Contra-thermodynamic E → Z isomerization of cinnamamides via selective energy transfer catalysis

Article abstract of DOI:10.1016/j.tet.2020.131198

A bio-inspired, photocatalytic E → Z isomerization of cinnamides is reported using inexpensive (?)-riboflavin (vitamin B₂) under irradiation at λ = 402 nm. This operationally simple transformation is compatible with a range of amide derivatives including –NR₂, –NHSO₂R and N(Boc)₂ (up to 99:1 Z:E). Selective energy transfer from the excited state photocatalyst to the starting E-isomer ensures that directionality is achieved: The analogous process with the Z-isomer is inefficient due to developing allylic strain causing chromophore deconjugation. This is supported by X-ray analysis and Stern-Volmer photo-quenching studies. Preliminary validation of the method in manipulating the conformation of a simple model Leu-enkephalin penta-peptide is disclosed via the incorporation of a cinnamamide-based amino acid.

Full text of DOI:10.1016/j.tet.2020.131198

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Contra-thermodynamic E → Z isomerization of cinnamamides via selective energy
transfer catalysis
Marc R. Becker, Tobias Morack, Jack Robertson, Jan B. Metternich, Christian Mück-
Lichtenfeld, Constantin Daniliuc, Glenn A. Burley, Ryan Gilmour
PII:
S0040-4020(20)30333-1
https://doi.org/10.1016/j.tet.2020.131198
TET 131198
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 March 2020
Accepted Date: 9 April 2020
Please cite this article as: Becker MR, Morack T, Robertson J, Metternich JB, Mück-Lichtenfeld C,
Daniliuc C, Burley GA, Gilmour R, Contra-thermodynamic E → Z isomerization of cinnamamides via
selective energy transfer catalysis, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131198.
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Contra-thermodynamic E → Z isomerization
of cinnamamides via selective energy
transfer catalysis
Leave this area blank for abstract info.
Marc R. Becker,a Tobias Morack,a Jack Robertson,b Jan B. Metternich,a Christian Mück-Lichtenfeld,a
Constantin Daniliuc,a Glenn A. Burley,b* Ryan Gilmoura*
a Organisch-Chemisches Institut, WWU Münster, Corrensstrasse 40, 48149 Münster, Germany
b Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street Glasgow, UK

1
Tetrahedron
journal homepage: www.elsevier.com
Contra-thermodynamic E→Z isomerization of cinnamamides via selective energy
transfer catalysis
Marc R. Beckera†, Tobias Moracka, Jack Robertsonb, Jan B. Metternicha‡, Christian Mück-Lichtenfelda,
Constantin Daniliuca, Glenn A. Burleyb and Ryan Gilmoura
a Organisch-Chemisches Institut, Westfäliwsche Wilhemls-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
b Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street Glasgow, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A bio-inspired, photocatalytic E → Z isomerization of cinnamides is reported using inexpensive
(-)-riboflavin (vitamin B2) under irradiation at λ = 402 nm. This operationally simple
transformation is compatible with a range of amide derivatives including -NR2, -NHSO2R and
N(Boc)2 (up to 99:1 Z:E). Selective energy transfer from the excited state photocatalyst to the
starting E-isomer ensures that directionality is achieved: The analogous process with the Z-
isomer is inefficient due to developing allylic strain causing chromophore deconjugation. This is
supported by X-ray analysis and Stern-Volmer photo-quenching studies. Preliminary validation
of the method in manipulating the conformation of a simple model Leu-enkephalin penta-
peptide is disclosed via the incorporation of a cinnamamide-based amino acid.
Available online
Keywords
Alkene
Catalysis
Energy Transfer
Isomerization
Peptide
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
(–)-Riboflavin (vitamin B2) is well-suited to the photo-
isomerization of (poly)enes,9 on account of its well-defined
photo-physical profile, and ability to mediate both energy
transfer10 and photo-induced SET processes.4c,11 In this study, the
Selective energy transfer from photo-excited small molecule
catalysts to pre-existing π-systems constitutes an expansive
platform to convert synthetically accessible E-alkenes to their
contra-thermodynamic Z-isomers.1 Through the involvement of a
photosensitizer, the excited state of substrate alkene can be
explored thereby mitigating the need for direct irradiation.2 This
activation mode significantly reduces the risk of potential side-
reactions, and can be harnessed to activate alkenes with closely
similar photo-physical behaviour.3 Geometric alkene isomers
embedded in styrenyl motifs lend themselves to selective energy
transfer (ET) from photo-excited catalysts due to the subtle
differences in conformation.4 Whilst planar E-isomers are
conjugated, 1,3-allylic strain in the Z-isomer reduces conjugation
and provides an expansive structural basis from which to
discriminate these π-systems.5 Since vulnerabilities associated
with ground state geometric isomerization (e.g. microscopic
reversibility) are circumvented, this general design concept has a
venerable history.6 The importance of isomerization in regulating
biomolecule function,1,7 and the ability of simple flavins to
facilitate biocompatible selective energy transfer,1b-d led us to
explore the photocatalytic E → Z isomerization of cinnamides8
upon incorporation into small, model peptides (Figure 1).
competence of (–)-riboflavin in catalyzing the
E → Z
isomerization of cinnamides via selective energy transfer is
demonstrated. Preliminary validation in manipulating the
conformation of a simple penta-peptide is also disclosed through
the development of a novel amino acid containing an activated
alkene motif.
Fig. 1. Contra-thermodynamic isomerization of cinnamides.
———
Ryan Gilmour. Tel.: +49 251 83 33271; e-mail: ryan.gilmour@uni-muenster.de
Glenn A. Burley. Tel.: +44 141 548 2792; e-mail: glenn.burley@strath.ac.uk

2
Tetrahedron
2. Results & Discussion
Under these conditions it was possible to generate Z-1 (98:2
Z:E) after 6 h. The reaction proved to be sensitive to changes in
the β-substituent (R) with substitution of Et to Me resulting in a
slight decrease in selectivity (Z-2, 93:7). As a control substrate,
the unsubstituted system Z-3 was subjected to the reaction
conditions. It was possible to generate the Z-isomer, albeit with a
reduction in selectivity (68:32 Z:E), thus highlighting the
importance of allylic-strain in driving selectivity. Changes to the
amino group were then systematically explored. The methyl
amino and dimethylamino derivatives were compatible with the
reaction conditions and thereby allowing Z-4 and Z-5 to be
isolated with synthetically useful levels of selectivity (97:3 and
98:2, respectively). It was also possible to generate the dimethyl
amide Z-5, although an extended reaction time of 22 h was
required to reach completion.
A short process of reaction optimization identified conditions
that enabled the smooth conversion of E-1 to Z-1 (Figure 2). This
operationally simple isomerization was achieved by charging a
flask with the substrate (E)-alkene, and (–)-riboflavin (5 mol%)
in acetonitrile and irradiated (λ
=
402 nm) until the
photostationary composition was reached.
Scope extension to include aromatic amines was possible as
exemplified by the p-CF3 aniline derivative Z-6 (Z/E 99:1). An
examination of common N-protecting groups revealed a general
compatibility with this simple protocol allowing the di-Boc
protected amide Z-7 to be isolated with a Z/E ratio of 99:1 in
86% isolated yield. The triflate group (Z-8) proved more
challenging leading to a Z:E ratio of 78:22 and a diminished
yield (42%). Toslyate and mesylate derivatives Z-9, 10, and 11
were unproblematic and encouraging levels of stereoselectivity
were observed (up to 99:1 Z:E). With a view to utilizing this
approach to modulate peptide conformation,12 two simple
dipeptides were prepared and studied under the isomerization
conditions. Both the L-alanine and L-valine derivatives Z-12 and
Z-13, respectively, were isolated in ≥95% yield and with a Z:E
ratio of 97:3. Cognizant that certain light sources, and in
particular UV-light, is known to cause the racemization of amino
acids,13 Z-13 was prepared by an independent method to allow
comparison of the specific optical rotation (Figure 2, bottom).
This was achieved by coupling the Z-configured carboxylic acid
Z-14 with the methyl ester of
Closely similar specific rotation values of [
were obtained.
L-valine using carbodiimide.
〈
]
25 – 49.8 and – 45.3
D
To support the proposal that a selective energy transfer
manifold was operational, a Stern-Volmer photo-quenching study
was performed under an argon atmosphere in a 1:1 mixture of
water and acetonitrile (Figure 4). Unfortunately, it was not
possible to perform the study in neat acetonitrile due to the
sparing solubility of (–)-riboflavin in this medium. To mitigate
the risk of catalyst quenching by oxygen, solvents were degassed
prior to use. A series of control experiments established the
importance of the light source and the photosensitizer (Figure 4,
centre left). Moreover, X-ray crystallographic analysis of Z-1
revealed an out of plane tilt of the phenyl ring [dihedral angle
φCCCC = –64.2(4)°] consistent with deconjugation of the π-
cinnamoyl chromophore in the product Z-isomer to minimize
A1,3-strain. The contra-thermodynamic nature of the title
transformation was validated by computational investigation of
the geometric isomers E-/Z-1 and E-/Z-3 at the
[DG298/(kcal/mol)] (PWPB95-D3+CPCM(MeCN)//TPSS-D3)
level of theory (Figure 4). For the model system containing a β-
substituent, E-1 → Z-1, the net isomerization was calculated to
be modestly contra-thermodynamic (∆G = +1.48 kcal•mol-1).
Deletion of the ethyl group (E-3 → Z-3) augments this difference
(∆G = +6.12 kcal•mol-1). Further analysis of the triplet states for
E-2 and Z-2 revealed that spin density is concentrated in the
alkene fragment. This is in stark contrast to styrenyl silanes
where the deconjugated product Z-isomer has spin density
localized in the aryl ring.
Fig. 2. Exploring the scope of the geometric isomerisation of
cinnamamides using (-)-riboflavin. Reactions were performed on
0.1 mmol scale (E/Z substrate >20:1) with 5 mol% (–)-riboflavin in
1.5 mL MeCN at ambient temperature (λ = 402 nm); combined
yields are given (isolated yields of the Z-isomer in parentheses).
Bottom: Ensuring that optical purity is not compromised under the
photoisomerization conditions.

3
Replacement of the Gly residue in position three with a
cinnamide motif proceeded smoothly using conventional Fmoc-
based coupling methods. Due to the low solubility of peptide E-
15•TFA in MeCN, the isomerization (E-15•TFA → Z-15•TFA)
was performed under slightly modified conditions: E-15•TFA
(0.020 mmol) and (–)-riboflavin (5 mol %) were dissolved in
deuterated dimethyl sulfoxide and irradiated at 402 nm at
ambient temperature for 24 h. Gratifyingly, geometric alkene
isomerization was observed with a Z:E selectivity of 76:24
(Figure 6, lower).
Fig. 6. Isomerization of a model penta-peptide.
Figure 4. Top: Stern-Volmer photo-quenching study of E-1 and Z-1;
Center left: Control experiments. Center right: X-ray crystal structure
of Z-1 showing 1,3-allylic strain and intermolecular hydrogen
bonding in the dimer (CCDC 1951608). Bottom: Lowest energy
conformations of E-1 / Z-1 and E-3 / Z-3 at the [DG298/(kcal/mol)]
(PWPB95-D3+CPCM(MeCN)//TPSS-D3) level of theory (please see
the Supporting Information).
3. Conclusion
In conclusion, a contra-thermodynamic isomerization of
cinnamamides has been devised using vitamin photocatalysis.
The transformation is compatible with a broad range of amide
derivatives including -NR2, -NHSO2R and N(Boc)2 (up to 99:1
Z:E). The importance of allylic strain in governing selectivity is
supported by structural probes and X-ray analysis, and selective
energy transfer is operational based on Stern-Volmer photo-
quenching studies. Preliminary validation of this bio-compatible
strategy to regulate structure is also disclosed in a model Leu-
enkephalin peptide.
Finally, to explore the potential of this transformation in
influencing peptide conformation, an analog based on the opioid
receptor-binding penta-peptide Leu-enkephalin (N-Tyr-Gly-Gly-
Phe-Leu-C) was prepared by solid phase peptide synthesis
(Figure 6). E-alkenes are effective peptide bond isosteres14,15 and,
given the prominence of flavins in bioconjugation,16 this
operationally simple energy transfer strategy to access the
corresponding Z-isomer might be advantageous. To that end, a
short model penta-peptide was conceived in which a novel
cinnamamide-based amino acid was introduced into the primary
sequence (Figure 6).
4. Experimental section
4.1. General Information
All chemicals were purchased as reagent grade and used without
further purification. Solvents for purification (extraction and
chromatography) were purchased as technical grade and distilled
on the rotary evaporator prior to use. For column
chromatography SiO2 (40−63 μm for flash chromatography,
VWR Chemicals) was used as stationary phase. Analytical thin
layer chromatography (TLC) was performed on aluminum foil
precoated with SiO2-60 F254 (Merck) and visualized with a UV-
lamp (254 nm) and KMnO4 solution. Concentration in vacuo was
performed at ∼10 mbar and 45 °C, drying at ∼10−2 mbar and
room temperature. NMR spectra were measured by the NMR
service of the Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität Münster on a Bruker AV300, Bruker
Fig. 5. Calculated spin densities for E-2 (left) and Z-2 (right).

4
Tetrahedron
1
AV400 or an Agilent DD2 600 spectrometer at rt. H NMR
4.2.2. Z-2
spectra are reported as follows: chemical shift (δ) in ppm
(multiplicity, number of protons, coupling constant J in Hz;
assignment of proton). 13C NMR spectra are reported as follows:
chemical shift (δ) in ppm (multiplicity, coupling constant JC-F in
Hz; assignment of carbon). 19F NMR spectra are reported as
follows: chemical shift (δ) in ppm (multiplicity, coupling
constant J in Hz; assignment of fluorine). Chemical shifts are
Prepared according to GP, E-2 (16 mg, 0.1 mmol, E:Z >20:1)
was converted to Z-2 in 24 h yielding a white solid (16 mg,
quant., Z:E 93:7) after filtration over
a SiO2-plug. The
spectroscopic data obtained were in accordance with those
described in the literature.4d
1
Rf = 0.06 (10% Et2O/n-pentane); M.p.: 88.2 – 89.3 °C; H NMR
1
referenced to the H and 13C signal of the respective deuterated
(600 MHz, CD3OD): δ = 7.39 – 7.34 (m, 2H; H6), 7.31 (tt,
J = 8.0, 1.5 Hz, 3H; H7/8), 5.99 (q, J = 1.5 Hz, 1H; H2), 2.18 –
2.17 (m, 3H; H4) ppm; 13C NMR (151 MHz, CD3OD): δ = 172.0
(C1), 150.7 (C3), 141.9 (C5), 129.2 (2C; C6), 128.9 (C8), 128.3
(2C; C7), 121.7 (C2), 26.6 (C4) ppm; IR (ATR): ῦ = 3326(w),
3080(w), 3057(w), 3046(w), 3023(w), 2999(w), 2957(w),
2906(w), 2556(m), 2464(w), 2391(m), 2341(w), 1988(w),
1962(w), 1938(w), 1885(w), 1764(w), 1666(m), 1640(m),
1609(s), 1597(s), 1572(s), 1492(m), 1442(m), 1402(m), 1346(s),
1312(m), 1289(m), 1266(m), 1217(w), 1144(m), 1079(w),
1035(w), 1025(w), 1011(w), 995(w), 964(w), 916(m), 879(m),
853(m), 841(m), 769(s), 750(m), 722(m), 698(s), 670(m) cm-1;
HR-ESI-MS: m/z calcd. for C10H11NONa+ [M+Na]+: 184.0738),
found: 184.0737.
solvent. The resonance multiplicity is described as: s (singlet), d
(doublet), t (triplet), q (quartet), p (pentet), m (multiplet), b
(broad). Unknown compounds were assigned by 2D NMR
spectra (gCOSY, gHMBC, gHSQC) and NOESY spectra. High
resolution mass spectometry was performed by the mass spec
service of the Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität Münster. Melting points were determined
using a Büchi B-545 melting point apparatus in open capillaries
and are uncorrected. Infrared spectra were recorded on a Perkin-
Elmer 100 FT-IR spectrometer and are reported in wavenumbers
(cm-1) with the following abbreviations: w (weak), m (medium), s
(strong), br (broad). Emission spectra for the Stern-Volmer
photoquenching study were measured on
a
Jasco
Spectrofluorometer FP8300. Optical rotations were determined
on a Jasco P-2000 polarimeter. Isomerization reactions were
performed utilizing an ACULED VHL (ACL01-SC-UUUU-E05-
C01-L-0000) by LED Solutions. The forward current per chip
was set to 350 mA, the resulting forward voltage was 14 V while
the resulting radiants flux was 1150 mW. Further isomerization
reactions were performed utilizing a set-up of four Winger
WEPUV3-S2 UV Power LED Star (Schwarzlicht) 1.2 W lamps.
The forward current per chip was set to 700 mA, the resulting
forward voltage was 3.4 V while the resulting radiant flux was
1200 mW. The reaction flask was placed approximately 1 cm
above the UV lamp.
4.2.3. Z-3
Prepared according to GP, E-3 (15 mg, 0.1 mmol, E:Z >20:1)
was converted to Z-3 in 24 h yielding a white solid (14 mg, 98%.,
Z:E 68:32) after filtration over a SiO2-plug. The spectroscopic
data obtained were in accordance with those described in the
literature.4d
Rf = 0.05 (10% Et2O/n-pentane); M.p.: 132.3 – 134.4 °C; 1H
NMR (400 MHz, CDCl3): δ = 7.50 – 7.45 (m, 2H; H5), 7.39 –
7.29 (m, 3H; H6/7), 6.84 (d, J = 12.6 Hz, 1H; H3), 5.98 (d,
J = 12.6 Hz, 1H; H2), 5.77 (s, 1H; N-H), 5.49 (s, 1H; NH) ppm;
13C NMR (101 MHz, CDCl3): δ = 169.1 (C1), 137.7 (C3), 135.0
(C4), 129.0 (2C; C5), 128.9 (C7), 128.7 (2C; C6), 124.0 (C2)
ppm; IR (ATR): ῦ = 3319(m), 3146(m), 3085(m), 3023(w),
1949(w), 1837(w), 1663(s), 1614(s), 1575(m), 1494(s), 1456(m),
1433(s), 1345(s), 1320(m), 1240(w), 1189(w), 1156(w),
1134(m), 1078(w), 1031(w), 1002(w), 987(w), 976(w), 925(m),
800(s), 762(s), 752(s), 711(m), 688(s) cm-1; HR-ESI-MS: m/z:
calcd. for C9H9NONa+ [M+Na]+: 170.0576; found 170.0577.
4.2. General Procedure (GP) for the Isomerization of α,β-
Unsaturated Amides
The respective α,β-unsaturated amide (0.1 mmol, 1 eq.) and (–)-
riboflavin (1.9 mg, 0.005 mmol, 0.05 eq.) were dissolved in
MeCN (1.5 mL) and stirred under UV-light irradiation (402 nm)
at rt until completion (monitored by TLC). Residual catalyst was
removed by filtration through a SiO2-plug and the products were
eluted by Et2O or EtOAc. The eluate was concentrated in vacuo
and purified by flash column chromatography. The E-/Z-isomer
ratio was determined by integration of the crude 1H NMR
spectra.
4.2.4. Z-4
Prepared according to GP, E-4 (19 mg, 0.1 mmol, 1.0 eq.) was
converted to Z-4 in 6 h yielding a white solid (16 mg, 86%) after
4.2.1. Z-1
separation
by flash
column
chromatography
(50%
EtOAc/cyclohexane).
Prepared according to GP, E-1 (18 mg, 0.1 mmol, 1.0 eq.) was
converted to Z-1 in 6 h yielding a white solid (13 mg, 74%) after
1
Rf = 0.15 (50% EtOAc/cyclohexane); M.p.: 98–100 °C; H NMR
(600 MHz, CD3OD): δ = 7.37 – 7.33 (m, 2H; H2), 7.33 – 7.28
(m, 1H; H1) 7.25 – 7.21 (m, 2H; H3), 5.93 (s, 1H; H8), 2.57 (d,
J = 2.0 Hz, 3H; H10), 2.49 (q, J = 7.3 Hz, 2H; H6), 1.04 (td,
J = 7.5, 2.0 Hz, 3H; H7) ppm; 13C NMR (151 MHz, CD3OD):
δ = 170.6 (C9), 155.2 (C5), 141.3 (C4), 129.1 (C2), 128.7
(C1/C3), 120.7 (C8), 33.3 (C10), 26.1 (C6), 12.7 (C7) ppm; IR
(ATR): ν = 3324 (m), 3058 (w), 2973 (w), 2939 (w), 2887 (w),
2478 (w), 1661 (m), 1627 (s), 1532 (s), 1492 (m), 1456 (m), 1403
(m), 1318 (m), 1259 (s), 1195 (m), 1156 (m), 1082 (m), 866 (s),
752 (s), 697 (s) cm-1; HR-ESI-MS: m/z calcd. C12H15NONa+ for
[M+Na]+: 212.1046, found: 212.1054.
separation
by flash
column
chromatography
(50%
EtOAc/cyclohexane). The spectroscopic data obtained were in
accordance with those described in the literature.4d
1
Rf = 0.11 (50% EtOAc/cyclohexane); M.p.: 96–100 °C; H NMR
(600 MHz, CD3OD): δ = 7.39 – 7.35 (m, 2H; H8), 7.34 – 7.30
(m, 1H; H9), 7.27 – 7.24 (m, 2H; H7), 5.96 (t, J = 1.4 Hz, 1H;
H2), 2.50 (qd, J = 7.4, 1.4 Hz, 2H; H4), 1.05 (t, J = 7.4 Hz, 3H;
H5) ppm; 13C NMR (151 MHz, CD3OD): δ = 172.2 (C1), 156.5
(C3), 141.2 (C6), 129.2 (H8), 128.8 (H9), 128.6 (C7), 120.4
(C2), 33.7 (C4), 12.6 (C5) ppm; IR (ATR): ν = 3476 (m), 3293
(m), 3057 (w), 2932 (w), 2885 (w), 1661 (s), 1634 (s), 1606 (s),
1597 (s), 1491 (m), 1423 (m), 1330 (m), 1307 (m), 1208 (m),
1052 (m), 906 (w), 887 (s), 766 (s), 738 (m), 699 (s) cm-1; HR-
ESI-MS: m/z calcd. for C11H13NONa+ [M+Na]+: 198:0889,
found: 198.0891.
4.2.5. Z-5
Prepared according to GP, E-5 (20 mg, 0.1 mmol,
1.0 eq.) was converted to Z-5 in 22 h yielding a
colorless oil (16 mg, 79%) after separation by flash
column chromatography (50% EtOAc/cyclohexane).

5
Rf = 0.17 (50% EtOAc/cyclohexane); 1H NMR (600 MHz,
CDCl3): δ = 7.33 – 7.28 (m, 2H; H2), 7.28 – 7.24 (m, 3H;
H1/H3), 5.91 – 5.90 (m, 1H; H8), 2.76 (s, 3H; H10/H11), 2.62 (s,
3H; H10/H11), 2.50 (qd, J = 7.4, 1.3 Hz, 2H; H6), 1.07 (t,
J = 7.4 Hz, 3H; H7) ppm; 13C NMR (151 MHz, CDCl3):
δ = 169.24 (C9), 148.71 (C5), 139.76 (C4), 128.15 (C2), 127.78
(C1), 127.21 (C3), 119.32 (C8), 37.70 (C10/C11), 34.25
(C10/C11), 30.60 (C6), 12.50 (C7) ppm; IR (ATR): ν = 3460
(br), 2966 (w), 2933 (w), 1610 (s), 1493 (m), 1442 (m), 1394 (s),
1266 (m), 1176 (m), 1153 (m), 1101 (w), 1083 (w), 1055 (m),
1028 (m), 989 (m), 917 (w), 848 (m), 771 (s), 749 (m), 700
(s) cm-1; HR-ESI-MS: m/z calcd. for C13H17NONa+ [M+Na]+:
226.1202, found: 226.1209.
(br), 2973 (w), 1708 (w), 1639 (m), 1618 (m), 1599 (w), 1491
(w), 1456 (m), 1384 (m), 1302 (s), 1275 (s), 1176 (s), 1133 (s),
1114 (s), 1042 (m), 948 (w), 869 (m), 760 (m), 699 (s) cm-1; HR-
ESI-MS: m/z calcd. for C12H11F3NO3S– [M-H]–: 306.0417, found:
306.0421.
4.2.9. Z-9
Prepared according to GP, E-9 (33 mg, 0.1 mmol, 1.0 eq.) was
converted to Z-9 in 23 h yielding a white solid (20 mg, 62%)
after separation by flash column chromatography (20%
EtOAc/cyclohexane).
Rf = 0.21 (1% MeOH/CH2Cl2); M.p.: Decomposition >116 °C;
1H NMR (600 MHz, CDCl3): δ = 7.76 – 7.73 (m, 2H; H10), 7.45
– 738 (m, 3H; H1/H2), 7.34 (bs, 1H; H8), 7.28 (d, J = 8.1 Hz,
2H; H11), 7.12 – 7.08 (m, 2H; H3), 5.81 (bs, J = 1.3 Hz, 1H;
H6), 2.44 (m, 5H; H13/H14), 1.01 (t, J = 7.4 Hz, 3H; H15) ppm;
13C NMR (151 MHz, CDCl3) δ = 163.4 (C7), 158.9 (C5), 144.9
(C9), 138.3 (C4), 135.7 (C12), 129.5 (C11), 129.4 (C1/C2),
129.3 (C1/C2), 128.6 (C10), 127.3 (C3), 119.4 (C6), 33.4 (C14),
21.8 (C13), 12.0 (C15) ppm; IR (ATR): ν = 3202 (br), 2969 (w),
2932 (w), 2872 (w), 1678 (s), 1632 (m), 1438 (s), 1346 (s), 1178
(s), 1138 (s), 1084 (s), 1041 (m), 880 (m), 856 (s), 812 (m), 780
(m), 756 (m), 730 (s), 695 (s), 659 (s) cm-1; HR-ESI-MS: m/z
calcd. for C18H19NO3SNa+ [M+Na]+: 352.0983, found: 352.0978;
m/z calcd. for C36H38N2O6S2Na+ [2M+Na]+: 681.2069, found:
681.2056.
4.2.6. Z-6
Prepared according to GP, E-6 (32 mg, 0.1 mmol, 1.0 eq.) was
converted to Z-6 in 8 h yielding a white solid (24 mg, 74%) after
separation
by flash
column
chromatography
(10%
EtOAc/cyclohexane).
Rf = 0.28 (20% EtOAc/cyclohexane); M.p.: 137–140 °C;
1H NMR (600 MHz, CD3OD): δ = 7.54 (d, J = 8.6 Hz, 2H; H11),
7.50 – 7.48 (m, 2H; H12), 7.33 – 7.29 (m, 2H; H2), 7.28 – 7.24
(m, 1H; H1), 7.24 – 7.21 (m, 2H; H3), 6.08 (t, J = 1.4 Hz, 1H;
H8), 2.52 (qd, J = 7.4, 1.4 Hz, 2H; H6), 1.05 (t, J = 7.4 Hz, 3H;
H7) ppm; 13C{19F} NMR (151 MHz, CD3OD): δ = 167.8 (C9),
158.5 (C5), 143.4 (C10), 141.3 (C4), 129.2 (C2), 128.8 (C1),
128.6 (C3), 126.9 (C12), 126.4 (C13), 125.7 (C14), 120.6 (C12),
120.5 (C8), 33.8 (C6), 12.7 (C7) ppm; 19F NMR (564 MHz,
CD3OD): 63.61 ppm; IR (ATR): ν = 3238 (w), 3052 (w), 2969
(w), 1659 (m), 1604 (s), 1539 (w), 1410 (m), 1314 (s), 1264 (s),
1181 (m), 1151 (s), 1111 (s), 1067 (s), 1015 (m), 995 (m), 866
(m), 840 (s), 785 (m), 769 (s), 699 (s) cm-1; HR-ESI-MS: m/z
calcd. for C18H16F3NONa+ [M+Na]+: 342.1076, found: 342.1071.
4.2.10. Z-10
Prepared according to GP, E-10 (25 mg, 0.1 mmol, 1.0 eq.) was
converted to Z-10 in 6.5 h yielding a white solid (22 mg, 88%)
after separation by flash column chromatography (50%
EtOAc/cyclohexane).
Rf = 0.25 (50% EtOAc/cyclohexane); M.p.: Decomposition
>141 °C; H NMR (400 MHz, CD3OD): δ = 7.38 – 7.28 (m, 3H;
4.2.7. Z-7
1
H1/H2), 7.23 – 7.17 (m, 2H; H3), 5.94 (t, J = 1.4 Hz, 1H; H8),
3.10 (s, 3H; H10), 2.51 (qd, J = 7.4, 1.4 Hz, 2H; H6), 1.04 (t,
J = 7.4 Hz, 3H; H7) ppm; 13C NMR (101 MHz, CD3OD):
δ = 166.8 (C9), 163.1 (C5), 140.9 (C4), 129.1 (C1/C2), 129.0
(C1/C2), 128.4 (C3), 117.7 (C8), 41.3 (C10), 34.2 (C6), 12.5
(C7) ppm; IR (ATR): ν = 3198 (w), 2972 (w), 2933 (w), 1702
(w), 1683 (s), 1630 (m), 1600 (w), 1449 (s), 1406 (m), 1331 (s),
1323 (s), 1230 (m), 1170 (m), 1122 (s), 1040 (m), 972 (s), 859
(s), 781 (m), 754 (s), 697 (s) cm-1; HR-ESI-MS: m/z calcd. for
C12H15NO3SNa+ [M+Na]+: 276.0665, found: 276.0649.
Prepared according to GP, E-7 (38 mg, 0.1 mmol, 1.0 eq.) was
converted to Z-7 in 6 h yielding a colorless oil (32 mg, 86%) after
separation by flash column chromatography (5% EtOAc/
cyclohexane).
Rf = 0.44 (20% EtOAc/cyclohexane); 1H NMR (600 MHz,
CDCl3): δ = 7.34 – 7.29 (m, 3H; H1/H2), 7.24 – 7.21 (m, 2H;
H3), 6.31 (t, J = 1.3 Hz, 1H; H8), 2.51 (qd, J = 7.4, 1.3 Hz, 2H;
H6), 1.48 (s, 18H; H12), 1.07 (t, J = 7.4 Hz, 3H; H7). ppm;
13C NMR (151 MHz, CDCl3): δ = 166.3 (C9), 159.4 (C5), 150.0
(C10), 139.8 (C4), 128.2 (C1/C2), 128.0 (C1/C2), 127.5 (C3),
118.7 (C8), 84.3 (C11), 33.1 (C6), 27.8 (C12), 12.3 (C7) ppm; IR
(ATR): ν = 2979 (w), 2936 (w), 1776 (m), 1742 (s), 1695 (m),
1626 (m), 1458 (w), 1444 (w), 1394 (w), 1370 (m), 1299 (s),
1245 (s), 1150 (s), 1114 (s), 1005 (m), 998 (m), 845 (s), 790 (m),
772 (m), 698 (s) cm-1; HR-ESI-MS: m/z calcd. for C21H29NO5Na+
[M+Na]+: 398.1938, found: 398.1961.
4.2.11. Z-11
Prepared according to GP, E-11 (38 mg, 0.1 mmol,
1.0 eq.) was converted to Z-11 in 24 h yielding a
white solid (35 mg, 92%) after separation by flash
column chromatography (10%→40%
EtOAc/cyclohexane).
4.2.8. Z-8
Rf = 0.31 (50% EtOAc/cyclohexane); M.p.: 145–148 °C;
1H NMR (600 MHz, CDCl3): δ = 8.26 (bs, 1H; H10), 7.79 (d,
J = 7.1 Hz, 2H; H12), 7.46 (d, J = 7.7 Hz, 2H; H3), 7.30 (d,
J = 7.8 Hz, 2H; H13), 7.17 (d, J = 7.8 Hz, 2H; H4), 5.91 (bs, 1H;
H8), 2.45 (bs, 3H; H15), 2.12 (bs, 3H; H7) ppm; 13C NMR
(151 MHz, CDCl3): δ = 162.9 (C9), 152.9 (C6), 145.3 (C14),
143.0 (C5), 135.6 (C11), 130.5 (q, JC-F = 32.5 Hz; C2), 129.7
(C13), 128.4 (C12), 127.5 (C4), 125.6 (q, JC-F = 3.8 Hz; C3),
124.0 (q, JC-F = 272.3 Hz; C1), 120.0 (C8), 26.5 (C7), 21.8
(C15) ppm; 19F NMR (564 MHz, CDCl3): 62.73 ppm; IR (ATR):
ν = 3112 (br), 2878 (w), 1672 (m), 1637 (m), 1615 (w), 1449 (s),
1406 (w), 1344 (s), 1323 (s), 1236 (w), 1143 (s), 1121 (s), 1107
(s), 1089 (s), 1063 (s), 1030 (s), 1018 (s), 863 (s), 835 (s), 814
Prepared according to GP, E-8 (31 mg, 0.1 mmol, 1.0 eq.) was
converted to Z-8 in 22 h under oxygen atmosphere yielding a
white solid (13 mg, 42%) after separation by flash column
chromatography (10%→30% →80% EtOAc/cyclohexane).
Rf = 0.42 (100% EtOAc); M.p.: Decomposition >98 °C; 1H NMR
(600 MHz, CD3OD): δ = 7.35 – 7.30 (m, 2H; H2), 7.30 – 7.25
(m, 1H; H1), 7.23 – 7.18 (m, 2H; H3), 6.01 (d, J = 2.2 Hz, 1H;
H8), 2.47 (q, J = 7.4 Hz, 2H; H6), 1.02 (td, J = 7.4, 1.7 Hz, 3H;
H7) ppm; 13C{19F} NMR (151 MHz, CD3OD): δ = 173.8 (C9),
159.0 (C5), 141.7 (C4), 128.9 (C2), 128.6 (C3), 128.4 (C1),
122.8 (C8), 121.5 (C10), 34.1 (C6), 12.7 (C7) ppm; 19F NMR
(564 MHz, CD3OD): –79.61 ppm; IR (ATR): ν = 3609 (w), 3364

6
Tetrahedron
(s) cm-1; HR-ESI-MS: m/z calcd. for C18H16F3NO3SNa+
J = 8.1 Hz, 1H, NH), 7.54 – 7.48 (m, 1H, H20), 7.34 (s, 1H,
[M+Na]+: 406.0701, found: 406.0702.
H22), 7.25 (t, J = 7.4 Hz, 2H, H11), 7.21 – 7.16 (m, 3H, H10,
H12), 7.11 (t, J = 7.9 Hz, 1H, H19), 7.07 (d, J = 8.5 Hz, 2H,
H29), 6.73 – 6.67 (m, 3H, H30, H18), 5.94 (d, J = 1.5 Hz, 1H,
H14), 4.46 (td, J = 9.2, 4.0 Hz, 1H, H7), 4.20 (q, J = 7.7 Hz, 1H,
H2), 4.02 (m, 1H, H26), 3.97 (m, 2H, H24), 3.03 (dd, J = 14.3,
5.1 Hz, 1H, H27), 3.00 – 2.94 (m, 1H, H8), 2.84 (dd, J = 14.2,
8.3 Hz, 1H, H27’), 2.70 (dd, J = 13.9, 9.9 Hz, 1H, H8’), 2.01 (d,
J = 1.4 Hz, 3H, H16), 1.64 – 1.54 (m, 1H, H4), 1.50 (t, J = 7.3
Hz, 2H, H3), 0.88 (d, J = 6.5 Hz, 3H, H5), 0.83 (d, J = 6.4 Hz,
3H, H5’) ppm; 13C NMR (151 MHz, d6-DMSO): δ = 174.0 (C1),
173.4 (C6), 168.6 (C23), 166.9 (C25), 164.6 (C13), 156.6 (C28),
147.2 (C17), 141.4 (C21), 137.9 (C9), 130.5 (C29), 129.1 (C10),
128.0 (C11), 127.9 (C19), 126.2 (C12), 124.8 (C31), 122.7
(C18), 121.1 (C14), 117.9 (C20), 117.7 (C22), 115.4 (C30), 53.7
(C26), 53.4 (C7), 50.3 (C2), 42.7 (C24), 40.1 (C4), 37.4 (C8),
36.3 (C27), 26.3 (C16), 24.2 (C4), 22.8 (C5), 21.4 (C5’) ppm;
4.2.12. Z-12
Prepared according to GP, E-12 (28 mg, 0.1 mmol, 1.0 eq.) was
converted to Z-12 in 7.5 h yielding a colorless oil (27 mg, 97%)
after separation by flash column chromatography (50%
EtOAc/cyclohexane).
Rf = 0.11 (20% EtOAc/cyclohexane); [ ]
〈
25 = –76.5 (c = 0.8,
D
1
MeOH); H NMR (400 MHz, CDCl3): δ = 7.40 – 7.29 (m, 3H;
H1/H2), 7.24 – 7.19 (m, 2H; H3), 5.88 (t, J = 1.4 Hz, 1H; H8),
5.55 (d, J = 7.6 Hz, 1H; H10), 4.39 (p, J = 7.2 Hz, 1H; H11),
4.08 (m, 2H; H14), 2.44 (qd, J = 7.2, 1.1 Hz, 2H; H6), 1.20 (t,
J = 7.1 Hz, 3H; H15), 1.07 – 1.01 (m, 6H; H7/H12) ppm;
13C NMR (101 MHz, CDCl3): δ = 172.8 (C13), 166.3 (C9), 154.0
(C5), 139.8 (C4), 128.7 (C1/C2), 128.2 (C1/C2), 127.5 (C3),
121.0 (C8), 61.4 (C14), 47.9 (C11), 32.9 (C6), 18.2 (C12), 14.2
(C15), 12.2 (C7) ppm; IR (ATR): ν = 3297 (m), 2977 (w), 2935
(w), 1743 (s), 1660 (m), 1634 (s), 1539 (s), 1454 (m), 1378 (m),
1347 (m), 1301 (m), 1264 (m), 1185 (s), 1159 (s), 1081 (w), 1026
(m), 989 (w), 888 (m), 776 (m), 697 (s) cm-1; HR-ESI-MS: m/z
calcd. for C16H21NO3Na+ [M+Na]+: 298.1414, found: 298.1423.
HR-ESI-MS: m/z: calcd. for C36H44N5O7 [M+H]+: 658.3236;
+
found 658.3231.
5. Acknowledgments
We acknowledge financial support from the WWU Münster, and
the Verband der Chemischen Industrie (Kekulé Fellowship to
TM and FCI Fellowship to JBM). GAB thanks the Alexander
von Humboldt Foundation for funding a research stay at WWU
Münster (2019). JR acknowledges support from the EPSRC and
GSK through an industrial CASE studentship.
4.2.13. Z-13
Prepared according to GP, E-13 (29 mg, 0.1 mmol, 1.0 eq.) was
converted to Z-13 in 7.5 h yielding a colorless oil (22 mg, 77%)
after separation by flash column chromatography (20% EtOAc/
cyclohexane).
6. References and notes
Rf = 0.14 (20% EtOAc/cyclohexane); [ ]
〈
25 = –49.8 (c = 0.2,
D
1. (a) Dugave, C.; Demange, L. Chem. Rev. 2003, 103, 2475-2532.
(b) Metternich, J. B.; Gilmour, R. Synlett 2016, 27, 2541–2552;
(c) Pearson, C. M.; Snaddon, T. N. ACS Cent. Sci. 2017, 3, 922-
924; (d) Molloy, J. J.; Morack, T.; Gilmour. R. Angew. Chem. Int.
Ed. 2019, 58, 13654-13664.
2. For selected reviews on photocatalysis highlighting energy
transfer, see: (a) Marzo, L.; Pagire, S. K.; Reiser, O.; König, B.
Angew. Chem. Int. Ed. 2018, 57, 10034-10072; (b) Zhou, Q. -Q.;
Zou, Y. -Q.; Lu, L. -Q.; Xiao, W.-J. Angew. Chem. Int. Ed. 2019,
58, 1586–1604. (c) Metternich, J. B.; Mudd, R. J.; Gilmour, R.
Flavins in Photochemistry. Science of Synthesis: Photocatalysis in
Organic Synthesis, 2019, 391-404.
1
MeOH); H NMR (600 MHz, CDCl3): δ = 7.41 – 7.37 (m, 2H;
H2), 7.34 – 7.30 (m, 1H; H1), 7.25 – 7.22 (m, 2H; H3), 5.91 (t,
J = 1.4 Hz, 1H; H8), 5.56 (d, J = 8.6 Hz, 1H; H10), 4.37 (dd,
J = 8.6, 4.7 Hz, 1H; H11), 3.62 (s, 3H; H16), 2.44 – 2.39 (m, 2H;
H6), 1.85 (hd, J = 6.9, 4.7 Hz, 1H; H12), 1.04 (t, J = 7.4 Hz, 3H;
H7), 0.64 (d, J = 6.9 Hz, 3H; H13/H14), 0.50 (d, J = 6.9 Hz, 3H;
H13/H14) ppm; 13C NMR (151 MHz, CDCl3): δ = 172.2 (C15),
166.7 (C9), 153.7 (C5), 139.9 (C4), 129.0 (C2), 128.2 (C1),
127.6 (C3), 121.2 (C8), 57.2 (C11), 52.0 (C16), 33.4 (C6), 30.9
(C12), 18.8 (C13/C14), 17.5 (C13/C14), 12.1 (C7) ppm; IR
(ATR): ν = 3278 (m), 3055 (w), 2964 (m), 2879 (w), 1745 (s),
1655 (m), 1631 (s), 1539 (s), 1463 (m), 1436 (m), 1372 (m),
1322 (m), 1280 (m), 1253 (m), 1195 (s), 1179 (s), 1153 (s), 885
(m), 767 (m), 670 (s) cm-1; HR-ESI-MS: m/z calcd. for
C17H23NO3Na+ [M+Na]+: 312.1574, found: 312.1578.
3. Faßbender, S. I.; Molloy, J. J.; Mück-Lichtenfeld, C.; Gilmour, R.
Angew. Chem. Int. Ed. 2019, 59, 330-334.
4. (a) Singh, K.; Staig, S. J.; Weaver, J. J. Am. Chem. Soc. 2014, 136,
5275-5278; (b) Metternich, J. B.; Gilmour, R. J. Am. Chem. Soc.
2015, 137, 11254-11257; (c) Metternich, J. B.; Gilmour, R. J. Am.
Chem. Soc. 2016, 138, 1040-1045; (d) Metternich, J. B.;
Artiukhin, D. G.; Holland, M. C.; Von Bremen-Kuhne, M.;
Neugebauer, J.; Gilmour, R. J. Org. Chem. 2017, 82, 9955-9977;
(e) Cai, W.; Fan, H.; Ding, D.; Zhang, Y.; Wang, W. Chem.
Commun. 2017, 53, 12918 – 12921; (f) Kurzawa, T.; Harms, K;
Koert, U. Org. Lett. 2018, 20, 1388-1391. (g) Molloy, J. J.;
Metternich, J. B.; Daniliuc, C. G.; Watson, A. J. B.; Gilmour, R.
Angew. Chem. Int. Ed. 2018, 57, 3168-3172; (h) Hostmann, T.;
Molloy, J. J.; Bussmann K.; Gilmour, R. Org. Lett. 2019, 21,
10164-10168; (i) Neveselý, T.; Daniliuc, C. G.; Gilmour, R. Org.
Lett. 2019, 21, 9724-9728; (j) Onneken, C.; Bussmann, K.;
Gilmour, R. Angew. Chem. Int. Ed. 2020, 59, 330-334.
5. Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860.
6. Arai, T.; Tokumaru, K. Chem. Rev. 1993, 93, 23-39.
7. Gozem, S.; Luk, H. L.; Schapiro, I.; Olivucci, M. Chem. Rev.
2017, 117, 13502-13565.
25
For comparative determination of the [α]D value Z-13 was
prepared according to GP-C (for details: see ESI), (Z)-3-
phenylpent-2-enoic acid (240 mg, 1.4 mmol, 1.0 eq.) was
converted to Z-13 in 16 h with
L-valine methylester
hydrochloride (268 mg, 1.6 mmol, 1.2 eq.) yielding a colourless
oil (328 mg, 83%) after flash column chromatography (50%
Et2O/n-pentane).
[α]D25 = –45.3 (c = 1, MeOH)
4.3. Isomerization of Peptide 15
E → Z Isomerization of peptide 15 was achieved by following a
modified procedure GP: The peptide (15.4 mg, 20.0 μmol,
1.0 eq.) and (–)-riboflavin (0.4 mg, 1.0 μmol, 0.05 eq.) was
dissolved in d6-DMSO and stirred under UV-light irradiation
(402 nm) at rt for 24 h. The crude reaction mixture was analyzed
by NMR-spectroscopy showing a clean reaction and a Z/E-ratio
of 76/24. An analytically pure sample of the Z-isomer for full
characterization was obtained by semi-preparative HPLC.
8. For examples of photo-isomerization of cinnamamides, see (a)
Lewis, F. D.; Elbert, J. E.; Upthagrove, A. L; Hale, P. D. J. Am.
Chem. Soc. 1988, 110, 5191-5192; (b) Lewis, F. D.; Elbert, J. E.;
Upthagrove, A. L.; Hale, P. D. J. Org. Chem. 1991, 56, 553-561;
(c) Shu, P.; Xu, H.; Zhang, L.; Li, J.; Liu, H.; Luo, Y.; Yang, X.;
Ju, Z.; Xu, Z. SynOpen 2019, 3, 103-107.
9. Walker, A. G.; Radda G. K. Nature 1967, 215, 1483.
10. Ultrafast laser pulse and time-resolved fluorescent measurements
1H NMR (600 MHz, d6-DMSO): δ = 10.04 (bs, 1H, NH), 9.34 (s,
1H, OH), 8.84 (bs, 1H, NH), 8.14 – 8.02 (bm, 4H, NH), 7.89 (d,
gave a quantum yield for ISC of
φT = 0.375 with a relatively long
phosphorescence lifetime of P = 27 µs, which makes riboflavin
τ

7
suitable for the application as a triplet sensitizers. Please see,
Zhao, J.; Wu, W.; Sun, J.; Guo, S. Chem. Soc. Rev. 2013, 42,
5323-5351.
11. Morack, T.; Metternich, J. B.; Gilmour, R. Org. Lett. 2018, 20,
1316-1319.
12. Mazzier, D.; Crisma, M.; De Poli, M.; Marafon, G.; Peggion, C.;
Clayden, J.; Moretto, A. J. Am. Chem. Soc. 2016, 138, 8007-8018.
13. Cai, S.; Saito, T.; Fuji, N. Free Radic. Biol. Med. 2013, 65, 1037-
1046.
14. Hann, M. M.; Sammes, P. G.; Kennewell, P. D.; Taylor, J. B. J.
Chem. Soc., Chem. Commun. 1980, 234-235. (b) Jenkins, C. L.;
Vasbinder, M. M.; Miller, S. J.; Raines, R. T. Org. Lett. 2005, 7,
132619-132622.
15. Kumar, M. G.; Thombare, V. J.; Katariya, M. M.; Veeresh, K.;
Raja, K. M. P.; Gopi, H. N. Angew. Chem. Int. Ed. 2016, 55,
7847-7851.
16. Bloom, S.; Liu, C.; Kölmel, D. K.; Qiao, J. X.; Zhang, Y.; Poss,
M. A.; Ewing, W. R.; MacMillan, D. W. C. Nat. Chem. 2018, 10,
205-211.
† Department of Chemistry, University of Michigan, 930 North
University Avenue, Ann Arbor, Michigan 48109, United States.
‡ Department of Chemistry & Chemical Biology, Harvard University,
Cambridge, Massachusetts 02138, United States.
7. Supporting Information
Supporting Information including experimental protocols, NMR
and X-ray data is available (PDF file).

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: