1H), 4.34e4.37 (m,1H), 4.50e4.57
(m, 1H); 13C NMR (125 MHz, CD3OD) dC 18.2, 18.3, 18.4, 18.6, 19.5,
19.7, 19.8, 28.7, 31.7, 31.8, 31.9, 32.0, 56.3, 56.5, 58.9, 59.0, 61.4, 61.7,
63.0, 63.1, 80.5, 80.6, 158.0, 172.2, 174.5, 174.7; HRMS (FAB) calcd for
(MþH)þ C18H34N3O7: 404.2397, found: 404.2412.
All reagents and solvents were used as supplied commercially.
1H NMR spectra were recorded in CD3OD and CDCl3 containing
tetramethylsilane as an internal standard, and were acquired on
either a 300 or a 500 MHz spectrometer. 13C NMR spectra were
acquired on either a 75 or a 125 MHz spectrometer. High-resolution
mass spectra were obtained using a time-of-flight mass spec-
trometer with a Fourier transform ion cyclotron resonance mass
spectrometer with ESI positive mode. The light source was high-
pressure mercury arc. Spectra data of 7 and 8 have been pre-
viously reported by us.7c,d,j
4.2.6. N-BocValTyrValOH 1f. Light yellow solid; mp 147e148 ꢀC; IR
(KBr, cmꢁ1) 3321, 2968, 1650; 1H NMR (500 MHz, CD3OD) dH
0.78e0.97 (m, 12H), 1.44 (s, 9H), 1.91e1.99 (m, 1H), 2.01e2.12 (m,
1H), 2.81e2.85 (m, 1H), 3.00e3.04 (m, 1H), 3.83 (d, J¼6.7 Hz, 1H),
4.29 (d, J¼5.8 Hz, 1H), 4.68 (t, J¼6.1 Hz, 1H), 6.67 (d, J¼8.2 Hz, 2H),
7.05 (d, J¼8.2 Hz, 2H); 13C NMR (125 MHz, CD3OD) dC 16.8, 16.9, 18.1,
18.2, 27.2, 30.4, 30.6, 36.7, 54.3, 57.5, 60.2, 79.1, 114.7, 127.4, 129.9,
155.7, 156.4, 171.9, 172.7, 172.8; HRMS (FAB) calcd for (MþH)þ
C24H38N3O7: 480.2710, found: 480.2706.
4.2. General procedure for synthesis of tripeptides 1
In order to avoid peptide solubility issues and side reaction with
base, tripeptides 1 were synthesized by using three methods.
4.2.1. Preparation of tripeptides 1aed, feg, k. EDC hydrochloride
(1.1 equiv) and HOBt (1.2 equiv) were added to solutions of N-
BocValOH (1.0 equiv), amino acid methyl ester hydrochlorides
(Xaa¼ValOMe, PheOMe, MetOMe, SerOMe, TyrOMe, TrpOMe,
Csy(S-Bn)OMe, 1.0 equiv), and i-Pr2NEt (1.1 equiv) in DMF at 0 ꢀC.
The mixtures were stirred for 2 h at 0 ꢀC and overnight at room
4.2.7. N-BocValTrpValOH 1g. Light yellow solid, mp 175e176 ꢀC; IR
(KBr, cmꢁ1) 3383, 2967, 1654; 1H NMR (500 MHz, CD3OD) dH
0.78e0.90 (m,12H),1.41 (s, 9H),1.94e1.98 (m,1H), 2.08e2.12 (m,1H),

K. Maeda et al. / Tetrahedron 71 (2015) 1117e1123
1121
3.14e3.28(m, 2H), 3.85(d, J¼6.5 Hz,1H), 4.26(d, J¼5.2 Hz,1H), 4.78(t,
J¼6.4 Hz, 1H), 7.00 (t, J¼7.0 Hz, 1H), 7.07 (t, J¼7.0 Hz, 1H), 7.12 (s, 1H),
7.30 (d, J¼8.0 Hz, 1H), 7.60 (d, J¼8.0 Hz, 1H); 13C NMR (125 MHz,
CD3OD) dC 18.3, 19.6,19.7, 28.8, 32.1, 55.2, 59.4, 61.7, 80.7, 110.8, 112.3,
119.8, 121.2, 122.4, 124.7, 128.9, 138.1, 158.0, 173.8, 174.3; HRMS (FAB)
calcd for (MþH)þ C26H39N4O6: 503.2870, found: 503.2823.
0.88e0.97 (m, 12H), 1.39e1.57 (m, 22H), 1.63e1.70 (m, 1H),
1.77e1.83 (m, 1H), 1.99e2.04 (m, 1H), 2.14e2.21 (m, 1H), 3.02 (t,
J¼6.7 Hz, 2H), 3.89 (d, J¼6.7 Hz, 1H), 4.30e4.43 (m, 1H), 4.45 (dd,
J¼13.7, 7.6 Hz, 1H); 13C NMR (125 MHz, CD3OD) dC 14.5, 18.3, 18.4,
18.5, 19.6, 19.7, 19.9, 23.7, 24.0, 28.7, 28.8, 30.5, 31.7, 31.8, 32.0, 32.7,
32.9, 41.2, 54.3, 58.8, 58.9, 61.4, 79.8, 80.5, 157.9, 158.5, 174.1, 174.3,
174.5; HRMS (FAB) calcd for (MþH)þ C26H49N4O8: 545.3550, found
545.3503.
4.2.8. N-BocValCys(Bn)ValOH 1k. White solid, mp 159e160 ꢀC; IR
(KBr, cmꢁ1) 3424, 3330, 2966, 1643; 1H NMR (500 MHz, CD3OD) dH
0.90e0.97 (m, 12H), 1.42 (s, 9H), 2.02e2.20 (m, 2H), 2.68 (dd,
J¼13.9, 7.6 Hz, 1H), 2.87 (dd, J¼13.9, 6.1 Hz, 1H), 3.73e3.79 (m, 2H),
3.92 (d, J¼6.1 Hz, 1H), 4.24e4.27 (m, 1H), 4.65e4.68 (m, 1H),
7.18e7.33 (m, 5H); 13C NMR (125 MHz, CD3OD) dC 18.3, 18.4, 18.5,
19.8, 19.9, 20.0, 28.7, 32.1, 32.3, 34.0, 34.2, 36.9, 37.1, 53.9, 60.1, 61.6,
61.7, 80.1, 128.0, 128.1, 129.4, 129.5, 130.1, 130.2, 139.4, 139.5, 157.9,
172.2, 174.4, 174.6; HRMS (FAB) calcd for (MþH)þ C25H40N3O6S:
510.2638, found: 510.2616.
4.3.4. N-BocValLys(Cbz)ValOH 1n. White solid, mp 165e166 ꢀC; IR
(KBr, cmꢁ1) 3424, 3327, 2965, 1690, 1645; 1H NMR (500 MHz,
CD3OD) dH 0.89e0.95 (m, 12H), 1.38e1.52 (m, 13H), 1.66e1.69 (m,
1H), 1.78e1.79 (m, 1H), 1.99e2.02 (m, 1H), 2.14e2.18 (m, 1H), 3.10 (t,
J¼6.8 Hz, 2H), 3.89 (d, J¼6.7 Hz, 1H), 4.25 (d, J¼5.5 Hz, 1H), 4.45 (m,
1H), 5.06 (s, 2H), 7.28e7.34 (m, 5H); 13C NMR (125 MHz, CD3OD) dC
18.4, 18.5, 19.9, 23.9, 28.7, 30.4, 32.0, 32.8, 41.6, 54.4, 59.8, 61.5, 67.4,
80.6, 128.8, 128.9, 129.4, 138.4, 158.0, 158.9, 173.9, 174.4, 176.4;
HRMS (FAB) calcd for (MþH)þ C29H47N4O8: 579.3394, found
579.3385.
4.3. Preparation of tripeptides 1e, 1l, 1m, 1n
EDC hydrochloride (1.1 equiv) and HOBt (1.2 equiv) were added
to the solution of N-BocXaaOH (Xaa¼Gln, Glu(OMe), Lys(N-Cbz),
1.0 equiv), TsOH salt of ValOBn (1.0 equiv), and i-Pr2NEt (1.1 equiv)
in DMF at 0 ꢀC. The mixture was stirred for 2 h at 0 ꢀC and
overnight at room temperature, and concentrated in vacuo. The
residue was dissolved in CH2Cl2, and washed with 4% NaHCO3, 1 M
HCl, and water. The organic layer was dried over Na2SO4 and
concentrated in vacuo giving a residue that was subjected to silica
gel column chromatography using hexane/AcOEt or CH2Cl2/MeOH
as eluents to give the desired protected dipeptide N-BocXaaVa-
lOBn (65e87%).
Boc group in this dipeptide was removed by using TFA in CH2Cl2
at 0 ꢀC to room temperature until starting material was consumed
completely (TLC monitoring). After reaction was complete, the
mixture was evaporated to give the TFA salt of XaaValOBn. Simi-
larly, using the repetitive peptide coupling sequence with N-Boc-
ValOH gave benzyl protected tripeptides N-BocValXaaValOBn (two
steps, 64e82%). Debenzylation of the peptide was performed by
treatment with 10% Pd/C and H2 in MeOH (in the case of Xaa¼Gln,
use of MeOH and 1,4-dioxane as a solvent with heating because of
difficult solubility) with TLC monitoring. After complete con-
sumption of starting material, the mixture was filtered through
Celite, and the filtrate was evaporated, and recrystallized with
MeOH and diethyl ether to give 1e, 1l, 1n (85e94%). In the case of
1m, 1n was debenzylated by 10% Pd/C and H2 in MeOH and pro-
tected with Boc using (Boc)2O to give 1m (89%).
4.4. Preparation of tripeptides 1hej
In a similar manner, reaction of N-BocValXaaOH (Xaa¼Tyr, Trp,
His, 1.0 equiv) with TsOH salt of ValOBn (1.0 equiv) gave the de-
sired protected tripeptide N-BocValXaaValOBn (60e82%). (Boc)2O
(1.2 equiv) was added to a CH2Cl2 solution of tripeptide, DMAP
(0.1 equiv), and i-Pr2NEt (1.2 equiv) at 0 ꢀC. The mixture was
stirred at room temperature (TLC monitoring). After reaction was
complete, the mixture was concentrated in vacuo. AcOEt was
added to the residue, which was washed with 4% NaHCO3, 1 M
HCl, and water. The organic layer was dried over Na2SO4 and
concentrated in vacuo giving a residue that was subjected to silica
gel column chromatography using CH2Cl2/AcOEt or CH2Cl2/MeOH
as eluents to give the desired protected dipeptide N-BocValXaa(-
Boc)ValOBn (63e81%). Debenzylation (see above) using 10% Pd/C
and H2 and recrystallization gave tripeptides 1hej, respectively
(75e95%).
4.4.1. N-BocValTyr(Boc)ValOH 1h. White solid, mp 134e135 ꢀC; IR
(KBr, cmꢁ1) 3421, 2971, 1734, 1640; 1H NMR (500 MHz, CD3OD) dH
0.79e0.93 (m, 12H), 1.39 (s, 9H), 1.61 (s, 9H), 1.93e1.97 (m, 1H),
2.12e2.16 (m, 1H), 3.06e3.22 (m, 2H), 3.84 (d, J¼6.7 Hz,1H), 4.30 (d,
J¼5.5 Hz, 1H), 7.19e7.28 (m, 2H), 7.62e7.64 (m, 1H), 8.06e8.07 (m,
1H); 13C NMR (125 MHz, CD3OD) dC 18.3, 18.4, 19.6, 19.7, 28.5, 28.7,
31.9, 32.0, 54.1, 59.1, 61.6, 80.6, 84.7, 116.0, 117.1, 120.1, 123.6, 125.4,
131.8, 136.9, 150.9, 157.8, 173.3, 174.3, 174.4; HRMS (FAB) calcd for
(MþH)þ C29H46N3O9: 580.3234, found: 580.3215.
4.3.1. N-BocValGlnValOH 1e. White solid, mp 204e205 ꢀC; IR (KBr,
cmꢁ1) 3320, 2968, 1649; 1H NMR (500 MHz, CD3OD) dH 0.88e1.06
(m, 12H), 1.44 (s, 9H), 1.91e2.22 (m, 4H), 2.39e2.43 (m, 2H), 3.88 (d,
J¼7.1 Hz, 1H), 4.30 (d, J¼5.5 Hz, 1H), 4.51 (t, J¼6.9 Hz, 1H); 13C NMR
(125 MHz, CD3OD) dC 18.3, 18.5, 19.7, 19.8, 28.7, 31.3, 31.8, 31.9, 53.7,
59.4, 61.5, 80.6, 158.0, 173.5, 174.5, 175.2, 177.0; HRMS (FAB) calcd
for (MþH)þ C20H37N4O7 445.2662, found: 445.2632.
4.4.2. N-BocValTrp(Boc)ValOH 1i. White solid, mp 162e163 ꢀC; IR
(KBr, cmꢁ1) 3413, 3330, 2971,1734, 1645; 1H NMR (500 MHz, CDCl3)
dH 0.81e0.89 (m, 12H), 1.37 (s, 9H), 1.63 (s, 9H), 2.08e2.19 (m, 2H),
3.11 (dd, J¼13.9, 6.7 Hz, 1H), 3.26 (dd, J¼13.9, 5.8 Hz, 1H), 4.02e4.04
(m,1H), 4.37e4.39 (m,1H), 4.85e4.89 (m,1H), 5.05 (d, J¼4.9 Hz,1H),
6.81 (d, J¼4.9 Hz,1H), 7.21e7.31 (m, 3H), 7.50 (s,1H), 7.61 (d, J¼7.6 Hz,
1H), 8.10 (br, 1H); 13C NMR (125 MHz, CDCl3) dC 17.5, 17.8, 18.8, 19.2,
27.8, 30.6, 30.8, 53.3, 57.9, 59.9, 80.3, 83.7, 115.3, 119.0, 122.7, 124.5,
124.6,130.2,135.4,149.6,156.0,171.1,172.0,173.6; HRMS (FAB) calcd
for (MþH)þ C31H47N4O8: 603.3394, found: 603.3394.
4.3.2. N-BocValGlu(OMe)ValOH 1l. White solid, mp 104e105 ꢀC; IR
(KBr, cmꢁ1) 3320, 2968, 1722, 1529; 1H NMR (500 MHz, CD3OD) dH
0.87e1.00 (m, 12H), 1.44 (s, 9H), 1.90e2.21 (m, 4H), 2.43e2.47 (m,
2H), 3.69 (s, 3H), 3.86 (d, J¼7.0 Hz,1H), 4.30 (d, J¼5.5 Hz,1H), 4.51 (t,
J¼6.8 Hz, 1H); 13C NMR (125 MHz, CD3OD) dC 18.2, 18.6, 19.6, 19.8,
28.5, 28.7, 30.9, 31.7, 31.9, 52.2, 53.5, 59.1, 61.6, 80.6, 158.0, 173.4,
174.5, 174.6, 175.1; HRMS (FAB) calcd for (MþH)þ C21H38N3O8:
460.2659, found: 460.2628.
4.4.3. N-BocValHis(Boc)ValOH 1j. White solid, mp 165 ꢀC; IR (KBr,
cmꢁ1) 3326, 2971, 1654; 1H NMR (500 MHz, CDCl3) dH 0.82e1.00
(m, 12H), 1.42 (s, 9H), 1.60 (s, 9H), 2.03e2.09 (m, 1H), 2.24e2.30 (m,
1H), 2.75e2.79 (m, 1H), 3.19e3.22 (m, 1H), 3.95e3.98 (m, 1H),
4.51e4.53 (m, 1H), 4.92e4.95 (m, 1H), 5.13 (d, J¼8.2 Hz, 1H), 7.19 (s,
1H), 7.90 (m, 1H), 8.08 (s, 1H); 13C NMR (125 MHz, CDCl3) dC 17.4,
17.9, 18.6, 19.2, 27.8, 28.3, 31.0, 31.3, 31.4, 52.9, 57.9, 59.6, 79.7, 86.3,
4.3.3. N-BocValLys(Boc)ValOH 1m. White solid, mp 104e105 ꢀC; IR
(KBr, cmꢁ1) 3320, 3081, 1694, 1652; 1H NMR (500 MHz, CD3OD) dH

1122
K. Maeda et al. / Tetrahedron 71 (2015) 1117e1123
115.4, 136.8, 138.0, 146.2, 155.8, 171.1, 171.4, 174.6; HRMS (FAB) calcd
HRMS (FAB) calcd for (MþH)þ C20H37N4O5: 413.2764, found:
for (MþH)þ C26H44N5O8: 554.3190, found: 554.3172.
413.2759.
4.5.6. Compound 3e (1:1 mixture of diastereomers). White solid, mp
213 ꢀC; IR (KBr, cmꢁ1) 3428, 3293, 3073, 2965, 2248, 1636; 1H NMR
(300 MHz, CD3OD) dH 0.89e0.98 (m, 12H), 1.45 (s, 9H), 1.66e1.79
(m, 2H), 1.89e2.09 (m, 4H), 2.11e2.50 (m, 4H), 3.67e3.87 (m, 2H),
4.27e4.31 (m, 1H), 13C NMR (75 MHz, CD3OD) dC 14.8, 18.5, 18.6,
18.9, 19.6, 19.7, 19.8, 28.4, 28.8, 28.9, 29.4, 31.6, 31.8, 32.6, 33.4, 33.5,
54.8, 55.2, 55.4, 61.8, 62.4, 80.7, 80.8, 120.9, 121.0, 173.9, 174.7, 174.8,
177.7, 177.9; HRMS (FAB) calcd for (MþH)þ C22H40N5O5: 454.3029,
found: 454.3029.
4.5. General procedure for photoreaction of tripeptide 1
An aqueous CH3CN solution (CH3CN 36 ml, H2O 4 ml) of tri-
peptide 1 (20 mM), acrylonitrile 2 (0.052 ml, 20 mM), Phen
(143 mg, 20 mM), and DCB (103 mg, 20 mM) in Pyrex vessels
(18 mmꢂ180 mm) was purged with argon for 10 min. The mixture
was irradiated with 100 W high-pressure mercury lamp for 6 h.
Removal of CH3CN gave an aqueous solution that was extracted
with EtOAc, dried over Na2SO4, and concentrated in vacuo, giving
a residue that was subjected to silica gel column chromatography
using CH2Cl2/AcOEt or CH2Cl2/MeOH as eluents to give adduct 3.
Other photoreactions such as reduction and substitution were also
performed by using a similar procedure.
4.5.7. Compound 3h (1:1 mixture of diastereomers). White solid,
mp 136e138 ꢀC; IR (KBr, cmꢁ1) 3326, 2966, 2933, 2248, 1761, 1646;
1H NMR (500 MHz, CDCl3) dH 0.74e0.92 (m, 12H), 1.40e1.89 (m,
21H), 2.11e2.24 (m, 3H), 3.08e3.19 (m, 2H), 3.71e3.81 (m, 2H),
4.57e4.75 (m, 1H), 7.10e7.23 (m, 4H); 13C NMR (125 MHz, CDCl3) dC
14.0, 14.1, 14.6, 17.5, 18.0, 18.9, 19.0, 19.2, 19.3, 27.7, 28.0, 28.1, 28.2,
28.3, 29.9, 30.1, 31.9, 32.2, 36.5, 36.9, 54.1, 54.2, 54.6, 60.8, 61.0, 80.7,
80.8, 83.5, 83.6, 119.8, 120.0, 121.7, 121.8, 130.0, 130.1, 133.8, 134.1,
150.2,150.3,151.6,151.7,156.4,156.6,170.6,170.7,171.4; HRMS (FAB)
calcd for (MþH)þ C31H49N4O7: 589.3601, found: 589.3581.
4.5.1. Procedure for catalytic photoreactions of 1b with 2. An aque-
ous CH3CN solution (CH3CN 13.5 ml, H2O 1.5 ml) of tripeptide 1b
(138 mg, 20 mM), acrylonitrile 2 (0.02 ml, 20 mM), Phen (13.4 mg,
5 mM or 3 mg, 1 mM), and DCB (10 mg, 5 mM or 2 mg, 1 mM) in
Pyrex vessels (18 mmꢂ180 mm) was purged with argon for 10 min.
Procedure for photoreaction and purification of 3b is the same as
the above mentioned method.
4.5.8. Compound 3i (1:1 mixture of diastereomers). White solid, mp
134e136 ꢀC; IR (KBr, cmꢁ1) 3314, 2969, 2248, 1735, 1644; 1H NMR
(500 MHz, CD3OD) dH 0.59e0.62 (m, 3H), 0.81e0.97 (m, 9H), 1.41 (s,
9H), 1.59e1.75 (m, 11H), 1.88e2.04 (m, 2H), 2.29e2.37 (m, 2H),
3.20e3.30 (m, 2H), 3.56e3.68 (m,1H), 3.83e3.85 (m,1H), 4.62e4.65
(m, 1H), 7.24e7.31 (m, 2H), 7.48e7.53 (m, 1H), 7.65e7.69 (m, 1H),
8.10e8.11 (m, 1H); 13C NMR (125 MHz, CD3OD) dC 14.1, 14.7, 18.3,
18.4, 18.9, 19.0, 19.5, 19.6, 28.0, 28.1, 28.4, 28.5, 28.6, 28.7, 31.9, 33.0,
33.3, 55.1, 55.2, 55.3, 61.7, 61.8, 80.7, 84.8, 85.0, 116.2, 116.3, 116.9,
117.1,120.2,120.3,120.7,121.0, 123.8,123.9,125.5,125.6,125.7, 131.4,
136.8,136.9,150.8,158.2,173.2,173.3,173.4,174.2,174.3; HRMS (FAB)
calcd for (MþH)þ C33H50N5O6: 612.3761, found: 612.3752.
4.5.2. Compound 3a (1:1 mixture of diastereomers). White solid,
mp 198e200 ꢀC; IR (KBr, cmꢁ1) 3443, 3330, 2964, 2248, 1637; 1H
NMR (500 MHz, CD3OD) dH 0.85e1.00 (m, 18H), 1.42 (s, 9H),
1.66e1.78 (m, 2H), 1.90e2.07 (m, 3H), 2.33e2.46 (m, 2H),
3.72e3.75 (m, 1H), 3.86e3.89 (m, 1H), 4.07e4.13 (m, 1H); 13C NMR
(125.7 MHz, CD3OD) dC 14.8, 14.9, 18.6, 18.7, 18.8, 19.0, 19.5, 19.6,
19.8, 19.9, 20.0, 28.6, 28.7, 29.2, 31.5, 31.6, 31.7, 31.8, 33.2, 33.3, 55.1,
60.7, 60.8, 61.6, 61.9, 80.6, 80.7, 120.8, 120.9, 158.0, 158.1, 173.6,
173.7, 174.4, 174.6; HRMS (FAB) calcd for (MþH)þ C22H41N4O4:
425.3128, found: 425.3145.
4.5.3. Compound 3b (1:1 mixture of diastereomers). White solid, mp
178e180 ꢀC; IR (KBr, cmꢁ1) 3342, 3314, 2966, 2242, 1642; 1H NMR
(500 MHz, CDCl3) dH 0.78e1.00 (m, 12H), 1.38 (s, 9H), 1.54e1.90 (m,
4H), 2.08e2.22 (m, 2H), 3.07e3.28 (m, 2H), 3.69e3.83 (m, 2H),
4.59e4.75 (m, 1H), 6.42e6.51 (m, 1H), 7.19e7.33 (m, 5H); 13C NMR
(125 MHz, CDCl3) dC 14.0, 14.5, 17.2, 17.4, 17.9, 18.6, 18.9, 19.0, 19.2,
19.3, 29.8, 30.1, 31.9, 32.2, 37.0, 37.5, 54.0, 54.1, 54.6, 60.8, 61.0, 80.6,
80.8, 119.9, 120.0, 127.3, 127.4, 128.9, 129.0, 129.2, 136.3, 136.5, 156.4,
156.6, 170.6, 170.7, 170.8, 171.2, 171.5; HRMS (FAB) calcd for (MþH)þ
C26H41N4O4: 473.3128, found: 473.3109.
4.5.9. Compound 3j (1:1 mixture of diastereomers). Light yellow
solid, mp 154e157 ꢀC; IR (KBr, cmꢁ1) 3289, 2969, 2246, 1757, 1646;
1H NMR (500 MHz, CDCl3) dH 0.55e1.06 (m, 12H), 1.40e2.27 (m,
24H), 2.83e2.87 (m, 1H), 3.23e3.27 (m, 1H), 3.62e3.63 (m, 1H),
3.83e3.88 (m, 1H), 4.60e4.63 (m, 1H), 4.96 (d, J¼3.95 Hz, 1H),
7.17e7.21 (m, 1H), 7.99e8.01 (m, 1H); 13C NMR (125 MHz, CDCl3) dC
14.1, 17.4, 17.6, 18.3, 18.9, 19.3, 19.5, 27.8, 27.9, 28.0, 28.3, 28.4, 28.5,
28.8, 29.9. 31.2, 31,8, 32.1, 32.4, 53.2, 54.0, 54.2, 61.3, 61.5, 80.6, 81.3,
85.9, 86.4, 115.1, 115.2, 119.5, 120.2, 136.7, 139.1, 139.4, 146.6, 146.7,
156.9, 170.7, 170.8, 171.6; HRMS (FAB) calcd for (MþH)þ
C28H47N6O6: 563.3557, found: 563.3533.
4.5.4. Compound 3c (1:1 mixture of diastereomers). White solid, mp
139e141 ꢀC; IR (KBr, cmꢁ1) 3306, 2966, 2247, 1642; 1H NMR
(500 MHz, CD3OD) dH 0.87e0.97 (m,12H),1.45 (s, 9H),1.70e1.76 (m,
2H), 1.91e2.11 (m, 5H), 2.36e2.57 (m, 4H), 3.71e3.85 (m, 2H),
4.40e4.45 (m, 1H), 13C NMR (125 MHz, CD3OD) dC 14.7, 14.8, 15.2,
18.5, 18.6, 18.9, 19.6, 19.7, 19.8, 28.8, 29.4, 31.1, 31.2, 31.6, 31.8, 32.5,
33.3, 33.4, 53.9, 54.2, 54.3, 55.2, 55.3, 55.4, 61.7, 62.1, 80.7, 80.8,
120.9,121.0,158.2,158.3,173.9,174.6; HRMS (FAB) calcd for (MþH)þ
C22H41N4O4S: 457.2849, found: 457.2815.
4.5.10. Compound 3k (1:1 mixture of diastereomers). White solid,
mp 150e152 ꢀC; IR (KBr, cmꢁ1) 3429, 3318, 2965, 2247, 1644; 1H
NMR (500 MHz, CD3OD) dH 0.87e0.98 (m, 12H), 1.44 (s, 9H),
1.73e1.78 (m, 2H), 1.94e2.03 (m, 2H), 2.37e2.88 (m, 4H), 3.70e3.81
(m, 4H), 4.46e4.49 (m, 1H), 7.21e7.34 (m, 5H); 13C NMR (125 MHz,
CD3OD) dC 14.7, 14.8, 14.9, 18.5, 18.6, 18.8, 19.7, 28.7, 29.3, 31.9, 33.4,
33.5, 36.9, 54.2, 54.4, 55.4, 55.5, 61.9, 80.8, 121.0, 128.1, 129.6, 130.2,
139.4, 158.2, 172.6, 172.8, 174.2; HRMS (FAB) calcd for (MþH)þ
C27H43N4O4S: 519.3005, found: 519.2986.
4.5.5. Compound 3d (1:1 mixture of diastereomers). White solid,
mp 105e106 ꢀC; IR (KBr, cmꢁ1) 3327, 3083, 2248, 1646; 1H NMR
(500 MHz, CD3OD) dH 0.88e1.00 (m, 12H), 1.42 (s, 9H), 1.69e1.77
(m, 2H), 1.92e2.10 (m, 2H), 2.36e2.51 (m, 2H), 3.71e3.87 (m, 4H),
4.32e4.39 (m, 1H); 13C NMR (125 MHz, CD3OD) dC 14.4, 14.6, 14.7,
14.8, 15.5, 15.6, 18. 3, 18.4, 18.6, 18.7, 18.8, 19.0, 19.6, 19.7, 19.8, 28.8,
29.3, 29.3, 29.4, 29.6, 31.5, 32.7, 55.4, 55.6, 56.9, 57.1, 62.1, 62.7,
80.7, 80.9, 121.1, 121.2, 158.0, 158.5, 172.5, 172.6, 174.4, 174.5, 174.8;
4.5.11. Compound 3l (1:1 mixture of diastereomers). White solid, mp
159 ꢀC; IR (KBr, cmꢁ1) 3317, 2964, 2248, 1740, 1644; 1H NMR
(500 MHz, CD3OD) dH 0.89e1.00 (m, 12H), 1.45 (s, 9H),1.67e2.15 (m,
6H), 2.36e2.49 (m, 4H), 3.66e3.85 (m, 5H), 4.29e4.33 (m, 1H); 13
C
NMR (125 MHz, CD3OD) dC 14.7, 14.8, 18.5, 18.6, 18.8, 19.5, 19.6, 19.7,
19.8, 28.0, 28.1, 28.7, 28.8, 29.3, 29.4, 31.0, 31.1, 31.6, 31.8, 33.3, 33.4,
52.2, 52.3, 54.3, 54.4, 54.5, 55.1, 55.2, 55.3, 55.4, 61.7, 62.1, 80.6, 80.7,

K. Maeda et al. / Tetrahedron 71 (2015) 1117e1123
1123
120.9,121.0,158.1,158.3,173.6,173.7,173.8,174.6,174.9,175.1; HRMS
References and notes
(FAB) calcd for (MþH)þ C23H41N4O6: 469.3026, found: 469.3016.
1. (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173e180; (b) Davie, E. A. C.; Mennen,
S. M.; Xu, Y.; Miller, S. J. Chem. Rev. 2007, 107, 5759e5812; (c) Horne, W. S.;
Gellman, S. H. Acc. Chem. Res. 2008, 41, 1399e1408; (d) Fiori, K. W.; Puchlopek,
A. L. A.; Miller, S. J. Nat. Chem. 2009, 1, 630e634; (e) Liu, R.; Suarez, J. M.;
Weisblum, B.; Gellman, S. H.; McBride, S. M. J. Am. Chem. Soc. 2014, 136,
14498e14504; (f) Cheloha, R. W.; Maeda, A.; Dean, T.; Gardella, T. J.; Gellman, S.
H. Nat. Biotechnol. 2014, 32, 653e655.
2. (a) Ghadiri, M. R.; Granja, J. R.; Milligan, R. A.; McRee, D. E.; Khazanovich, N.
Nature 1993, 366, 324e327; (b) Ghadiri, M. R.; Granja, J. R.; Buehler, L. K. Nature
1994, 369, 301e304; (c) Garcia-Fandino, R.; Amorín, M.; Castedo, L.; Granja, J. R.
Chem. Sci. 2012, 3, 3280e3285; (d) Montenegro, J.; Ghadiri, M. R.; Granja, J. R.
Acc. Chem. Res. 2013, 46, 2955e2965.
4.5.12. Compound 3m (1:1 mixture of diastereomers). White solid,
mp 140e142 ꢀC; IR (KBr, cmꢁ1) 3424, 2967, 2246, 1689, 1642; 1H
NMR (500 MHz, CD3OD) dH 0.88e0.96 (m, 12H), 1.39e1.51 (m, 22H),
1.64e2.05 (m, 6H), 2.32e2.51 (m, 2H), 3.02 (t, J¼6.5 Hz, 1H),
3.68e3.74 (m, 1H), 3.83e3.87 (m, 1H), 4.23e4.29 (m, 1H); 13C NMR
(125 MHz, CD3OD) dC 14.8, 14.9, 18.6, 18.7, 18.8, 19.6, 19.7, 19.8, 24.2,
24.3, 28.7, 28.8, 29.4, 30.4, 31.8, 32.0, 32.6, 32.7, 33.3, 33.4, 41.1, 48.5,
48.7, 48.9, 49.0, 49.2, 49.4, 49.5, 55.1, 55.3, 61.5, 61.9, 79.8, 80.6, 80.7,
120.9, 121.0, 158.1, 158.2, 158.5, 174.4, 174.5; HRMS (FAB) calcd for
(MþH)þ C28H52N5O6: 554.3918, found: 554.3899.
3. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40,
2004e2021; (b) Iha, R. K.; Wooley, K. L.; Nystrom, A. M.; Burke, D. J.; Kade, M. J.;
Hawker, C. J. Chem. Rev. 2009, 109, 5620e5686.
€
4. (a) Griesbeck, A. G.; Heinrich, T.; Olegemoller, M.; Lex, J.; Molis, A. J. Am. Chem.
Soc. 2002, 124, 10972e10973; (b) Griesbeck, A. G.; Hoffmann, N.; Warzecha, K.-
D. Acc. Chem. Res. 2007, 40, 128e140.
4.5.13. Compound 3n (1:1 mixture of diastereomers). White solid,
mp 146e148 ꢀC; IR (KBr, cmꢁ1) 3327, 2965, 2248, 1696, 1641; 1H
NMR (500 MHz, CD3OD) dH 0.88e0.96 (m, 12H), 1.39e1.55 (m, 13H),
1.66e2.05 (m, 6H), 2.32e2.47 (m, 2H), 3.11 (t, J¼6.1 Hz, 2H),
3.67e3.74 (m,1H), 3.83e3.88 (m,1H), 4.23e4.29 (m,1H), 5.05e5.06
(m, 2H), 7.28e7.34 (m, 5H); 13C NMR (125 MHz, CD3OD) dC 14.7,
14.9, 18.4, 18.5, 18.7, 18.8, 19.6, 19.7, 19.8, 24.1, 24.2, 28.7, 28.8, 29.4,
30.4, 31.8, 32.0, 32.5, 32.6, 33.3, 33.4, 41.4, 55.1, 55.2, 61.4, 61.9, 67.3,
80.6, 80.7, 120.9, 121.0, 128.8, 128.9, 129.4, 138.3, 138.4, 158.0, 158.2,
158.9, 174.3, 174.4, 174.5; HRMS (FAB) calcd for (MþH)þ
C31H50N5O6: 588.3761, found 588.3712.
5. (a) Yoon, U. C.; Jin, Y. X.; Oh, S. W.; Park, C. H.; Park, J. H.; Campana, C. F.; Cai, X.;
Duesler, E. N.; Mariano, P. S. J. Am. Chem. Soc. 2003, 125, 10664e10671; (b) Cho,
D. W.; Yoon, U. C.; Mariano, P. S. Acc. Chem. Res. 2011, 44, 204e215.
6. (a) Aimetti, A. A.; Shoemaker, R. K.; Lin, C. C.; Anseth, K. S. Chem. Commun. 2010,
4061e4063; (b) Aimetti, A. A.; Feaver, K. R.; Anseth, K. S. Chem. Commun. 2010,
5781e5783; (c) Kramer, J. R.; Deming, T. J. J. Am. Chem. Soc. 2012, 134,
4112e4115.
7. (a) Yoshimi, Y.; Itou, T.; Hatanaka, M. Chem. Commun. 2007, 5244e5246; (b)
Itou, T.; Yoshimi, Y.; Morita, T.; Tokunaga, Y.; Hatanaka, M. Tetrahedron 2009, 65,
263e269; (c) Yoshimi, Y.; Masuda, M.; Mizunashi, T.; Nishikawa, K.; Maeda, K.;
Koshida, N.; Itou, T.; Morita, T.; Hatanaka, M. Org. Lett. 2009, 11, 4652e4655; (d)
Yoshimi, Y.; Hayashi, S.; Nishikawa, K.; Haga, Y.; Maeda, K.; Morita, T.; Itou, T.;
Okada, Y.; Ichinose, N.; Hatanaka, M. Molecules 2010, 15, 2623e2630; (e)
Yoshimi, Y.; Kobayashi, K.; Kamakura, H.; Nishikawa, K.; Haga, Y.; Maeda, K.;
Morita, T.; Itou, T.; Okada, Y.; Hatanaka, M. Tetrahedron Lett. 2010, 51,
2332e2334; (f) Itou, T.; Yoshimi, Y.; Nishikawa, K.; Morita, T.; Okada, Y.; Ichi-
nose, N.; Hatanaka, M. Chem. Commun. 2010, 6177e6179; (g) Nishikawa, K.;
Yoshimi, Y.; Maeda, K.; Morita, T.; Takahashi, I.; Itou, T.; Inagaki, S.; Hatanaka, M.
J. Org. Chem. 2013, 78, 582e589; (h) Nishikawa, K.; Ando, T.; Maeda, K.; Morita,
T.; Yoshimi, Y. Org. Lett. 2013, 15, 636e638; (i) Yoshimi, Y.; Washida, S.; Okita, Y.;
Nishikawa, K.; Maeda, K.; Hayashi, S.; Morita, T. Tetrahedron Lett. 2013, 54,
4324e4326; (j) Yoshimi, Y.; Hayashi, S.; Nishikawa, K.; Okita, Y.; Maeda, K.;
Morita, T.; Itou, T. Res. Chem. Intermed. 2013, 39, 397e402.
8. Very recently, the similar photoinduced decarboxylative radical reactions of
carboxylic acids by using Ir, TiO2, and Fukuzumi catalyst have been reported. Ir
catalyst: (a) Zuo, Z.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 5257e5260;
(b) Chu, L.; Ohta, C.; Zuo, Z.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136,
10886e10889 TiO2: (c) Manley, D. W.; McBurney, R. T.; Miller, P.; Walton, J. C. J.
Org. Chem. 2014, 79, 1386e1398; (d) Shimaoka, K.; Kuwahara, S.; Yamashita, M.;
Katayama, K. Anal. Sci. 2014, 30, 619e621 Fukuzumi catalyst: (e) Cassani, C.;
Bergonzini, G.; Wallentin, C. J. Org. Lett. 2014, 16, 4228e4231.
9. Similar quenching by tyrosine and tryptophan in the photoinduced de-
carboxylation of phthalimide derivatives has been reported Griesbeck, A. G.;
Neudorfl, J.; Kiff, A. Beilstein J. Org. Chem. 2011, 7, 518e524.
10. Oxidation potential versus SCE was estimated by using values versus NHE given
the references Harriman, A. J. Phys. Chem. 1987, 91, 6102e6104.
4.5.14. Compound 5. White solid, mp 177 ꢀC; IR (KBr, cmꢁ1) 3309,
3087, 1686, 1640; 1H NMR (300 MHz, CD3OD) dH 0.77e0.84 (m,
12H), 1.42 (s, 9H), 1.63e1.72 (m, 1H), 1.90e1.97 (m, 1H), 2.78e2.87
(m, 4H), 3.80 (d, J¼6.6 Hz, 1H), 4.61 (t, J¼7.5 Hz, 1H), 7.15e7.28 (m,
5H); 13C NMR (75 MHz, CD3OD) dC 18.5, 19.6, 20.5, 38.9, 56.0, 62.0,
80.7, 127.8, 129.5, 130.3, 138.3, 158.2, 173.0, 174.1; HRMS (FAB) calcd
for (MþH)þ C23H38N3O4: 420.2862, found 420.2885.
4.5.15. Compound 6 (1:1 mixture of diastereomers). White solid, mp
136 ꢀC; IR (KBr, cmꢁ1) 3305, 2966, 2229, 1646; 1H NMR (300 MHz,
CDCl3) dH 0.69e0.94 (m, 12H), 1.36e1.63 (m, 9H), 1.91e2.22 (m, 2H),
3.00e3.16 (m, 2H), 3.65e3.90 (m, 1H), 4.62e4.71 (m, 2H), 7.12e7.33
(m, 7H), 7.54e7.60 (m, 2H); 13C NMR (75 MHz, CD3OD) dC 18.4, 18.5,
18.6, 19.2, 19.4, 19.5, 19.7, 20.1, 20.2, 28.7, 33.8, 34.1, 34.2, 55.9, 56.0,
56.1, 60.8, 61.2, 61.6, 111.6, 111.7, 119.7, 127.7, 127.8, 127.9, 129.3,
129.4, 129.5, 129.6, 130.2, 130.3, 130.4, 133.2, 138.1, 148.7, 149.1,
158.0, 172.6, 174.1; HRMS (FAB) calcd for (MþH)þ C30H41N4O4:
521.3128, found 521.3138.
11. Thanasekaran, P.; Rajagopal, S.; Srinivasan, C.; Ramaraj, R.; Ramamurthy, P.;
Venkatachalapathy, B. J. Phys. Chem. A 1997, 101, 8195e8199.
12. Oxidation potentials of carboxylate ions (RCOꢁ2 ) show a slight dependence on R.
Thus, the value of oxidation potential for the carboxylate ion of 1 might be
similar to that of the hexanoate ion. Galicia, M.; Gonzalez, F. J. J. Electrochem.
Soc. 2002, 149, D46eD50.
Supplementary data
1H and 13C NMR spectra data for all new compounds. This ma-
terial is available free of charge via internet. Supplementary data
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2014.12.075.
13. Murov, S. L.; Carmichael, I.; Hug, G. L. Handbook of Photochemistry; Marcel
Dekker: New York, NY, 1993; p 271.