One Photocatalyst, n Activation Modes Strategy for Cascade Catalysis: Emulating Coumarin Biosynthesis with (-)-Riboflavin

Article abstract of DOI:10.1021/jacs.5b12081

Generating molecular complexity using a single catalyst, where the requisite activation modes are sequentially exploited as the reaction proceeds, is an attractive guiding principle in synthesis. This requires that each substrate transposition exposes a catalyst activation mode (AM) to which all preceding or future intermediates are resistant. While this concept is exemplified by MacMillan's beautiful merger of enamine and iminium ion activation, examples in other fields of contemporary catalysis remain elusive. Herein, we extend this tactic to organic photochemistry. By harnessing the two discrete photochemical activation modes of (-)-riboflavin, it is possible to sequentially induce isomerization and cyclization by energy transfer (E_T) and single-electron transfer (SET) activation pathways, respectively. This catalytic approach has been utilized to emulate the coumarin biosynthesis pathway, which features a key photochemical E → Z isomerization step. Since the ensuing SET-based cyclization eliminates the need for a prefunctionalized aryl ring, this constitutes a novel disconnection of a pharmaceutically important scaffold.

Full text of DOI:10.1021/jacs.5b12081

Subscriber access provided by CMU Libraries - http://library.cmich.edu
Article
A “One Photocatalyst, n Activation Modes” Strategy for Cascade
Catalysis: Emulating Coumarin Biosynthesis with (–)-Riboflavin
Jan B. Metternich, and Ryan Gilmour
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b12081 • Publication Date (Web): 30 Dec 2015
Downloaded from http://pubs.acs.org on December 30, 2015
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 free 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 accessible to all
readers and 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.
Journal of the American Chemical Society 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 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
A “One Photocatalyst, n Activation Modes” Strategy for Cascade Ca-
talysis: Emulating Coumarin Biosynthesis with (–)-Riboflavin.
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
Jan B. Metternich and Ryan Gilmour*.
Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster,
Germany.
ABSTRACT: Generating molecular complexity using a single catalyst, where the requisite activation modes are sequen-
tially exploited as the reaction proceeds, is an attractive guiding principle in synthesis. This requires that each substrate
transposition exposes a catalyst activation mode (AM) to which all preceding or future intermediates are resistant. Whilst
this concept is exemplified by MacMillan’s beautiful merger of enamine and iminium ion activation, examples in other
field of contemporary catalysis remain elusive. Herein we extend this tactic to organic photochemistry. By harnessing the
two discrete photochemical activation modes of (–)-riboflavin, it is possible to sequentially induce isomerization and cy-
clization by energy transfer (ET) and single electron transfer (SET) activation pathways, respectively. This catalytic ap-
proach has been utilized to emulate the coumarin biosynthesis pathway, which features a key photochemical E→Z isom-
erization step. Since the ensuing SET-based cyclization eliminates the need for a pre-functionalized aryl ring, this consti-
tutes a novel disconnection of a pharmaceutically important scaffold.
INTRODUCTION
small molecule catalysis paradigm was selected as the
benchmark transformation (Scheme 1, upper). This would
require sequential engagement of the energy transfer and
single electron transfer activation modes of the inexpen-
sive photocatalyst (–)-riboflavin.11 By correlating structure
to activation mode, a one-step conversion of simple E-
cinnamic acids to this privileged drug scaffold was envis-
aged.12
Orchestrating multiple activation modes of a single cata-
lyst to perform sequential transformations on a specific
precursor is an attractive guiding principle in generating
molecular complexity.1 To be effective, this necessarily
requires that each substrate transposition exposes a cata-
lyst activation mode to which all preceding or future in-
termediates are resistant. Consequently, this strategy in-
stalls an intrinsic directionality to the overall catalytic
sequence, thus conserving selectivity.2 The efficiency of
what is formally cascade catalysis using a single catalyst is
exemplified by MacMillan’s seminal merger of iminium
and enamine activation modes using a low molecular
weight imidazolidinone.3 This unification of two discrete
catalytic cycles to generate multiple bonds in a highly
stereoselective manner is a compelling endorsement for
the development of this approach in contemporary catal-
ysis. Conceptually, this notion may be considered antipo-
dal to the established fields of synergistic (n catalysts → 1
product)4 or divergent catalysis (n catalysts → n products,
n > 1),5 both of which also begin with a common precursor
(Figure 1). Inspired by these and other conceptually relat-
ed examples employing multiple catalysts,6 changes in
reaction conditions,7 or a heterogeneous platform,8 efforts
to translate this concept from the realm of covalent or-
gano-catalysis to non-covalent photo-catalysis9 were initi-
ated; this seemed judicious on account of the multiple
activation modes (AM) that are inherent to the majority
of common photocatalysts.10
Figure 1. An overview of the “one catalyst, n activation
modes” strategy, and conceptual comparison with synergistic
and divergent catalysis. AM = activation mode.
A striking manifestation of Nature’s conversion of light
into chemical energy is the pivotal E→Z photo-
isomerization in coumarin biosynthesis.13 Originating
from phenylalanine via the phenylpropanoid pathway, the
biosynthesis of the 1,2-benzopyrone scaffold is character-
ized by a postulated cytochrome P450-mediated C(sp2)
oxidation, followed by an isomerization – glycolysis - lac-
tonization sequence (Scheme 1, upper).14 Given the fre-
quency with which this structural element appears in bi-
ology, it is perhaps unsurprising that it has a distin-
For this preliminary validation, an intramolecular cascade
was sought after to simplify any subsequent mechanistic
analyses. Translating the biosynthesis of coumarin into a
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 8
guished lineage in pharmaceutical development, and con- in the presence of 5 mol% photocatalyst (Table 1, catalyst
stitutes the core of numerous natural products.15 Perti-
nent examples include the natural and non-natural thera-
peutics, novobiocin and warfarin, respectively (Scheme 1,
lower). Unsurprisingly, the ubiquity of coumarins in ther-
apeutic medicine and chemical biology has stimulated the
development of numerous synthetic strategies most of
which rely on lactone formation as the key step.16 Howev-
er, these approaches require pre-functionalized aryl moie-
ties prior to cyclization, which often erodes step econo-
my. To complement existing methodology, efforts to de-
vise a bio-inspired, catalysis-based route were investigat-
ed.
a).. This optimization process quickly revealed
MeCN/MeOH (1:1) to be the reaction medium of choice,17b
with molecular oxygen proving to be a clean and effective
oxidant.19 Investigation of the effect of olefin geometry
(E/Z) and comparison of the (–)-riboflavin (a) with 3-
methyllumiflavin (b) completed this process, and gave
rise to a set of standard conditions, by which coumarin
formation proved to be efficient (90% yield). To address
the well-documented propensity of (–)-riboflavin to un-
dergo photo-degradation following prolonged exposure to
UV light,20 a second batch of photo-catalyst (5 mol%) was
added to the reaction after 12 h; this ensured that the en-
suing cyclization step was not impeded.
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
Scheme 1. Upper: The biosynthesis of the coumarin scaf-
fold and the envisaged photocatalytic strategy employ-
ing (–)-riboflavin. Below: Bioactive natural products
containing a coumarin core.
Table 1. Reaction optimization.
Catalyst
Yield
[%]
Substrate
geometry
Solvent
(5 mol%)
E
E
E
E
E
a
a
a
a
a
MeCN
30[a]
37[a]
< 10[a]
61[a]
MeOH
DMSO
MeCN/MeOH (1:1)
MeCN/MeOH (9:1)
51[a]
MeCN/MeOH
(7.5:2.5)
E
a
46[a]
E
E
E
E
Z
E
a
MeCN/EtOAc (1:1)
MeCN/H2O (1:1)
37[a]
41[a]
<30[a]
36[b]
90
a
a
MeCN/HFIP (1:1)
MeCN/MeOH (1:1)
MeCN/MeOH (1:1)
MeCN/MeOH (1:1)
b
a
a[c]
Herein, we report a concise, one-pot strategy that does
not rely on a phenol-derived starting material, but instead
utilizes commercially available (E)-cinnamic acids. It was
envisaged that the need for a pre-functionalized aryl ring
could be surpassed by employing (–)-riboflavin as a pho-
tocatalyst, thereby sequentially exploiting the energy
transfer (ET)17 based olefin isomerization, with concomi-
tant cyclization facilitated by single electron transfer
(SET) catalysis.18 Engaging the two activation modes of (–
)-riboflavin would thereby allow the biogenetic route to
the coumarin nucleus to be emulated, whilst providing a
novel disconnection of this important core using simple
starting materials (highlighted in red, Scheme 1).19
90
[a]
Standard reactions conditions: Reactions were performed
with 0.1 mmol substrate (E:Z >20:1) at ambient temperature
under 24 hours of UV-light irradiation (402 nm) and an oxy-
gen atmosphere.
on TLC. Significant remaining E-isomer detected on TLC.
[c] Addition of a second portion (5 mol%) of the catalyst after
12h. (–)-Riboflavin is commercially available from Sigma-
Aldrich (CAS 83-88-5).
[a]
Significant remaining Z-isomer detected
[b]
Having devised a catalysis protocol, the scope and limita-
tions of the transformation were investigated with a range
of structurally and electronically modulated substrates. In
view of the importance of fluorine incorporation in drug
discovery,21 the influence of bio-isosteric H to F substitu-
tion at the α− and β−positions of the starting cinnamic
acids was first examined. In both cases, the expected,
RESULTS
To evaluate this hypothesis, a representative (E)-cinnamic
acid was independently dissolved in various polar solvent
combinations and exposed to UV irradiation (402 nm, for
full characterization of the UV light source see SI page S2)
ACS Paragon Plus Environment

Page 3 of 8
Journal of the American Chemical Society
opening was reflected in a slightly lower yield (59%).
fluorinated coumarins were isolated in 77% and 38%
1
2
3
4
5
6
7
8
yields (2 and 3, respectively).
Substituents on the aryl ring were generally well tolerat-
ed as is exemplified by the series 10 (OMe), 11 (Me) and 12
(F): 81, 60 and 48% yield, respectively. Interestingly, the
lower yield of 7-fluorine substituted coumarin 12 can be
attributed to a competing photochemical C-F bond acti-
vation23 and subsequent trapping with MeOH to yield 10
as a side product. In view of the importance of aryl bro-
mides in cross coupling transformations, coumarin 13 was
prepared to demonstrate functional group tolerance (69%
yield). The trifluormethylated derivative 14 could also be
accessed under the standard conditions, albeit with a
slight reduction in yield (48%). Highly activated systems
such as the trimethoxy derivative 15 were also well toler-
ated (63%, 12 h). Furthermore, the naphthyl-derived
coumarin 16, a common precursor in the synthesis of var-
ious naphthopyran-2-ones,24 was formed regioselectively
starting from 3-(naphthalenyl)-but-2-enoic acid (16, 51%).
In this particular case, the reaction time had to be signifi-
cantly reduced (to 8 h) due the high UV-sensitivity of the
product which itself can function as a photo-sensitizer.25
Scheme 2. Scope and limitations of the photo-
catalysis route to coumarins catalyzed by (–)-
riboflavin.[a]
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
DISCUSSION
Since the reaction proceeds efficiently, irrespective of the
starting E/Z olefin geometry, a single-step mechanism can
reasonably be discounted. Thus, a tentative hypothesis
based on two distinct photocatalyst activation modes was
envisaged (Scheme 3). Previously, this laboratory has re-
ported that (–)-riboflavin efficiently catalyzes the E→Z
isomerization of activated olefins embedded within the
cinnamaldhyde sub-structure.17b A mechanism consistent
with selective triplet state energy transfer (ET) to the E-
isomer generates the intermediate I-1 possessing biradical
character: this has been corroborated by stereomutation
experiments. Following this initial selective excitation, all
ensuing processes are energetically “downhill” and can
give rise to either the E- or Z-isomer. Stereoselectivity
arises from the differing photophysical properties of the
reactant and product isomers: the Z-isomer is not re-
excited by energy transfer as a consequence of de-
conjugation of the now twisted π-system (A1,3-strain) in
the product resulting in significantly increased triplet
state energies.26
[a]
Standard reaction conditions: Reactions were performed
under oxygen atmosphere with 0.1 mmol substrate (E:Z
>20:1) at ambient temperature in MeCN/MeOH using 5
mol% catalyst loading. An additional 5 mol% catalyst was
added every 12 h. The specified time of UV-light irradiation
(402 nm) is given in parentheses.
Next, validation of the method in the synthesis of the
natural product herniarin (4) was performed. Exposure of
p-methoxy cinnamic acid to the optimized photo-
catalysis condition furnished the target molecule 4 in 61%
yield after 6.5 h: this provides complementary route to the
current state-of-the-art strategies.22
Scheme 3. Tentative mechanistic proposal.
Systematically augmenting the beta substituent from CH3
(5), C2H5 (6) and C3H7 (7) led to enhanced reaction yields
[83, 90 and 91% respectively. cf 79% for H (1)]. This obser-
vation can be rationalized by the radical stabilizing effect
of the substituent during the initial isomeriza-
tion step.17b The deuterated analog 8 was in-
cluded in this study (76%) with a view to
probing the mechanism in a later kinetic anal-
ysis. To explore the notion of an intermediary
radical species, the cyclopropyl derivative was
exposed to the standard photo-catalysis con-
ditions. The expectation that formation of 9
would compete with radical-induced ring
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 8
This postulation is accompanied with the caveat that an initial catalyst loading (5 mol%) can be attributed to re-
1
2
3
4
energy transfer process can be excluded from the ensuing
cyclization. It seemed likely that a single electron transfer
(SET) process was operational in the second step of the
coumarin formation.
sidual oxygen in the reaction media. Nonetheless, these
data support the notion that the reduced riboflavin
formed during the reaction is subsequently oxidized by
atmospheric O2.
5
6
7
8
Interestingly, a SET process catalyzed by (–)-riboflavin
can occur via two discrete pathways: (a) deprotonation of
the carboxylic acid Z by (–)-riboflavin yielding I-2a with
subsequent excitation at 402 nm resulting in the abstrac-
tion of an electron27 or (b) excitation of (–)-riboflavin re-
sulting in electron abstraction to generate intermediate I-
2b followed by deprotonation.19 Independent of the acti-
vation pathway the radical intermediate I-3 is ultimately
formed, which can undergo cyclization to intermediate I-
4. In the final step, formal abstraction of a hydrogen atom
by riboflavin in an H-atom transfer or SET / deprotona-
tion step yields the target coumarin and liberates reduced
RFH2; this is subsequently oxidized by O2 to generate (–)-
riboflavin thus closing the catalytic cycle. In an effort to
further delineate the mechanism, a series of control ex-
periments were performed (Scheme 4).
To further support the involvement of protonated (–)-
riboflavin (pathway a) in the stage preceding cyclization,
the reaction was performed at 450 nm (for full characteri-
zation of the UV light source see SI p S3): this corre-
sponds to the second absorption maximum of the photo-
catalyst. An absorption shift to 402 nm is expected upon
protonation of (–)-riboflavin.28 Under these conditions,
only trace amounts of product were formed (<5%) further
strengthening this hypothesis. Whilst it was not possible
to validate this spectroscopically using the substrate due
to limited solubility, the absoprion shift to 402 nm is
clearly visible when adding TFA to a solution of (–)-
riboflavin in MeCN/H2O (Figure 2).
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
Scheme 4. Control experiments to support the mech-
anistic hypothesis.[a]
exploring the effect of olefin geometry
H3C
standard
photocatalysis
conditions
O
O
OH
2
OH
CH3
2
(Z)
(E)
isomerization
(ET)
cyclization
(SET)
cyclization
(SET)
1
Figure 2. The effect of TFA on the absorption of (–)-
riboflavin. Measurements performed in H2O:MeCN (1:1).
Standard (90%)
no (_)-RF (0%)
no UV-light (0%)
no O2 (8%)
Standard (90%)
no (_)-RF (0%)
no UV-light (0%)
no O2 (9%)
H3C
The saturated analog 3-phenylbutanoic acid (Scheme 4,
lower) was submitted to the standard reaction conditions
to demonstrate the requirement of an olefin moiety in
this transformation. No product formation was observed
validating the importance of the conjugated system.
O
O
450 nm (< 5%)
450 nm (< 5%)
saturated system
no reaction
standard
photocatalysis
conditions
CH3
O
CH3
OH
O
O
The isomerization and cyclization stages of the process
were then monitored over a period of 24 h using an elec-
tron rich (E- and Z-21; Figure 3 a and b) and an electron
deficient olefin pair (E- and Z-29; Figure 3 c and d). For all
systems, complete Z-selective isomerization was observed
over the course of 3 h. This formation and accumulation
of a stable, isolable reaction intermediate is in line with
the proposal that two different mechanisms are operating
in concert. Moreover, the slow consumption of the inter-
mediate Z-isomer suggests that the cyclization is the
overall rate determining step. In both cases starting from
the E-isomer (Figure 3 a and c), a short induction period
of ca. 1 h was recorded during which coumarin formation
was not observed. This induction phase suggests that the
cyclization is linked to a second mechanism starting from
the Z-isomer.
[a]
Standard reaction conditions: Reactions were performed
under oxygen atmosphere with 0.1 mmol substrate at ambi-
ent temperature in MeCN/MeOH using 5 mol% catalyst
loading. An additional 5 mol% catalyst was added every 12 h.
Initially, both geometric isomers E-21 and Z-21 were inde-
pendently submitted to the standard photocatalytic con-
ditions. These conditions were then successively modified
and the resulting yields were compared to those recorded
for the standard conditions. As expected, both stages of
the reaction require UV-irradiation and (–)-riboflavin as a
catalyst (ca. 90% yield). Performing the reaction in the
absence of oxygen using degassed solvents led to drastic
drops in yield (8% and 9% for the E- and Z-isomer, re-
spectively) supporting the notion that O2 is the terminal
oxidant. The marginal deviation of these yields from the
Direct comparison of reactions starting from the E- or Z-
isomers proved to be instructive. In the case of the sub-
ACS Paragon Plus Environment

Page 5 of 8
Journal of the American Chemical Society
consistent with a report from Denney et al.29 for an analo-
strates E- and Z-21 (p-H, β-Et; Figure 3 a and b, respec-
1
2
3
4
gous, thermally induced cyclization of the 2-(2-
deuteriophenyl)-benzoylperoxide system (kH/kD = 1.3,
Scheme 5 right). Based on literature precedent, it is plau-
sible that the attack of the benzoyl radical is reversible
and consequently one of the SET processes is likely the
rate determining step of the cyclization.30
tively), product formation reached a common percentage
after 7 h, independent of the olefin geometry. The result-
ing conversions to the coumarin were 93% and 97%, after
9 and 24 h respectively.
5
6
7
8
9
Finally, the effect of acidic (TFA) or basic (NaOMe) addi-
tives was investigated (Figure 4). Whereas the addition of
one equivalent of NaOMe results in an increase in rate
due to deprotonation of cinnamic acid prior to excitation,
the addition of an equimolar quantity of TFA significantly
retards the process. Since carboxylate anions are known
for rapid electron transfer in interaction with an excited
electron acceptor, deprotonation likely increases the reac-
tion rate; this process is inhibited by addition of TFA.31
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. Reaction progress monitoring starting from the E-
and Z-isomers of two model substrates (a: substrate E-21; b:
substrate Z-21; c: E-29; and d: Z-29).
That the cyclization is rate determining is significantly
more pronounced in the deactivated substrate pair (E-
and Z-29; p-CF3,
β-Me; Figure 3 c and d, respectively).
Despite the isomerization reaching completion after only
3 hours, the cyclization required extended reaction times
and the rate of product formation further decreased after
reaching approximately 30% conversion. This erosion of
reaction rate can be explained by in situ quenching of the
excited state of (–)-riboflavin by the product, thus impact-
ing the overall yield.
Figure 4. Reaction progress monitoring to probe the effect of
acidic and basic additives on the conversion of Z-isomer (Z-
21) to the corresponding coumarin 6.
Scheme 5. Kinetic isotope effect study.[a]
An increase in reaction rate under basic conditions may
indicate that excitation is occurring via pathway b
(Scheme 3), since (–)-riboflavin [pKa (RFH+ = 0.25)]28c will
be deprotonated in the presence of NaOMe. Since neither
extreme is representative of the standard reaction condi-
tions, neither pathway can be entirely excluded.
Denney et al.
(1958)
D5
D
standard
photocatalysis
conditions
O
O
kH
kD
H3C
OH
H3C
OH
CO2OH
Z-20
Z-23
kH/kD
= 1.3
ꢀ
CONCLUSIONS
H/D
H/D Me
In conclusion, the concept of sequentially engaging mul-
tiple activation modes of a single catalyst to generate mo-
lecular complexity has been translated to the paradigm of
non-covalent (photo-cascade) catalysis, and benchmarked
in a direct synthesis of coumarins from E-cinnamic acids.
This biomimetic strategy does not require pre-
functionalisation of the aryl ring prior to cyclization and
thus constitutes a novel disconnection of these pharma-
ceutically important compounds. Conceptually, this work
complements established “one catalyst, two reaction” ap-
proaches in that it does not require a change in condi-
tions, and that simple substrate transpositions stimulate
D/H
D/H
5/8
kH/kD = 1.1
O
O
O
H/D
O
To probe the final cyclization step, a kinetic isotope effect
and additive study was performed (Scheme 5). Reactions
of the non-deuterated and deuterated Z-isomers (Z-20
and Z-23) were monitored, and the region of linear reac-
tion progress between 0 h and 5 h was compared. As a
result, a kinetic isotope effect of 1.1 was measured: this is
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
(5)
For seminal examples of stereodivergent dual catalysis
contrasting catalysis behaviors. Through a combination of
control experiments, progress monitoring experiments
and kinetic isotope studies, it has been possible to vali-
date the initial mechanistic hypothesis that merges ener-
gy transfer (ET) and subsequent single electron transfer
(SET) processes. In view of the current interest in organic
photocatalysis, and the wealth of information pertaining
to light-induced activation modes, it is envisaged that this
guiding principle will evolve to complement the antipodal
field of synergistic catalysis.
1
2
3
4
5
6
7
8
see (a) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M.,
Science, 2013, 340, 1065-1068. b) Krautwald, S.; Schafroth, M. A.;
Sarlah, D.; Carreira, E. M., J. Am. Chem. Soc. 2014, 136, 3020-3023.
For a recent perspective see: Schindler, C. S.; Jacobsen, E. N.;
Science, 2013, 340, 1052-1053.
(6)
For a recent discussion of orthogonal tandem catalysis
see: Lohr, T. L.; Marks, T. J., Nat. Chem., 2015, 7, 477-482.
(7)
(8)
S. E.; Soejima, T.; Aliaga, C. E.; Somorjai, G. A.; Yang, P., Nat.
Chem., 2015, 3, 372-376.
Shi, S.-L.; Buchwald, S. L., Nat. Chem. 2015, 7, 38-44.
Yamada, Y.; Tsung, C.-K.; Huang, W.; Huo, Z.; Habas,
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
(9)
(a) Lin, Q.-Y.; Xu, X.-H.; Qing, F.-L., J. Org. Chem.,
2014, 79, 10434-10446. (b) For recent reviews on organic photoca-
talysis see: Yoon, T. P.; Ischay; M. A.; Du, J., Nature Chemistry
2010, 2, 527-532. Narayanam, J. M. R.; Stephenson, C. R. J., Chem.
Soc. Rev. 2011, 40, 102–113. Xuan, J.; Xiao, W., Angew. Chem. Int.
Ed. 2012, 51, 6828-6838; Angew. Chem. 2012, 124, 6934-6944. Pri-
er, C. K.; Rankic, D. A.; MacMillan, D. W. C., Chem. Rev. 2013,
113, 5322–53263. Koike, T.; Akita, M., Synlett 2013, 24, 2492–2505.
Yoon, T. P.; Stephenson, C. R. J., Adv. Synth. Catal. 2014, 356,
2739-2739. Schultz, D. M.; Yoon, T. P., Science 2014, 343, 1239176.
Nicewicz, D. A.; Nguyen, T. M., ACS Catal. 2014, 4, 355-360.
Brimioulle, R.; Lenhart, D.; Maturi, M. M.; Bach, T., Angew.
Chem. Int. Ed. 2015, 54, 3872-3890; Angew. Chem. 2015, 127, 3944-
3963.
ASSOCIATED CONTENT
Supporting Information
NMR spectra, absorption spectra, experimental procedures
and mechanistic studies. Supporting information is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*ryan.gilmour@uni-muenster.de
(10)
Turro, N. J.; Ramamurthy, V.; Scaiano, J. C., Modern
Molecular Photochemistry of Organic Molecules (2010).
(11)
(12)
Massey, V., Biochem. Soc. Trans., 2000, 28, 283-296.
Peng, X. M.; Damu, G. L.; Zhou, C., Curr. Pharm. Des.
Notes
The authors declare no competing financial interest.
2013, 19, 3884-3930.
(13)
655-661.
(14)
Edwards, K. G.; Stoker, J. R., Phytochemistry, 1967, 6,
(a) Matern, U.; Lüerm, P.; Kreusch, D., Biosynthesis of
Author Contributions
Coumarins (1999) in Comprehensive Natural Product Chemistry,
Vol. 1: Polyketides and other Secondary Metabolites (Ed.: U.
Sankawa) Pergamon, Oxford.
All authors have given approval to the final version of the
manuscript.
(15)
(a) Estévez-Braun, A.; González, A. G., Nat. Prod. Rep.,
1997, 14, 465-475. (b) O’Kennedy, R.; Thomas, R. D., Eds. 1997,
Coumarins: Biology, Applications, and Mode of Action; Wiley:
Chichester, UK.
ACKNOWLEDGMENT
We acknowledge generous financial support from the WWU
Münster, the Deutsche Forschungsgemeinschaft (SFB 858,
and Excellence Cluster EXC 1003 “Cells in Motion – Cluster of
Excellence”), and the Fonds der Chemischen Industrie (FCI
Fellowship to J. B. Metternich). This study is dedicated to
Prof. Dr. Steven V. Ley FRS on the occasion of his 70th birth-
day.
(16)
Boeck, F.; Blazejak, M.; Anneser, M. R.; Hintermann,
L., Beilstein J. Org. Chem., 2012, 8, 1630-1638, and references cited
therein.
(17)
1960, 41, 538-541. (b) Metternich, J. B.; Gilmour, R., J. Am. Chem.
Soc. 2015, 137, 11254–11257.
(18)
2117-2125. (b) Surdhar, P. S.; Armstrong, D., Int. J. Radiat. Biol.
1987, 52, 419-435. (c) Fukuzumi, S.; Kuroda, S.; Tanaka, T., J. Am.
Chem. Soc. 1985, 107, 3020-3027. (d) Murahashi, S.; Oda, T.;
Masui, Y., J. Am. Chem. Soc. 1989, 111, 5002-5003. (e) Martin, C.
B.; Tsao, M.-L.; Hadad, C. M.; Platz, M. S., J. Am. Chem. Soc.
2002, 124, 7226-7234. (f) Imada, Y.; Iida, H.; Ono, S.; Murahashi,
S.-I., J. Am. Chem. Soc. 2003, 125, 2868-2869. (g) Megerle, U.;
Wenninger, M.; Kutta, R.-J.; Lechner, R.; König, B.; Dick, B.;
Riedle, E., PhysChemChemPhys 2011, 13, 8869-8880. (h) Dadova,
J.; Kümmel, S.; Feldmeier, C.; Cibulkova, J.; Pazout, R.; Maixner,
J.; Gschwind, R. M.; König, B.; Cibulka, R., Chem. Eur. J. 2013, 19,
1066-1075. (i) Feldmeier, C.; Bartling, H.; Magerl, K.; Gschwind,
R. M., Angew. Chem. Int. Ed. 2015, 54, 1347-1351; Angew. Chem.
2015, 127, 1363-1367.
(a) Posthuma, J.; Berends, W., Biochim. Biophys. Acta
(a) Land, E. J.; Swallow, A. J., Biochemistry 1969, 8,
REFERENCES
(1)
(a) Wender, P. A., Nat. Prod. Rep., 2014, 31, 433-440. (b)
Wender, P. A.; Miller, B. L., Nature, 2009, 460, 197–201. (c) Trost,
B. M., Science 1996, 245, 1471-1477.
(2)
Walji, A. M.; MacMillan, D. W. C., Synlett, 2007, 10,
1477-1489.
(3)
(a) Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.;
MacMillan, D. W. C., Proc. Nat. Acad. Sci. USA, 2004, 101, 5482-
5487. (b) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D.
W. C., J. Am. Chem. Soc., 2005, 127, 15051-15053. (c) For an exam-
ple of enantioselective organo-SOMO cascade cycloadditions
see: Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C., J. Am. Chem.
Soc., 2010, 132, 10015-10017.
(19)
(a) For a discussion of the reaction of carboxylic acid
anions with (_)-riboflavin see Heelis, P. F., Chem. Soc. Rev. 1982,
11, 15-39; (b) For a recent catalytic, dehydrogenative lactonization
of 2-arylbenzoic acids to benzocoumarins invoking this interme-
(4)
For a review of synergistic catalysis see: Allan, A. E.;
MacMillan, D. W. C., Chem. Sci., 2012, 3, 633-658.
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
diate see: Ramirez, N. P.; Bosque, I.; Gonzalez-Gomez, J. C., Org.
Lett. 2015, 17, 4550-4553.
1
(20) (a) Smith, E. C.; Metzler, D. E., J. Am. Chem. Soc. 1963,
85, 3285-3288. (b) Guttman, D. E.; Platek, T. E., J. Pharm. Sci.
1966, 55, 1363-1368. (c) de La Rochette, A.; Silva, E.; Birlouez-
Aragon, I.; Mancini, M.; Edwards, A.-M.; Morlière, P.; Photo-
chem. Photobiol. 2000, 72, 815-820. (d) Sheraz, M. A.; Kazi, S. H.;
Ahmed, S.; Anwar, Z.; Ahmad, I., Beilstein J. Org. Chem. 2014, 10,
1999-2012.
2
3
4
5
6
7
8
(21)
(a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur,
9
V., Chem. Soc. Rev. 2008, 37, 320-330. (b) Gouverneur, V.; Müller,
K. (Eds.), Fluorine in Pharmaceutical and Medicinal Chemistry,
Imperial College Press, London, 2010.
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) For recent examples of coumarin synthesis strategies
see: (a) Trost, B. M.; Toste, F. D.; Greenman, K., J. Am. Chem.
Soc. 2003, 125, 4518-4526. (b) Ferguson, J.; Zeng, F.; Alper, H.,
Org. Lett. 2012, 14, 5602-5605. (c) Sasano, K.; Takaya, J.; Iwasawa,
N., J. Am. Chem. Soc. 2013, 135, 10954-10957. (d) Zhang, X.-S.; Li,
Z.-W.; Shi, Z.-J., Org. Chem. Front. 2014, 1, 44-49. (e) Medina, F.
G.; Marrero, J. G.; Marciás-Alonso, M.; González, M. C.; Córdova-
Guerrero, I.; Teissier García, A. G.; Osegueda-Robles, S., Nat.
Prod. Rep. 2015, 32, 1472-1507. (f) Liu, X.-G.; Zhang, S.-S.; Jiang,
C.-Y.; Wu, J.-Q.; Li, Q.; Wang, H., Org. Lett. 2015, 17, 5404-5407.
(g) Gadakh, S. K.; Dey, S.; Sudalai, A., J. Org. Chem. 2015, 80
11544–11550.
(23) (a) Senaweera, S. M.; Singh, A.; Weaver, J. D., J. Am.
Chem. Soc. 2014, 136, 3002-3005. (b) Singh, A.; Kubik, J. J.;
Weaver, J. D., Chem. Sci. 2015, 6, 7206-7212. (c) Dewanji, A.;
Mück-Lichtenfeld, C.; Bergander, K.; Daniliuc, C. G.; Studer, A.,
Chem. Eur. J. 2015, 21, 12295-12298.
(24) Saleh, R. M.; Soliman, A. Y.; El Nagdy, S.; Bakeer, H.
M.; Mostafa, M. M., Phosphorus, Sulfur Silicon Relat. Elem. 1990,
48, 285-288.
(25) (a) Hammond, G. S.; Stout, C. A.; Lamola, A. A., J. Am.
Chem. Soc. 1964, 86, 3103-3106. (b) Hoffman, R.; Wells, P.; Morri-
son, H., J. Org. Chem. 1971, 36, 102-108. (c) Winters, B. H.;
Mandelberg, H. I.; Mohr, W. B., Appl. Phys. Lett. 1974, 25, 723-
725. (d) von Trebra, R. J.; Koch, T. H.; J. Photochem. 1986, 35, 33-
46.
(26) For a discussion of relevant triplet state energies (ET) and
the corresponding Stern-Volmer quenching plot of the isomeri-
zation step using an ethyl ester see reference 17b. Repeated at-
tempts to perform a Stern-Volmer quenching analysis of the
cyclization process failed. It was not possible to generate suffi-
ciently concentrated solutions of the substrate in the aqueous
media required to dissolve (_)-riboflavin.
(27) Fukuzumi, S.; Tanii, K.; Tanaka, T., J. Chem. Soc.,
Chem. Commun. 1989, 816-818.
(28) (a) Islam, S. D. M.; Susdorf, T.; Penzkofer, A.; Hege-
mann, P., Chem. Phys. 2003, 295, 137-149. (b) Kowalczyk, R. M.;
Schleicher, E.; Bittl, R.; Weber, S., J. Am. Chem. Soc. 2004, 126,
11393-11399. (c) Li, G.; Glusac, K. D., J. Phys. Chem. A 2008, 112,
4573-4583. (d) Quick, M.; Weigel, A.; Ernsting, N. P., J. Phys.
Chem. B. 2013, 117, 5441-5447.
(29) Denney, D. B.; Klemchuk, P. P., J. Am. Chem. Soc. 1958,
80, 3289-3290.
(30) (a) Kenner, G. W.; Murray, M. A.; Tylor, C. M. B., Tet-
rahedron 1957, 1, 259-268. (b) Coyle, J. C., Chem. Rev. 1978, 78,
97-123.
(31)
Costentin, C.; Rovert, M.; Savéant, J.-M., J. Am. Chem.
Soc. 2006, 128, 8726-8727.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 8
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
8
ACS Paragon Plus Environment