Peptoid Helix Displaying Flavone and Porphyrin: Synthesis and Intramolecular Energy Transfer

Article abstract of DOI:10.1021/acs.joc.9b02358

Natural light-harvesting complexes (LHCs) absorb a broad spectrum of sunlight using a collection of photosynthetic pigments whose spatial arrangement is controlled by a protein matrix and exhibit efficient energy transfer. We constructed a novel light-harvesting protein mimic, which absorbs light in the UV to visible region (280-700 nm) by displaying flavone and porphyrin on a peptoid helix. First, an efficient synthesis of 4′-derivatized 7-methoxyflavone (7-MF, 3 and 4) was developed. The flavone-porphyrin-peptoid conjugate (FPPC) was then prepared via Miyaura borylation on a resin-bound peptoid followed by Suzuki coupling between the peptoid and pigment. Circular dichroism spectroscopy indicated that the FPPC underwent helix-to-loop conversion of the peptoid scaffold upon changing the solvent conditions. A distinct intramolecular energy transfer was observed from 7-MF to porphyrin with greater efficiency in the helix than that in the loop conformation of the peptoid, whereas no clear evidence of energy transfer was obtained for unstructured FPPC. We thus demonstrate the value of the helical peptoid, which provided a controlled orientation for 7-MF and porphyrin and modulated the energy transfer efficiency via conformational switching. Our work provides a way to construct a sophisticated LHC mimic with enhanced coverage of the solar spectrum and controllable energy transfer efficiency.

Full text of DOI:10.1021/acs.joc.9b02358

Subscriber access provided by Université de Strasbourg - Service Commun de la Documentation
Article
Peptoid helix displaying flavone and porphyrin:
Synthesis and intramolecular energy transfer
Woojin Yang, Junhyuk Jo, Hyeongyeol Oh, Hohjai Lee, Won-jin Chung, and Jiwon Seo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02358 • Publication Date (Web): 28 Oct 2019
Downloaded from pubs.acs.org on October 28, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Peptoid helix displaying flavone and porphyrin: Synthesis and
intramolecular energy transfer
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Woojin Yang,† Junhyuk Jo,† Hyeongyeol Oh,† Hohjai Lee,* Won-jin Chung,* Jiwon Seo*
Department of Chemistry, School of Physics and Chemistry, Gwangju Institute of Science and
Technology, 123 Cheomdan-gwagiro, Buk-gu, Gwangju 61005, South Korea.
* Corresponding authors
Email: jseo@gist.ac.kr (J. Seo), wjchung@gist.ac.kr (W.-j. Chung), and hohjai@gist.ac.kr (H.
Lee)
† These authors contributed equally to this work.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 30
1
2
3
4
5
6
Abstract
7
8
9
Natural light-harvesting complexes (LHCs) absorb a broad spectrum of sunlight using a
collection of photosynthetic pigments whose spatial arrangement is controlled by a protein
matrix and exhibit efficient energy transfer. We constructed a novel light-harvesting protein
mimic, which absorbs light in the UV to visible region (280−700 nm) by displaying flavone
and porphyrin on a peptoid helix. First, an efficient synthesis of 4'-derivatized 7-
methoxyflavone (7-MF, 3 and 4) was developed. The flavone-porphyrin-peptoid conjugate
(FPPC) was then prepared via Miyaura borylation on a resin-bound peptoid followed by Suzuki
coupling between the peptoid and pigment. Circular dichroism spectroscopy indicated that the
FPPC underwent helix-to-loop conversion of the peptoid scaffold upon changing the solvent
conditions. A distinct intramolecular energy transfer was observed from 7-MF to porphyrin
with greater efficiency in the helix than that in the loop conformation of the peptoid, while no
clear evidence of energy transfer was obtained for unstructured FPPC. We thus demonstrate
the value of the helical peptoid, which provided a controlled orientation for 7-MF and
porphyrin and modulated the energy transfer efficiency via conformational switching. Our
work provides a way to construct a sophisticated LHC mimic with enhanced coverage of the
solar spectrum and controllable energy transfer efficiency.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 3 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
Introduction
7
8
9
Light harvesting is the first step in natural photosynthesis. Photosynthetic antenna proteins,
often called light-harvesting complexes (LHCs), absorb incoming photons and transfer light
energy to reaction centers, which generate excited electrons and oxidize water molecules.
LHCs are composed of a spatial arrangement of photosynthetic pigments such as chlorophylls,
carotenoids, and flavonoids, which absorb blue/red, green, and ultraviolet light, respectively,
covering most of the sunlight available.1 Inspired by natural photosynthetic proteins, artificial
LHCs have been constructed on various scaffolds (e.g., peptides and DNA) displaying
porphyrins and carotenoids.2–5 However, the flavonoids have been rarely utilized for this
purpose.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Flavonoids perform multiple roles in plants.6 As the origin of their name suggests (from the
Latin word flavus, which means yellow), flavonoids are pigments found in flowers and fruits,7
but more importantly they are phytoprotective substances against ultraviolet light (i.e., UV-B,
280–315 nm) or oxidative damage.8–10 The function of flavonoids further encompasses
detoxification,11 signaling,12 and antimicrobial activity.13
Flavones have diverse molecular structures and properties. The basic skeleton of the flavones
consists of three parts: Two phenyl rings (ring A and B) and one 4-pyrone ring (ring C)
(compound 4, Scheme 1).14 The photophysical and chemical properties of the flavones can be
readily modulated by hydroxylation or methoxylation.15–17 Specifically, their light absorption
spectrum shifts toward the red light region when the number of oxygen substituents is
increased.17 Self-association of these flavonoids modulates their optical and electronic
characteristics as well: a phenomenon known as copigmentation occurs via non-covalent
interactions such as π–π stacking, hydrophobic interaction, or hydrogen bonding.18
Alternatively, the properties of the flavonoids can be altered upon conjugation with other
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 30
1
2
3
4
5
6
7
8
9
molecules. For example, conjugates with phthalocyanine,19 fullerene,20 and paclitaxel21 have
been reported, which lead to distinct spectroscopic, antioxidant, and cytotoxic properties,
respectively.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
i
ii
Me
OH
Me
OMe
HO
MeO
MeO
OMe
2
Br
1
resacetophenone
O
O
iii
iv
A
C
MeO
O
MeO
O
3
B
Bpin
4
Br
Scheme 1. Synthesis of 7-methoxyflavone derivatives 3 and 4. Reaction conditions: (i) MeI,
K2CO3, 94%; (ii) NaHMDS, methyl 4-bromobenzoate, 63%; (iii) 48% HBr (aq), NaI, AcOH,
55%; (iv) B2pin2, PdCl2(dppf), KOAc, 50%.
Attempts to conjugate flavonoids with porphyrin, a synthetic analog of the photosynthetic
pigment chlorophyll, have been reported.22–23 Cavaleiro and coworkers synthesized flavone-
porphyrin dyads employing either 1,3-dipolar cycloaddition22 or Buchwald-Hartwig
amination23 reactions. Considering their use in photodynamic therapy applications, the
photophysical properties of the flavone-porphyrin dyads were evaluated, and the coupling of
the flavone to porphyrin led to either increased or decreased quantum yields depending on the
position of the flavone linkage or the presence of a porphyrin core metal. During an energy
transfer study, Song and coworkers conjugated coumarin to porphyrin and demonstrated that
the spectral overlap between the emission of coumarin and the absorption of porphyrin directly
affects the intramolecular energy transfer efficiency in the complex.24 More recently, Gust and
coworkers constructed a hexad from four coumarins and two zinc porphyrins, in which zinc
metal was used as a coordination site to connect an electron-accepting fullerene molecule.25
The artificial coumarin–porphyrin–fullerene system displayed energy transfer between the
ACS Paragon Plus Environment

Page 5 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
coumarin and porphyrin moieties, followed by photoinduced electron transfer from the
pigments to fullerene, mimicking the natural photosynthetic reaction center. Coumarin can be
considered as a simplified form of the flavonoids, where the peripheral phenyl ring of the
flavone (ring B) is removed. Unlike coumarin, natural flavonoids (e.g., 7-methoxyflavone)
have been rarely reported for the construction of artificial light-harvesting systems due to the
lack of established conjugation methods involving the pigment component.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In this study, peptoids (or N-substituted glycine oligomers) were used as a scaffold to display
flavone and porphyrin in a face-to-face arrangement. Upon the incorporation of chiral aromatic
side chains, the peptoid folds into a stable poly-proline type I (PPI) like helix, which has a pitch
length of ~6.0 Å and periodicity of three residues per turn.26 Structural investigations have
elucidated several parameters (e.g., chain length or monomer composition) that affect the
helical conformation.27–32 Peptoids have also been shown to form other types of secondary
structure, such as a peptoid ribbon structure,33 and most notably, a threaded-loop conformation
reported for peptoid nonamers in aprotic solvents.34
In previous work, we have exploited the unique structural properties of peptoids to construct
porphyrin-peptoid conjugates (PPCs) displaying two or three porphyrins on the peptoid
helix.35–38 Initially, two tetraphenylporphyrins (TPPs) were displayed at different positions on
the peptoid helix using a diaminobutane linkage between porphyrin and peptoid backbone,
which provided a precise control over the spatial arrangement of the two porphyrins.35 By
switching one TPP to Zn-TPP, the energy transfer efficiency from the donor (i.e., Zn-TPP) to
acceptor (i.e., free base TPP) was modulated with great precision by controlling the relative
inter-porphyrin distance and orientation.36 The conformational heterogeneity of the PPC was
minimized by replacing the flexible n-butyl linkage with a more rigid phenyl linker to anchor
the pigment to the peptoid backbone. Subsequently, enhanced control over the characteristic
porphyrin interactions via intermolecular J-aggregation or intramolecular excitonic coupling
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 30
1
2
3
4
5
6
7
was achieved.37 Thereafter, the potential application of the PPC was demonstrated in host-guest
interactions and chiral recognition.38
8
9
During our continued efforts to construct peptoid-based artificial light-harvesting protein
mimics using photosynthetic pigments, we noticed that the flavonoids have been less studied
when compared to the porphyrins despite their unique photophysical properties. As mentioned
above, flavone-porphyrin conjugates have been previously reported; however, flavone itself
without any –OH or –OMe substituents is weakly fluorescent and less efficient for light-
harvesting applications.39 In the present study, we have developed an efficient synthetic route
to prepare 4'-derivatized 7-methoxyflavone (7-MF, 3 and 4, shown in Scheme 1) and
successfully conjugated the pigment onto a peptoid scaffold using Miyaura borylation on a
resin-bound peptoid followed by a Suzuki cross-coupling reaction. Unlike the parent
(unsubstituted) flavone, the emission region of 7-MF (400−450 nm) overlaps with the
maximum absorption wavelength of porphyrin (400−430 nm) making energy transfer between
the two pigments feasible. The structural and photophysical properties of the flavone-
porphyrin-peptoid conjugate (FPPC) were investigated using circular dichroism (CD), UV-vis,
and fluorescence spectroscopies. Our donor-acceptor dyad represents a unique energy transfer
system employing two important photosynthetic pigments, flavonoid and porphyrin, and
potentially provides a model system to better understand the photophysical events occurring in
natural photosynthesis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Results and Discussion
Synthesis of the flavones
A Bpin-containing flavone derivative, 4'-(pinacolboryl)-7-methoxyflavone (4, 7-MF-Bpin),
was synthesized from resacetophenone over four steps (Scheme 1). The two phenolic hydroxyl
ACS Paragon Plus Environment

Page 7 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
groups of resacetophenone were initially protected as methyl ether upon reaction with MeI.40
Then, the resulting methyl ketone (1) underwent a Claisen condensation with methyl 4-
bromobenzoate to produce 1,3-diketone 2, which contains an aryl bromide moiety.
Subsequently, the flavone backbone was constructed via demethylative cyclization upon
treatment with HBr (aq) and NaI in AcOH.41 Gratifyingly, the unwanted demethylation of the
para-methoxy group did not take place. It is proposed that the ortho-methoxy group is
preferentially protonated via the assistance of the neighboring ketone moiety, thus resulting in
the selective mono-demethylation reaction. Finally, the Miyaura borylation of aryl bromide 3
with B2pin2 afforded the desired product (4).42 The overall yields of 7-MF-Br (3) and 7-MF-
Bpin (4) were 33 and 16%, respectively.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of the flavone-porphyrin-peptoid conjugate (FPPC)
Table 1. The sequences and structures of peptoids 58.
R2 =
R1 =
MeO
N
R1
N
O
NH
N
O
O
R2
HN
H
NH2
9
Npm(R2)
Npm
7-MF
Nspe
TPP
Compound
Sequence
5
6
7
8
H-Nspe-Nspe-Nspe-Npm(TPP)-Nspe-Nspe-Npm(7-MF)-Nspe-Nspe-NH2
H-Nspe-Nspe-Nspe-Npm-Nspe-Nspe- Npm(7-MF)-Nspe-Nspe-NH2
H-Nspe-Nspe-Nspe-Npm-Nspe-Nspe-Npm(TPP)-Nspe-Nspe-NH2
H-Npm-Npm-Npm-Npm(TPP)-Npm-Npm- Npm(7-MF)-Npm-Npm-NH2
As shown in Table 1, peptoid nonamers 5−8 were designed to have a direct C-C linkage
between the peptoid and pigment. Peptoid 5 is composed of a chiral submonomer ((S)-(–)-1-
phenylethylamine, Nspe) except at the positions of pigment conjugation, and a right-handed
helical fold is expected.26 The pigments were incorporated at the 3rd and 6th positions from
the C-terminus, so the two pigments are at i and i+3 and spatially co-facial.37 Control peptoids
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 30
1
2
3
4
5
6
7
8
9
6 and 7, which contain only 7-MF or TPP, respectively, were prepared. Peptoid 8, a non-helical
version of 5, was synthesized using an achiral monomer (benzylamine, Npm). The synthesis of
the conjugates was achieved by repeating two processes: peptoid chain elongation and pigment
conjugation (Scheme 2). For the synthesis of 5, the peptoid pentamer containing one para-
iodophenyl side chain was prepared via a solid-phase submonomer protocol (Scheme 2(a)).43
Subsequently, the Miyaura borylation reaction of the aryl iodide on the resin-bound peptoid
gave the Bpin-functionalized peptoid (Scheme 2(b) and 2(c)).44 In our hands, the reaction was
successfully carried out in DMF, but not in DMSO (data not shown). The overall conversion
was calculated to be 70% from the iodophenyl peptoid using analytical HPLC (Figure S1). 7-
MF-Br (3) was conjugated to the Bpin functionalized peptoid via a Suzuki-Miyaura cross-
coupling reaction using the previously optimized conditions.37 The peptoid was elongated to
the desired chain length, and a cross-coupling reaction between TPP-Bpin and the iodophenyl
side chain was carried out to yield the desired peptoid (5). Employing the same cross-coupling
conditions, peptoids 6 and 7 were prepared using 7-MF-Bpin (4) and TPP-Bpin, respectively.
All the conjugates were purified by preparative HPLC (>97%) and characterized using ESI-
HRMS (Figure S2–6).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 9 of 30
The Journal of Organic Chemistry
1
2
3
4
(a) Solid-phase peptoid synthesis
5
6
7
8
TPP-Bpin
repeat
O
O
R'
O
HN
N
N
Br
O
B
O
R'-NH2
NMP
OH
DIC, DMF
Br
HN
HN
R
N
R
N
R
9
NH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(b) General synthetic strategy
I
Bpin
Suzuki
coupling
Miyaura
borylation
Br
resin-bound peptoid
I
(i) Suzuki
coupling
peptoid
elongation
Bpin
(ii) cleavage
flavone-porphyrin-peptoid conjugate (FPPC)
(c) Synthesis of 5, 6, and 7
I
I
iii, v
peptoid
O
O
O
O
O
O
O
O
6
7
HN
N
N
HN
N
N
N
N
N
N
N
H
N
N
N
N
N
H
elongation
O
O
O
O
O
O
iv, v
i, ii
Flv
Flv
peptoid
iv, v
O
O
O
O
O
O
O
O
5
HN
N
N
HN
N
N
N
N
N
N
N
H
N
N
N
N
N
H
elongation
O
O
O
O
O
O
I
Scheme 2. (a) Peptoid submonomer synthesis. (b) Schematic representation of the general
synthetic strategy used to prepare the FPPC. (c) Synthesis of 5, 6, and 7. Reaction conditions:
(i) B2pin2, PdCl2(dppf), dppf, KOAc, DMF, 80 °C, 24 h. (ii)−(iv) Pigment, Pd(PPh3)4, SPhos,
K2CO3 (aq), DMF, H2O, microwave irradiation, 80 °C, 3 h (pigment: (ii) 3, (iii) 4, and (iv)
TPP-Bpin). (v) 50% TFA in CH2Cl2 (v/v), rt, 30 min.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 30
1
2
3
4
5
Spectroscopic analysis of the peptoid conjugates
6
7
8
9
Peptoid oligomers composed of α-chiral side chains (e.g., Nspe) typically exhibit helical
secondary structures.26 However, nonameric peptoids can adopt two distinct conformations,
namely a helix or threaded-loop conformation, depending on the solvent used.34 In aprotic
solvents (e.g., MeCN), intramolecular hydrogen bonds formed between the N-terminal cationic
ammonium and backbone carbonyl groups promote the formation of a threaded-loop
conformation, while in protic media (e.g., MeCN/MeOH (1:1, v/v)), the peptoid converts back
to its helical conformation. The circular dichroism (CD) spectra recorded for peptoids 57 in
these two solvents demonstrate the conformational behavior of the peptoid nonamers (Figure
1). In MeCN, the increased negative ellipticity at 202 nm indicates a greater population of
threaded-loop peptoids (Figure 1(a)), but in the presence of a protic solvent, the peptoids
mainly show a helical CD signature with an intense cis-amide conformer peak at 220 nm
(Figure 1(b)). The overall CD intensity observed for peptoids 57 confirms that the peptoid
backbone was well-folded after the pigment conjugation step.37 As expected, peptoid 8 was
CD-silent in both solvents studied.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Circular dichroism (CD) spectra obtained for peptoids 5–8 (50 μM, 20 °C) recorded
in (a) MeCN and (b) MeCN/MeOH (1:1, v/v).
ACS Paragon Plus Environment

Page 11 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
UV-vis spectroscopy was used to characterize the pigments displayed on the peptoid in the
range of 200–700 nm (Figure 2). Peptoids 6 and 7 show similar absorption spectra when
compared to 7-MF (λmax = 309 nm) or TPP (λmax = 413 nm) (Figure S7) except for the strong
peak observed at ~200 nm corresponding to the absorption of the aromatic side chains in the
peptoid. The helical FPPC (5) exhibits characteristic peaks from both 7-MF and TPP. The
absorption peaks observed for 5 are approximately the sum of the peaks of 6 and 7 without the
appearance of a new peak or any peak shift. This indicates that the coupling between the ground
state orbitals of 7-MF and TPP in 5 is negligible even when the two pigments are conjugated
together on the peptoid. 7-MF displayed on helical peptoids 5 and 6 clearly shows a
characteristic absorption at λmax = 315 nm.15 However, this peak was diminished when 7-MF
was conjugated to non-helical peptoid 8. Considering the poor solubility of 8 in both of the
solvent systems studied, it was speculated that the non-specific aggregation of 8 affects the
weak and broadened peak at ~327 nm. In helical peptoids 5 and 7, the characteristic porphyrin
absorption peaks can also be clearly identified.37 In both MeCN and MeCN/MeOH, a sharp
Soret band (λmax = 414 nm) and four distinctive Q-bands (480–700 nm) were observed. In our
previous study, a peptoid helix with a face-to-face display of two porphyrins showed dramatic
porphyrin J-aggregation.35,37 However, in 5 and 7, neither the appearance of a red-shifted Soret
band or a change in the Q-band intensity was observed, indicating the absence of porphyrin J-
aggregation. Again, non-helical peptoid 8 showed diminished porphyrin Soret band and Q-
bands. By comparing the UV-vis spectra of 5 and 8, we confirmed that the helical structure of
the peptoid scaffold is important to keep the pigments soluble in the polar media and to
maintain the individual photophysical properties (e.g., extinction coefficient) of the conjugated
pigments.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 30
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. UV-vis absorption spectra obtained for peptoids 5–8 (50 μM, 20 °C) recorded in (a)
MeCN and (b) MeCN/MeOH (1:1, v/v). The insets show the Q-band absorption region (450–
700 nm).
Energy transfer in the FPPC
Fluorescence emission spectroscopy was used to investigate the energy transfer from 7-MF
to TPP. Figures 3(a) and (b) show the emission spectra of 5−8 recorded in MeCN and
MeCN/MeOH (1:1, v/v), respectively at the same concentration (5 μM). The excitation
wavelength was 310 nm at which 7-MF is dominantly excited. The 7-MF emission of 6 occurs
at 402 nm in MeCN and at 423 nm in MeCN/MeOH (1:1, v/v); the red-shift in the 7-MF
emission observed in the latter can be explained by the hydrogen bonding between 7-MF and
MeOH, which stabilizes the excited 7-MF species.45 As shown in Figure 2, TPP has a minor
absorption at 310 nm, resulting in the two emission bands of 7 observed between 630 nm and
750 nm in both of the solvent systems studied.
ACS Paragon Plus Environment

Page 13 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Fluorescence emission spectra of peptoids 5−8 (5 μM) recorded under the specific
excitation wavelength of 7-MF (λex = 310 nm) in (a) MeCN and (b) MeCN /MeOH (1:1, v/v).
The insets show the magnified spectra around the 7-MF emission region. In (a), 5−8 are
magnified 80 times. In (b), 5, 7, and 8 are magnified 10 times.
Quantitative analysis of the emission spectra can provide useful information regarding the
energy transfer from 7-MF to TPP. For peptoids conjugated with a single pigment (6 and 7),
the emissive process occurs without energy transfer from 7-MF to TPP, whereas the emission
spectra of FPPC 5 includes the emissive process of the displayed pigments with energy transfer.
When peptoid scaffold is in the helical conformation (Figure 3(b)), the TPP emission in 5 is
strongly enhanced compared to that in 7 (shown by the gray arrow), while the 7-MF emission
in 5 is drastically diminished compared to that in 6. For the threaded-loop conformer (Figure
3(a)), similar trends of spectral change, but with much smaller magnitudes, were observed.
Based on the absolute areas of the emission bands, the extents to which the TPP emission was
enhanced and the 7-MF emission was decreased were compared (Table S1 and S2); the energy
transfer from 7-MF to TPP is clearly more efficient when the peptoid is in a helical
conformation. The energy transfer can be attributed to Förster resonance energy transfer
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 30
1
2
3
4
5
6
7
8
9
(FRET) facilitated by the short distance between 7-MF and TPP, and the spectral overlap of
the donor emission and acceptor absorption (Figure S8).46 This explanation was also supported
by the valley observed at 414 nm in the 7-MF emission band of 5 (Figure 3, inset). This
wavelength corresponds to the Soret band of TPP shown in Figure 2. Under both solvent
conditions, unstructured FPPC 8 showed no clear evidence of energy transfer compared to that
shown by 5, demonstrating the importance of the spatially controlled orientation of the donor
and acceptor pigments. We also examined the effect of photoexcitation at 550 nm with which
only TPP can be excited and found no change in the emission bands observed for 5 and 7,
which indicates energy transfer does not occur in the reverse direction from TPP to 7-MF
(Figure S9).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Energy transfer in 5 is more efficient in MeCN/MeOH than in MeCN, which reflects the effect
of the peptoid backbone structure holding the donor and acceptor. In MeCN/MeOH, 7-MF and
TPP in 5 are arranged in a co-facial manner on the well-defined helical peptoid with an inter-
pigment distance of ~6 Å.36 The increased population of threaded-loop conformers in MeCN
results in the separation between 7-MF and TPP becoming larger (~14 Å).34 In addition, the
strongly enhanced 7-MF emission observed in MeCN/MeOH should be taken into account (6
in Figure 3(b)). To confirm the effect of MeOH on the unusual enhancement of the 7-MF
emission, we measured the fluorescence emission spectrum in a binary solvent system
consisting of MeCN/MeOH with an increasing MeOH content (Figure S10). When the MeOH
content was increased from 1 to 99%, the 7-MF emission peak area increased ~170-fold for 6
(Figure S11). However, this enhancement was much smaller for 7-MF alone (13-fold increment
in the peak area). The enhancement in the emission of 7-MF in 6 was attributed to the protic
solvent effect, which can restrict the degree of freedom of the molecular geometry of 7-MF;
the direct C-C bond between 7-MF and the peptoid aromatic side chain or hydrophobic
environment provided by helical peptoid backbone may play a role in this observation.47–49
ACS Paragon Plus Environment

Page 15 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
However, further in-depth studies are warranted to explain this unexpected emission
enhancement.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conclusion
In summary, we have developed a synthetic route for the preparation of a flavone-porphyrin-
peptoid conjugate (FPPC) as a novel artificial light-harvesting complex. An efficient synthesis
of 4'-derivatized 7-methoxyflavone (7-MF-Bpin or 7-MF-Br) and the subsequent conjugation
of 7-MF on a resin-bound peptoid using a Miyaura borylation followed by Suzuki cross-
coupling reaction have been accomplished. Our optimized methods broaden the scope of the
direct C-C bond forming conjugation reactions that can be applied to peptoids; any peptoid
containing an aryl halide side chain can be converted into a peptoid containing the Bpin
functionality, which can be used as a conjugation site to attach a variety of aryl halides (e.g.,
7-MF-Br).
The helical structure of the peptoid scaffold was important in (1) keeping the hydrophobic
pigments soluble in a polar medium and (2) maintaining the individual photophysical
properties of each conjugated pigment. The steady-state fluorescence spectra indicate that
characteristic intramolecular energy transfer occurs from the 7-MF donor to the porphyrin
acceptor, transferring the absorbed UV energy into a visible light emission. The energy transfer
efficiency was greater in the helix than that in the loop conformation of the peptoid. Our results
demonstrate that helical peptoids provide excellent scaffolds for directing the interactions
between the displayed pigments and can tailor their photophysical properties. Employing our
synthetic pathway, it is possible to design more elaborate pigment-peptoid conjugates as
efficient organic light-harvesting molecular machines with functional properties overcoming
the weaknesses of natural systems.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 30
1
2
3
4
5
6
7
8
Experimental Section
9
General information
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reactions were performed in oven-dried (140 °C) or flame-dried glassware under an
atmosphere of dry argon unless otherwise noted. Tetrahydrofuran (THF, Fisher, HPLC grade)
dried by
and 1,4-dioxane (Fisher, HPLC grade) were
percolation through a column packed
with neutral alumina and a column packed with Q5 reactant, a supported copper catalyst for
scavenging oxygen, under a positive pressure of argon. Acetone (Daejung) was distilled from
MgSO4 under argon, and acetic acid (Daejung) was distilled without a drying agent under argon
prior to use. Solvents for recrystallization
, work-up, and chromatography were hexanes
CH2Cl2 (Daejung, Extra Pure), Et2O (Daejung, Extra Pure), EtOAc
(Duksan, Extra Pure),
(Daejung, Extra Pure), and MeOH (Daejung, Extra Pure).
and column
Filtration
chromatography were performed using Merck silica gel (SiO ) 60 Å (0.040 0.063 mm). For
–
2
reactions carried out above room temperature, oil bath was used as a heat source.
MeI (Alfa), K2CO3 (Duksan), NaHMDS (Alfa), HBr (aq. 48% (w/w), Daejung), NaI
(Samchun), B2pin2 (Alfa), PdCl2(dppf) (BePharm), KOAc (Duksan), Fmoc-Rink Amide
MBHA resin (100–200 mesh, 0.65 mmol/g, Merck Millipore), and N,N-
diisopropylcarbodiimide (DIC, Advanced ChemTech) were used as received. For peptoid
synthesis and Suzuki coupling reactions, peptide synthesis grade N,N-dimethylformamide
(DMF; 99.8%) was used. The following reagents were recrystallized from the indicated
solvent: resacetophenone (Alfa, CH2Cl2/hexanes) and methyl 4-bromobenzoate (Alfa, MeOH).
13
1H NMR and C{1H} NMR spectra were recorded on a Jeol ECS400 (400 MHz/1H, 100
MHz/13C{1H}) spectrometer. 1H NMR and 13C{1H} NMR spectra were referenced to residual
1
13
chloroform (7.26 ppm, H, 77.23 ppm, C{1H}). Chemical shifts are reported in ppm, and
ACS Paragon Plus Environment

Page 17 of 30
The Journal of Organic Chemistry
1
2
3
4
5
multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), bs (broad singlet),
6
7
8
9
Analytical thin-layer
and m (multiplet). Coupling constants, J, are reported in Hertz.
chromatography (TLC) was conducted on Merck silica gel 60 F254 TLC plates. Visualization
was accomplished with UV (254 nm), KMnO , and staining solution. High
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
p-anisaldehyde
4
resolution electrospray ionization mass spectrometry (ESI-HRMS) was performed on an
Agilent 6520 quadrupole-time-of-flight (Q-TOF) spectrometer. Data are reported in the form
of (m/z).
Synthetic procedure for 1–4
Compound 1.40, 50 2',4'-dimethoxyacetophenone; To a stirred mixture of resacetophenone (1.5
g, 10 mmol) and dry K2CO3 (76 g, 550 mmol, 55 equiv) in acetone (15 mL) was added MeI
(15 mL, 240 mmol, 24 equiv) at room temperature under Ar, and the mixture was refluxed.
After 44 h, the reaction mixture was cooled to room temperature, diluted with CH2Cl2, and
filtered through a glass frit. The filter cake was rinsed with CH2Cl2. The filtrate was
concentrated under reduced pressure. The residue was diluted with EtOAc and washed with
water. The aqueous layer was extracted with EtOAc twice. The combined organic layers were
dried over MgSO4, filtered through a glass frit, and concentrated under reduced pressure to
give brownish orange solid. The crude material was purified by column chromatography (SiO2,
ϕ: 4.5 cm, l: 13 cm, EtOAc:hexanes = 1:6, Rf = 0.3, UV 254 nm) to afford 1 in 94% yield as
off-white solid (1.7 g, 9.4 mmol). 1H-NMR (400 MHz, CDCl3): δ 7.83 (d, J = 8.9, 1H), 6.52
(dd, J = 8.7, 2.3, 1H), 6.46 (d, J = 2.4, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 2.58 (s, 3H). 13C{1H}-
NMR (100 MHz, CDCl3): δ 198.0, 164.7, 161.3, 132.9, 121.4, 105.2, 98.5, 55.75, 55.66, 32.1.
Compound 2. 1-(4-bromophenyl)-3-(2,4-dimethoxyphenyl)-1,3-propanedione; To a stirred
solution of 1 (2.0 g, 11 mmol) and methyl 4-bromobenzoate (2.6 g, 12 mmol, 1.1 equiv) in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 30
1
2
3
4
5
6
7
8
9
THF (20 mL) was added a solution of NaHMDS (4.2 g, 23 mmol, 2.1 equiv) in THF (20 mL)
at room temperature under Ar, and the flask was rinsed with THF (20 mL) twice. After 19
hours, the reaction mixture was partially concentrated under reduced pressure, diluted with
Et2O, and acidified until pH = 3 with aq 1 N HCl. The organic layer was separated, and the
aqueous layer was extracted with Et2O twice. The combined organic layers were dried over
MgSO4, filtered through a glass frit, and concentrated under reduced pressure to give orange
solid. The crude material was purified by column chromatography (SiO2, ϕ: 3 cm, l: 14 cm,
CH2Cl2, Rf = 0.6, UV 254 nm) and recrystallized from EtOAc/hexanes to afford 2 in 63% yield
as yellow fibers (2.5 g, 6.9 mmol). m. p.: 133.6-134.7 ℃. 1H-NMR (400 MHz, CDCl3): δ 17.06
(bs, 1H), 8.00-7.97 (m, 1H), 7.80-7.78 (m, 2H), 7.60-7.57 (m, 2H), 7.13 (s, 1H), 6.58 (dd, J =
8.7, 2.3, 1H), 6.48 (d, J = 2.3, 1H), 3.93 (s, 3H), 3.86 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3):
δ 184.01, 183.96, 164.4, 160.7, 135.2, 132.4, 131.9, 128.7, 126.8, 117.5, 105.5, 98.8, 97.6,
55.9, 55.7. HRMS (ESI): m/z: calcd for C17H1679BrO4 [M + H]+, C17H1681BrO4 [M + H]+:
363.0232, 365.0212, found 363.0214, 365.0185.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 3.41, 51 4'-bromo-7-methoxyflavone; To a stirred solution of 2 (2.2 g, 6.0 mmol) and
NaI (4.5 g, 30 mmol, 5.0 equiv) in AcOH (34 mL, 590 mmol, 99 equiv) was added 48% (w/w)
aq HBr (14 mL, 120 mmol, 20 equiv) at room temperature under Ar, and the mixture was
heated to 80 ℃. After 17 h, the reaction mixture was cooled to room temperature and poured
to anhydrous K2CO3 (100 g). The mixture was diluted with water and extracted with Et2O. The
aqueous layer was extracted with EtOAc three times. The combined organic layers were
washed with sat. aq NaHSO3, dried over MgSO4, and filtered through a glass frit. The filter
cake was rinsed with CH2Cl2. The filtrate was concentrated under reduced pressure to give pink
solid. The crude material was purified by column chromatography (SiO2, ϕ: 3 cm, l: 12.5 cm,
loading: CH2Cl2, elution: EtOAc:hexanes = 2:5, Rf = 0.2, UV 254 nm) and recrystallized from
ACS Paragon Plus Environment

Page 19 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
EtOAc to afford 3 in 55% yield as pink crystals (1.1 g, 3.3 mmol). m. p.: 181.3-182.6 ℃. 1H-
NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.9, 1H), 7.73 (m, 2H), 7.62 (m, 2H), 6.96 (dd, J =
8.9, 2.4, 1H), 6.92 (d, J = 2.4, 1H), 6.72 (s, 1H), 3.91 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3):
δ 177.8, 164.5, 162.1, 158.0, 132.4, 130.8, 127.7, 127.2, 126.3, 117.8, 114.8, 107.7, 100.5,
56.1. HRMS (ESI): m/z: calcd for C16H1279BrO3 [M + H]+, C16H1281BrO3 [M + H]+: 330.9970,
332.9949, found 330.9960, 332.9937.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 4.42 4'-(pinacolboryl)-7-methoxyflavone; A stirred mixture of 3 (0.33 g, 1.0 mmol),
B2pin2 (0.51 g, 2.0 mmol, 2.0 equiv), PdCl2(dppf) (37 mg, 0.051 mmol, 5 mol%), and KOAc
(0.39 g, 4.0 mmol, 4.0 equiv) in degassed 1,4-dioxane (4 mL) was heated to 85 ℃ under Ar.
After 44 hours, the reaction mixture was cooled to room temperature and concentrated under
reduced pressure. The residue was diluted with CH2Cl2 and washed with sat. aq NaHCO3. The
aqueous layer was extracted CH2Cl2 three times. The combined organic layers were dried over
MgSO4, filtered through a glass frit, and concentrated under reduced pressure to give pale
brown solid. Because 4 is somewhat unstable on SiO2, the crude material was quickly filtered
through SiO2 (ϕ: 4 cm, l: 7 cm, EtOAc, Rf = 0.9, UV 254 nm) and precipitated from
CH2Cl2/hexanes to afford 4 in 50% yield as off-white powder (189 mg, 0.500 mmol). 1H-NMR
(400 MHz, CDCl3): δ 8.12-8.10 (m, 1H), 7.94-7.87 (m, 4H), 6.99-6.96 (m, 2H), 6.82 (s, 1H),
3.92 (s, 3H), 1.36 (s, 12H). 13C{1H}-NMR (100 MHz, CDCl3): δ 178.0, 164.5, 163.1, 158.2,
135.4, 134.2, 132.6, 127.2, 125.4, 117.9, 114.9, 108.0, 100.5, 84.4, 56.1, 25.1. HRMS (ESI):
m/z: calcd for C22H24BO5 [M + H]+: 379.1717, found 379.1723.
Synthetic procedure for peptoids 5–8
Peptoid synthesis protocol. Peptoids were synthesized by the microwave-assisted solid-phase
submonomer synthesis method.43 The reactions were run in a cartridge (Applied Separations,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 30
1
2
3
4
5
6
7
8
9
Allentown, PA, USA, 25 mL) assembled with a filter (Applied Separations, 20 micron) and
accelerated by a CEM MARS 230/60 microwave reaction system (CEM Corp., Matthews, NC,
USA) using a fiber optic temperature probe and magnetic stirrer under atmospheric pressure.
The resin (0.25 mmol, 0.48 g) was swelled in DMF for 20 min and was treated twice with 20%
(v/v) piperidine in DMF (5 min and 20 min, 10 mL each) for Fmoc deprotection.
Bromoacetylation was performed by the addition of bromoacetic acid (6.25 mmol, 1.2 M in
DMF, 5.21 mL) and DIC (5.63 mmol, 0.87 mL). The mixture was stirred in a microwave oven
(300 W max power, 35 °C, ramp 30 s) for 1 min and washed with CH2Cl2 and DMF. Amine
displacement was carried out by the addition of (S)-(-)--methylbenzylamine (Nspe, 3.75
mmol, 1.0 M in NMP, 3.75 mL), benzylamine (Npm, 3.75 mmol, 1.0 M in NMP, 3.75 mL), or
4-iodobenzylamine (Npib, 3.75 mmol, 1.0 M in NMP, 3.75 mL) to the bromoacetylated
peptoids. The mixture was stirred in a microwave oven (300 W max power, 80 °C, ramp 2 min)
for 90 s and washed with CH2Cl2 and DMF. Bromoacetylation and amine displacement were
repeated until the desired sequence was obtained. Peptoids were cleaved from the resin with
50:50 (v/v) TFA/ for 30 minutes at room temperature. The cleavage reaction solution was
filtered by solid-phase extraction (SPE) cartridges with 20 μ PE frit (Applied Separations,
Allentown, PA, USA), and the volatiles were removed by a stream of nitrogen. The crude
peptoid was dissolved in MeCN and analyzed by ESI-MS and analytical HPLC as described
below.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of resin-bound peptoid-boronic acid pinacol ester. The resin-bound iodophenyl-
containing peptoids (0.125 mmol) were suspended in CH2Cl2 for 20 min, and the solvent was
drained. Miyaura borylation reactions were conducted by the addition of
bis(pinacolato)diboron (B2pin2; 127.0 mg, 0.500 mmol), 1,1’-ferrocenediyl-
bis(diphenylphosphine) (dppf; 6.2 mg, 0.011 mmol), Pd(dppf)Cl2 (16.5 mg, 0.023 mmol), and
ACS Paragon Plus Environment

Page 21 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
a sonicated solution of potassium acetate in degassed DMF (0.2 M, 3.75 mL). The mixture was
stirred for 24 h at 80 °C. The resin was washed with CH2Cl2 and DMF.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General conditions for Suzuki-Miyaura cross-coupling reactions on-resin. The resin-bound
peptoids (0.019 mmol) were suspended in CH2Cl2 for 20 min, and the solvent was drained. To
the resin was added 4 (35.9 mg, 0.095 mmol) or TPP-Bpin37 (70.4 mg, 0.095 mmol), Pd(PPh3)4
(6.5 mg, 0.006 mmol), 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl (SPhos; 12.8 mg,
0.011 mmol), and DMF (2.0 mL), and aqueous potassium carbonate solution (1.3 M, 0.07 mL)
was added to initiate the reaction. The mixture was stirred for 3 h at 80 °C (microwave open,
300 W, opened in the air, ramp 2 min). The resin was successively washed with CH2Cl2 and
DMF.
HPLC purification. Analytical HPLC was conducted using a Waters reversed-phase HPLC
system (Waters 2489 UV/visible detector, Waters 1525 Binary HPLC pump, Waters 2707
Autosampler, and Waters 5CH column oven) on a C18 column (SunFire C18, 4.6  250 mm,
5 μm) at 40 °C. A binary mobile phase system (A: deionized water + 0.1% TFA, B: MeCN +
0.1% TFA) was employed as follows: 5 min 30% of B, a linear gradient to 100% of B during
15 min, and then holding 100% of B for 13 min. The flow rate was 1 mL/min. The purity of
the compound was monitored by measuring absorbance at 220 nm. All the peptoids were
purified on a Waters preparative HPLC system (Waters 2489 UV/visible detector, Waters 2545
Quaternary HPLC pump, Waters fraction collector III) with a C18 column (SunFire C18, 19 x
150 mm, 5 μm) at room temperature. The flow rate was set to 14 mL/min, and a binary mobile
phase system (A: deionized water + 0.1% TFA, B: MeCN + 0.1% TFA) was used under the
following conditions: 5 min 30% of B, a linear gradient to 100% B during 20 min, followed by
100% of B for 5 min. Sample elution was monitored by measuring the absorbance at 220 nm,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 30
1
2
3
4
5
6
7
8
9
and the purity of each fraction (>97%) was confirmed by analytical HPLC. ESI-MS analysis
was carried out on an Agilent 1260 Infinity liquid chromatography system with an Agilent
6120 single quadrupole mass spectrometer. Fractions containing the pure product were
collected, lyophilized, and stored at 80 °C. The amount of purified peptoid and overall yield
based on the resin loading are shown as follows: 5 (5.7 mg, 15%), HRMS (ESI): m/z: calcd for
C148H136N14O12 [M + H]+: 2301.0462, found 2302.0498. Purity according to analytical HPLC:
97%. 6 (5.7 mg, 17%), HRMS (ESI): m/z: calcd for C104H108N10O12 [M + H]+: 1688.8148,
found 1689.8207. Purity according to analytical HPLC: 99%. 7 (9.6 mg, 24%), HRMS (ESI):
m/z: calcd for C132H126N14O9 [M + H] +: 2050.9832, found 2051.9874. Purity according to
analytical HPLC: 99%. 8 (0.5 mg, 3%), HRMS (ESI): m/z: calcd for C141H122N14O12 [M + H]
+: 2202.9367, found 2203.9365. Purity according to analytical HPLC: 97%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Spectral analysis
CD spectra were recorded on a Jasco model 810 spectropolarimeter (Jasco, Easton, MD, USA)
in a quartz cell with 1 mm path length. The response time was set to 1 second with 1.0 nm
bandwidth for all spectra. The samples were prepared in either MeCN or MeOH, and the
spectra were acquired in the 190−260 nm range with a 20 nm min-1 scanning speed at 20 °C.
The spectra were measured three times and averaged. The results were expressed in terms of
per-residue molar ellipticity, [θ] (deg cm2 dmol-1). ([θ] = θ / (n × c × l), where θ = the ellipticity
of the polarization, n = the number of amide groups present, c = the molar concentration, l =
the optical path length).26
UV-vis spectra were recorded on an Ultrospec 2100 Pro UV-vis spectrophotometer (GE
Healthcare, Buckinghamshire, UK) in the range of 200−700 nm, in a quartz cell with 1 mm
path length at ambient temperature. Baseline correction for each spectrum was performed with
blank solvent.
ACS Paragon Plus Environment

Page 23 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Fluorescence emission and excitation spectra were observed on an FLS980 fluorescence
spectrometer (Edinburgh Instruments, Livingston, UK). All peptoids were prepared at
concentration 5 μM with solvent MeCN or MeCN/MeOH (1:1, v/v). All spectra measurements
were performed with Xe Lamp installed in FLS980 with excitation and emission spectral
bandwith of 1 nm both, dwell time of 0.1 and repetition of 5 times. Fluorescence emission
spectra of all samples were obtained with excitation wavelength at 310 nm and 550 nm.
Fluorescence excitation spectra were performed at emission wavelength 425 nm for
MeCN/MeOH (1:1, v/v) or 400 nm for MeCN and 650 nm for both solvents.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Associated content
Supporting Information.
The Supporting Information is available free of charge on the ACS Publication website at DOI:
xxx/xxx.
13
1H and C{1H} NMR spectra for 1–4, HPLC data and ESI-HRMS (ToF) data for 5–8,
additional UV-vis absorption spectra and fluorescence emission spectra, and fluorescence
photographs.
Acknowledgments
This work was financially supported by the National Research Foundation of Korea (NRF-
2018R1A2B6007535 to J.S.) and by the Creative Materials Discovery Program (NRF-
2018M3D1A1052659 to J.S.), which is funded by the National Research Foundation (NRF)
under the Ministry of Science and ICT. H.L. and H.O. were supported by GIST Research
Institute (GRI) grant funded by the GIST in 2019.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 30
1
2
3
4
5
6
References
7
8
9
1. Blankenship, R. E. Molecular mechanism of photosynthesis. 2nd ed.; Wiley-Blackwell:
Oxford, U.K., 2014.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2. Springer, J. W. P.-L., P. S.; Reddy, K. R.; Krayer, M.; Jiao, J.; Lee, G. M.; Niedzwiedzki,
D. M.; Harris, M. A.; Kirmaier, C.; Bocian, D. F.; Lindsey, J. S.; Holten, D.; Loach, P. A.
Biohybrid photosynthetic antenna complexes for enhanced light-harvesting. J. Am. Chem. Soc.
2012, 134, 4589–4599.
3. Woller, J. G. H., J. K.; Albinsson B. Self-assembled nanoscale DNA-porphyrin complex for
artificial light harvesting. J. Am. Chem. Soc. 2013, 135, 2759–2768.
4. Gust, D. M., T. A.; Moore, A. L.; Devadoss, C.; Liddell, P. A.; Hermant, R.; Nieman, R. A.;
Demanche, L. J.; DeGraziano, J. M.; Gouni, I. Triplet and singlet energy transfer in carotene-
porphyrin dyads: role of the linkage bonds. J. Am. Chem. Soc. 1992, 114, 3590–3603.
5. Sun, Y. G., F.; Zuo, T.; Hua, J.; Diao, G. Stimulus-responsive light-harvesting complexes
based on the pillararene-induced co-assembly of b-carotene and chlorophyll. Nat. Commun.
2016, 7, 12042.
6. Samanta, A.; Das, G.; Das, S. K. Roles of flavonoids in plants. Int. J. Pharm. Sci. Tech.
2011, 6, 12–35.
7. Clegg, M. T.; Durbin, M. L. Flower color variation: a model for the experimental study of
evolution. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7016–7023.
8. Agati, G.; Tattini, M. Multiple functional roles of flavonoids in photoprotection. New
Phytologist 2010, 186, 786–793.
9. Vidovic, M.; Morina, F.; Milic, S.; Zechmann, B.; Albert, A.; Winkler, J. B.; Jovanovic, V.
Ultraviolet-B component of sunlight stimulates photosynthesis and flavonoid accumulation in
variegated Plectranthus coleoides leaves depending on background light. Plant, Cell &
ACS Paragon Plus Environment

Page 25 of 30
The Journal of Organic Chemistry
1
2
3
4
5
Environ. 2015, 38, 968–979.
6
7
8
9
10. Fini, A.; Brunetti, C.; Ferdinando, M. D.; Ferrini, F.; Tattini, M. Stress-induced flavonoid
biosynthesis and the antioxidant machinery of plants. Plant Signal. Behav. 2011, 6, 709–711.
11. Yamasaki, H.; Sakihama, Y.; Ikehara, N. Flavonoid-peroxidase reaction as a detoxification
mechanism of plant cells against H2O2. Plant Physiol. 1997, 115, 1405–1412.
12. Peer, W. A.; Murphy, A. S. Flavonoids as signal molecules: targets of flavonoid action.
Springer: New York, 2006; p 239–268.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13. Cushnie, T. P. T.; Lamb, A. J. Antimicrobial activity of flavonoids. Int. J. Antimicrob.
Agents 2005, 26, 343–356.
14. Panche, A. N.; Diwan, A. D.; Chandra, S. R. Flavonoids: an overview. J. Nut. Sci. 2016, 5,
1–15.
15. Halbwirth, H. The creation and physiological relevance of divergent hydroxylation patterns
in the flavonoid pathway. Int. J. Mol. Sci. 2010, 11, 595–621.
16. Chebil, L.; Humeau, C.; Anthoni, J.; Dehez, F.; Engasser, J.-M.; Ghoul, M. Solubility of
flavonoids in organic solvents. J. Chem. Eng. Data 2007, 52, 1552–1556.
17. Marby, T. J.; Markham, K. R.; Thomas, M. B. The systematic identification of flavonoids.
Springer-Verlag: Berlin-Heidelberg-New York, 1970; p 33–250.
18. Trouillas, P.; Sancho-Garcia, J. C.; De Freitas, V.; Gierschner, J.; Otyepka, M.; Dangles,
O. Stabilizing and modulating color by copigmentation: insights from theory and experiment.
Chem. Rev. 2016, 116, 4937–4982.
19. Yıldız, S. Z.; Küçükislamog˘lu, M.; Tuna, M. Synthesis and characterization of novel
flavonoid-substituted phthalocyanines using (±)naringenin. J. Organomet. Chem. 2009, 694,
4152–4161.
20. Enes, R. F.; Farinha, A. S. F.; Tomé, A. C.; Cavaleiro, J. A. S.; Amorati, R.; Petrucci, S.;
Pedulli, G. F. Synthesis and antioxidant activity of [60]fullerene-flavonoid conjugates.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 30
1
2
3
4
5
Tetrahedron 2009, 65, 253–262.
6
7
8
9
21. Nakagawa-Goto, K.; Yamada, K.; Nakamura, S.; Chen, T.-H.; Chiang, P.-C.; Bastow, K.
F.; Wang, S.-C.; Spohn, B.; Hung, M.-C.; Lee, F.-Y.; Lee, F.-C.; Lee, K.-H. Antitumor agents.
258. Syntheses and evaluation of dietary antioxidant—taxoid conjugates as novel cytotoxic
agents. Bioorg. Med. Chem. Lett. 2007, 17, 5204–5209.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
22. Sousa, R. M. S.; Pinto, D. C. G. A.; Silva, A. M. S.; Serra, V. V.; Barros, A. I. R. N. A.;
Faustino, M. A. F.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. Flavone-nitrogen heterocycle
conjugate formation by 1,3-dipolar cycloadditions. Eur. J. Org. Chem. 2012, 132–143.
23. Lopes, S. P.; Menezes, J. C. J. M. D. S.; Hackbarth, S.; Pinto, D. C. G. A.; Faustino, M. A.
F.; Silva, A. M. S.; Neves, M. G. P. M. S.; Roder, B.; Cavaleiro, J. A. S. New flavonoid-
porphyrin conjugates via Buchwald-Hartwig amination: synthesis and photophysical studies.
Tetrahedron Lett. 2013, 54, 5253–5256.
24. Mao, M.; Song, Q.-H. Non-conjugated dendrimers with a porphyrin core and coumarin
chromophores as peripheral units: synthesis and photophysical properties. Dyes Pigments 2012,
92, 975–981.
25. Garg, V.; Kodis, G.; Liddell, P. A.; Terazono, Y.; Moore, T. A.; Moore, A. L.; Gust, D.
Artificial photosynthetic reaction center with a coumarin-based antenna system. J. Phys. Chem.
B 2013, 117, 11299–11308.
26. (a) Armand, P.; Kirshenbaum, K.; Falicov, A.; Dunbrack Jr, R. L.; Dill, K. A.; Zuckermann,
R. N.; Cohen, F. E. Chiral N-substituted glycines can form stable helical conformations. Fold.
Des. 1997, 2, 369–375. (b) Armand, P.; Kirshenbaum, K.; Goldsmith, R. A.; Farr-Jones, S.;
Barron, A. E.; Truong, K. T. V.; Dill, K. A.; Mierke, D. F.; Cohen, F. E.; Zuckermann, R. N.;
Bradley, E. K. NMR determination of the major solution conformation of a peptoid pentamer
with chiral side chains. Proc. Natl. Acad. Sci. 1998, 95, 4309–4314. (c) Kirshenbaum, K.;
Barron, A. E.; Goldsmith, R. A.; Armand, P.; Bradley, E. K.; Truong, K. T. V.; Dill, K. A.;
ACS Paragon Plus Environment

Page 27 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Cohen, F. E.; Zuckermann, R. N. Sequence-specific polypeptoids: a diverse family of
heteropolymers with stable secondary structure. Proc. Natl. Acad. Sci. 1998, 95, 4303–4308.
27. Wu, C. W.; Sanborn, T. J.; Huang, K.; Zuckermann, R. N.; Barron, A. E. Peptoid oligomers
with a-chiral, aromatic side chains: sequence requirements for the formation of stable peptoid
helices. J. Am. Chem. Soc. 2001, 123, 6778–6784.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
28. Stringer, J. R.; Crapster, J. A.; Guzei, I. A.; Blackwell, H. E. Extraordinarily robust
polyproline type I peptoid helices generated via the incorporation of a-chiral aromatic N-1-
Naphthylethyl side chains. J. Am. Chem. Soc. 2011, 133, 15559–15567.
29. Shin, H.-M.; Kang, C.-M.; Yoon, M.-H.; Seo, J. Peptoid helicity modulation: precise
control of peptoid secondary structures via position-specific placement of chiral monomers.
Chem. Commun. 2014, 50, 4465–4468.
30. Laursen, J. S.; Harris, P.; Fristrup, P.; Olsen, C. A. Triangular prism-shaped β-peptoid
helices as unique biomimetic scaffolds. Nat. Commun. 2015, 6, 7013.
31. Wellhöfer, I.; Frydenvang, K.; Kotesova, S.; Christiansen, A. M.; Laursen, J. S.; Olsen, C.
A. Functionalized helical β-peptoids. J. Org. Chem. 2019, 84, 3762–3779.
32. Gimenez, D.; Zhou, G.; Hurley, M. F. D.; Aguilar, J. A.; Voelz, V. A.; Cobb, S. L.
Fluorinated aromatic monomers as building blocks to control α-peptoid conformation and
structure. J. Am. Chem. Soc. 2019, 141, 3430–3434.
33. Crapster, J. A.; Guzei, I. A.; Blackwell, H. E. A peptoid ribbon secondary structure. Angew.
Chem. Int. Ed. 2013, 52, 5079–5084.
34. Huang, K.; Wu, C. W.; Sanborn, T. J.; Patch, J. A.; Kirshenbaum, K.; Zuckermann, R. N.;
Barron, A. E.; Radhakrishnan, I. A threaded loop conformation adopted by a family of peptoid
nonamers. J. Am. Chem. Soc. 2006, 128, 1733–1738.
35. Kang, B.; Chung, S.; Ahn, Y. D.; Lee, J.; Seo, J. Porphyrin-peptoid conjugates: face-to-
face display of porphyrins on peptoid helices. Org. Lett. 2013, 15, 1670–1673.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 30
1
2
3
4
5
6
7
8
9
36. Kang, B.; Yang, W.; Lee, S.; Mukherjee, S.; Forstater, J.; Kim, H.; Goh, B.; Kim, T.-Y.;
Voelz, V. A.; Pang, Y.; Seo, J. Precisely tuneable energy transfer system using peptoid helix-
based molecular scaffold. Sci. Rep. 2017, 7, 4786.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
37. Yang, W.; Kang, B.; Voelz, V. A.; Seo, J. Control of porphyrin interactions via structural
changes of a peptoid scaffold. Org. Biomol. Chem. 2017, 15, 9670–9679.
38. Lee, Y. J.; Kang, B.; Seo, J. Metalloporphyrin dimers bridged by a peptoid helix: host-guest
interaction and chiral recognition. Molecules 2018, 23, 2741.
39. (a) Schipfer, R.; Wolfbeis, O. S.; Knierzinger, A. pH-dependent fluorescence spectroscopy.
Part 12. flavone, 7-hydroxyflavone, and 7-methoxyflavone. J. C. S. Perkin II 1981, 1443–1448.
(b) Christoff, M.; Toscano, V. G.; Baader, W. J. Influence of methoxy substitution on flavonoid
photophysics: a steady state and laser flash photolysis study. J. Photochem. Photobiol. A 1996,
101, 11–20.
40. Khatib, S.; Nerya, O.; Musa, R.; Shmuel, M.; Tamir, S.; Vaya, J. Chalcones as potent
tyrosinase inhibitors: the importance of a 2,4-substituted resorcinol moiety. Bioorg. Med. Chem.
2005, 13, 433–441.
41. (a) Lee, J. I.; Son, H. S.; Jung, M. G. A novel synthesis of flavones from 2-methoxybenzoic
acids. Bull. Korean Chem. Soc. 2005, 26, 1461–1463. (b) Kawasaki, I.; Matsuda, K.; Kaneko,
T. Preparation of 1,7-bis(p-hydroxyphenyl)heptane. Bull. Chem. Soc. Jpn. 1971, 44, 1986–
1987.
42. Gu, B.; Wu, W.; Xu, G.; Feng, G.; Yin, F.; Chong, P. H. J.; Qu, J.; Yong, K.-T.; Liu, B.
Precise two-photon photodynamic therapy using an efficient photosensitizer with aggregation-
induced emission characteristics. Adv. Mater. 2017, 29, 1701076.
43. Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. Efficient method for the
preparation of peptoids [oligo(N-substituted glycines)] by submonomer solid-phase synthesis.
J. Am. Chem. Soc. 1992, 114, 10646–10647.
ACS Paragon Plus Environment

Page 29 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
44. Afonso, A.; Roses, C.; Planas, M.; Feliu, L. Biaryl peptides from 4-iodophenylalanine by
solid-phase borylation and Suzuki-Miyaura cross-coupling. Eur. J. Org. Chem. 2010, 8, 1461–
1468.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
45. Park, H.; Yu, D.; Park, J. K.; Bark, K. Spectroscopic properties of flavonoids in various
aqueous-organic solvent mixtures. Bull. Korean Chem. Soc. 2013, 34, 211–220.
46. Turro, N. J.; Ramamurthy, V.; Scaiano, J. C. Principles of Molecular Photochemistry: An
Introduction; 1st Ed. University Science Books: Sausalito-California, 2009; p 400–411.
47. Fuller, A. A.; Seidl, F. J.; Bruno, P. A.; Plescia, M. A.; Palla, K. S. Use of environmentally
sensitive fluorophore 4-N,N-dimethylamino-1,8-naphthalimide to study peptoid helix
structures. Pep. Sci. 2011, 96, 627–638.
48. Fuller, A. A.; Yurash, B. A.; Schaumann, E. N.; Seidl, F. J. Self-association of water-
soluble peptoids comprising (S)-N-1-(naphthylethyl)glycine residues. Org. Lett. 2013, 15,
5118–5121.
49. Shi, Y.; Yin, G.; Yan, Z.; Sang, P.; Wang, M.; Brzozowski, R.; Eswara, P.; Wojtas, L.;
Zheng, Y.; Li, X.; Cai, J. Helical sulfono-γ-AApeptides with aggregation-induced emission
and circularly polarized luminescence. J. Am. Chem. Soc. 2019, 141, 12697–12706.
50. Lindh, J.; Sjöberg, P. J. R.; Larhed, M. Synthesis of aryl ketones by palladium(II)-catalyzed
decarboxylative addition of benzoic acids to nitriles. Angew. Chem. Int. Ed. 2010, 49, 7733–
7737.
51. Ghani, S. B. A.; Weaver, L.; Zidan, Z. H.; Ali, H. M.; Keevil, C. W.; Brown, R. C. D.
Microwave-assisted synthesis and antimicrobial activities of flavonoid derivatives. Bioorg.
Med. Chem. Lett. 2008, 18, 518–522.
ACS Paragon Plus Environment