Transformation of Streptonigrin to Streptonigrone: Flavin Reductase-Mediated Flavin-Catalyzed Concomitant Oxidative Decarboxylation of Picolinic Acid Derivatives

Article abstract of DOI:10.1021/acscatal.6b00154

In the flavin-reductase-catalyzed reducing condition, a mild and efficient α-hydroxylation and decarboxylation procedure using natural flavins as a catalyst and atmospheric oxygen as an external oxidizing agent has been successfully developed and applied

Full text of DOI:10.1021/acscatal.6b00154

Subscriber access provided by Mount Allison University | Libraries and Archives
Letter
Transformation of streptonigrin to streptonigrone:
flavin reductase mediated flavin-catalyzed concomitant
oxidative decarboxylation of picolinic acid derivatives
Jing Wo, Dekun Kong, Nelson Lloyd Brock, Fei Xu, Xiufen Zhou, Zixin Deng, and Shuangjun Lin
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00154 • Publication Date (Web): 29 Mar 2016
Downloaded from http://pubs.acs.org on March 30, 2016
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.
ACS Catalysis 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 5
ACS Catalysis
1
2
3
4
5
6
7
8
Transformation of streptonigrin to streptonigrone: flavin re-
ductase mediated flavin-catalyzed concomitant oxidative de-
carboxylation of picolinic acid derivatives
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Jing Wo, Dekun Kong, Nelson L. Brock, Fei Xu, Xiufen Zhou, Zixin Deng, Shuangjun Lin*
State Key Laboratory of Microbial Metabolism, Joint International Laboratory on Metabolic & Developmental Sciences,
School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
ABSTRACT: In the flavin reductase-catalyzed reducing condition, a mild and efficient -hydroxylation and decarboxylation pro-
cedure using natural flavins as a catalyst and atmospheric oxygen as an external oxidizing agent has been successfully developed
and applied to the synthesis of streptonigrone from streptonigrin. This reaction was not only achieved with streptonigrin analogues,
but also structurally diverse electron-rich picolinic acid derivatives. The hydroxylation and decarboxylation may take place in a
concerted manner.
Streptonigrin (1), streptonigrone (2), and lavendamycin (3), a
group of highly functionalized alkaloids, constitute a natural
product family called “streptonigrinoids” with other related
discovered as a minor component in streptonigrin-producing
strains and prepared conventionally by chemical synthesis
1
a,6
with a low yield. Based on a comparison of their structures,
it has been proposed that 2 arises biosynthetically by
decarboxylation and hydroxylation of 1. This reaction is most
likely catalyzed by a flavoenzyme similar to two-component
flavin-dependent monooxygenases such as salicylate-1-
monooxygenase or 6-hydroxynicotinate-3-monooxygenase
1
congeners (Figure 1). Streptonigrinoids have drawn
considerable scientific attention due to their diverse and
2
remarkable bioactivities. For instance, both 1 and 3 are
3
known as antibacterial and antifungal agents, while 2 inhibits
the NO-dependent activation of human guanylyl cyclase
4
7
despite the lack of antimicrobial activity.
(Scheme 1).
Scheme 1. Proposed conversion of streptonigrin to streptonigrone
catalyzed by a flavoprotein.
To find suitable conditions for the conversion of 1 to 2, a
range of flavoenzymes (including StnD, StnH2 and StnH3
Figure S1) from the biosynthetic gene cluster of 1 was
evaluated. Based on the reactions catalyzed by two-component
flavin-dependent monooxygenases, the test reaction mixtures
included 1, flavin adenine dinucleotide (4, FAD), nicotinamide
adenine dinucleotide in reduced form (NADH), and the
Escherichia coli flavin reductase Fre in phosphate buffer
Figure 1. Chemical structures of streptonigrin (1), streptonigrone
(2), lavendamycin (3), FAD (4), FMN (5), and riboflavin (6).
(Supporting Information). Reactions were initiated by addition
of flavin reductase Fre which catalyzes the reduction of FAD
Structurally, both 1 and 3 contain a pyridine-2-carboxylic acid
to supply FADH for the activation of molecular oxygen using
2
(picolinic acid) moiety while 2 comprises a 2-pyridone moiety
8
NADH as a hydride donor. Surprisingly, 1 could be converted
instead. Genetic and biochemical studies have demonstrated
5
to 2 without any other flavoprotein, but flavin reductase Fre,
FAD, and NADH are required (Figure S2). The identity of 2
was confirmed by NMR analysis and high-resolution mass
spectrometry (HR-MS, Figures S3 and S4). The molecular
that 3 is a biosynthetic intermediate of 1. However, the
relationship between 1 and 2 remains obscure due to the lack
of full understanding of their biosynthesis. 2 has been
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 5
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
weight of 2 increased by two mass units when reactions were
reactions catalyzed by two-component flavin-dependent
15
1
8
18
carried out in
atmospheric oxygen ( O ), demonstrating that the keto group
O-labeled oxygen ( O ) instead of
monooxygenases.
Similar replacement of the flavin
2
1
6
reductase with DTT for the coupled hydroxylation/
decarboxylation was possible, but the reaction efficiency was
about two-fold lower than under the standard conditions
(Figure S9). Furthermore, reaction attempts using sodium
sulfide Na S (1 and 10 mM) and sodium dithionite Na S O (1
2
of 2 originates from molecular oxygen (Figure S4). In recent
decades, catalysis of diverse reactions by flavins or flavin
mimics had been reported, in particular the oxidation of
9
10
amines and sulfur groups, Baeyer-Villiger reactions, the
2
2
2
4
1
1
aromatization of dihydro-pyridines and benzothiazolines, the
and 10 mM) as reducing agents could only produce trace
amounts of 2 (Figure S9).
1
2
hydrogenation of olefins
and the oxidation of aryl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
aldehydes. To the best of our knowledge, no precedence of a
concurrent hydroxylation/ decarboxylation catalyzed by a
natural flavin utilizing atmospheric oxygen as an oxidant has
Alternative oxidants like hydrogen peroxide or peroxy acids
are known for some flavin-catalyzed oxidations such as the
1
6
Baeyer-Villiger reaction and Dakin reaction. Therefore,
hydrogen peroxide, m-choroperoxybenzoic acid, and tert-butyl
hydroperoxide were tested as potential oxidants. Strikingly,
none of them could be utilized as an oxidant to convert 1 to 2
both with and without FAD (Figure S10). Furthermore, the
natural flavins such as flavin mononucleotide (5, FMN) and
riboflavin (6) were tested and found to be capable of
catalyzing the conversion of 1 to 2 with similar efficiency as
FAD (Figure S11). All of these natural flavins have a reduced
form that is capable of activating atmospheric oxygen as the
actual oxidizing agent. In summary, these results indicated that
the flavin is essential for the catalytic hydroxylation/
decarboxylation of streptonigrin (1) and the actual oxidizing
14
been reported.
To explore the potential of natural flavins to catalyze the
combined hydroxylation/decarboxylation reaction, 1 was
utilized as a standard substrate to optimize the reaction
conditions. First of all, the effects of the catalyst concentration
and reaction time on the reaction efficiency were tested. All
reactions were carried out with 100 M 1 and 5 mM NADH as
the hydride donor for the reduction of FAD to generate
FADH at 25C for 5 min. The reactions were monitored by
2
HPLC. Moderate conversion of 30% was observed with 1 M
FAD and the conversion could be increased to 60% with 10

M FAD, while higher FAD concentrations (100 M and 1
agent is FADH -activated molecular oxygen. This resembles
mM) would make reactions reach a maximum conversion of
about 75% (Figure S5). However, by allowing a prolonged
reaction time of 10 min, 1 could be almost completely
converted to 2 with 10 M FAD as the catalyst (Figure 2).
Subsequently, the effect of the pH of the reaction buffer was
examined and the highest conversions were found in a pH
range of 7.0-9.0. Lowering the pH significantly impaired the
reaction system and hardly any conversion of 1 to 2 was
detected at pH values below 6.0. On the other hand,
decomposition of 1 was observed at pH values above 10.0
2
1
4
other flavin-catalyzed oxidations.
In the next step, the substrate scope of this natural flavin-
catalyzed reaction was further explored. Similar to
streptonigrin, all streptonigrin analogues could be converted to
their corresponding streptonigrone analogues with similar
conversion rates (Figure 2 and Figures S12-16). Interestingly,
this reaction also worked for lavendamycin (3) where the
carboxylic acid is attached to a tricyclic pyrido[3,4-b]indole
moiety (Figures 1 and S16), albeit with lower efficiency (53%
conversion). The reaction product of 1b was characterized by
(
Figure S6). Finally, the impact of the reaction temperature on
1
the reaction was evaluated. When the flavin reductase Fre was
H NMR spectrum (Figure S17) and HR-MS, but other
used to generate FADH , almost complete conversion of 1 to 2
reaction products were confirmed by HR-MS due to the
limited amounts available of the substrates.
2
was observed at temperatures lower than 50C, while no
conversion occurred at temperatures higher than 60C
probably due to inactivation of the flavin reductase which
terminated the supply of FADH (Figure S7). Furthermore,
2
decomposition of 2 started at temperatures higher than 40C
(
Figure S7). Consequently, a standard reaction condition was
defined for all follow-up reactions using 10 M FAD as a
catalyst in a phosphate buffer at pH 7.5 for 10 min at room
temperature. Under this standard condition, the time-
dependent reactions were performed. The increase of 2 nearly
perfectly matched the decrease of 1, and also matched the
trend of the NADH consumption. However, about 80%
NADH was converted to NAD within 2 min, while only about
Figure 2. FAD-catalyzed hydroxylation/decarboxylation of strep-
a
tonigrin analogues under standard reaction conditions. Conver-
sion rates were determined by HPLC based on the ratio of the
peak area of the substrate after reaction to that of a control.
5
0% 2 was formed at the same period of time (Figure S8).
These observations suggested that the most of the generated
Overall, the observed substrate scope implicated that the
natural flavin-catalyzed hydroxylation/decarboxylation may be
applicable to a wider range of picolinic acid substrates.
Therefore, several commercially available picolinic acids were
tested as putative substrates (Figure 3). The conversion was
monitored by HPLC via comparison with authentic standards
FADH from NADH catalyzed by Fre was not used to perform
2
the oxidation of 1.
The requirement for the flavin reductase Fre in this reaction
seems to be a limitation for potential applications in organic
synthesis. Therefore, alternative reducing agents were tested
as potential substitutes of Fre in the reduction of FAD to its
(
Figure S18-23). Firstly, amino-substituted picolinic acids
reduced form FADH . It has been reported previously that the
2
were tested that bear structural similarity to the multi-
substituted pyridine-2-carboxylic acid moiety of streptonigrin.
flavin reductase can be replaced by dithiothreitol (DTT) for
ACS Paragon Plus Environment

Page 3 of 5
ACS Catalysis
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Complete conversion was found for 3-aminopicolinic acid (7)
follows the general addition-elimination mechanism of
and 84% conversion for 5-aminopicolinic acid (9), but no
conversion was detected for 4- and 6-aminosubstituted
picolinic acids 8 and 10 (Figure 3). Subsequently, various
hydroxy-substituted picolinic acids were tested in the same
manner. The highest conversion rate (58%) was found for 3-
hydroxypicolinic acid (11), while no reaction product could be
detected for 4- and 6-hydroxypicolinic acids 12 and 13. These
findings are in line with the reactivity patterns of electrophilic
aromatic substitutions. Electron donating groups activate the
ortho- or para-positions and consequently, disfavor the
reaction in the meta-positions. Inspired by these results, the
corresponding benzoic acids bearing hydroxyl or amino
groups at the ortho position (14 and 15) and both ortho- and
para-positions (16) were tested. Surprisingly, none of the
expected products could be detected even though electrophilic
aromatic substitution at the benzene ring should be favored
due to its higher electron density. In order to examine whether
the electron donating groups at the picolinic acid are necessary
at all, picolinic acid (17) and pyridine-2,3-dicarboxylic acid
electrophilic aromatic substitutions (Scheme 2), because the
involvement of radicals and superoxides can be ruled out by
adding commonly used radical scavengers including
hydroxylamine and 5,5-Dimethyl-1-pyrroline N-oxide (DMPO)
to the reaction mixture (Figure S24) and using
hypoxanthine/xanthine oxidase and potassium superoxide to
generate superoxides, instead of flavin, or adding superoxide
scavenger SOD to the standard reaction mixture (Figure S25).
The initial driving force of the oxidative decarboxylation
process is anticipated to be the electron-donating properties of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the –NH group and the poor aromaticity of the pyridine
2
moiety. In the first step, the attack at the flavin peroxide gives
the resonance-stabilized arenium ion (complex),
a
dearomatized intermediate, as shown in Scheme 2.
Subsequently, the resultant intermediate is deprotonated by
flavin oxide and further undergoes a β-keto acid type
decarboxylation under release of the 2-hydroxy-substituted
pyridine which can tautomerize to the corresponding 2-
pyridone. Re-introducing aromaticity may serve as an
additional driving force for the decarboxylation. The arenium
intermediate might be stabilized by interaction with the flavin
C-4 keto group. This would give another possible explanation
for the failure of the reaction with the benzoic acid derivatives
where the stabilization of the  complex might be inefficient
due to the increased steric bulk of the additional hydrogen
atom at the benzene ring. Indeed, the flavin peroxide is ready
(18) with a weak electron withdrawing ortho-substituent were
tested, but no conversion could be detected by HPLC analysis,
consistent with electrophilic aromatic substitutions. Moreover,
no conversion was found for pyridin-3-amine (19) suggesting
that the reaction requires the decarboxylation of the ipso-
position as its driving force.
17
to decompose to release hydroperoxide and recycle flavin,
which is in line with our observation that only small portion of
the consumed NADH was used to generate the product 2
(
Figure S8).
Scheme 2. Possible mechanism of the electrophilic aromatic ipso-
substitution with concomitant decarboxylation.
Figure 3. FAD-catalyzed hydroxylation/decarboxylation of other
picolinic acid derivatives under standard reaction conditions.
Conversion rates were determined by HPLC based on the ratio of
the peak area of the substrate after reaction to that of a control.
Among literature-known flavin-catalyzed reactions, our
discovery of an electrophilic aromatic hydroxylation with
concomitant ipso-decarboxylation of electron-rich picolinic
acid derivatives catalyzed by natural flavins is the first
example, compared to the two-step procedure for the
transformation of picolinic acid into the corresponding 2-
hydroxypyridines/2-pyridones via N-oxides catalyzed by
Furthermore, other picolinic acid derivatives were tested: 5%
conversion was observed for isoquinoline-1-carboxylic acid
(20), and trace amounts of the hydroxylation/ decarboxylation
products were detected when quinoline-2-carboxylic acid (21)
and 5-aminopyrimidine-4-carboxylic acid (22) were used
1
8
lower aliphatic anhydrides and triethylamine. The reaction
developed here enables the scalable preparation of
streptonigrone (2) from streptonigrin (1) that is available by
fermentation, although it was carried out on a 30-mg scale (22
mg product purified yield, Supporting Information). Moreover,
the substituted 2-pyridone moiety of the reaction products, has
been used as a versatile core structure for drug design. For
(
Figure 3 and Figure S21-23). Although conversions are very
low for 20 and 21, it can be expected that this reaction might
be successfully applied to structurally similar substrates that
are activated by electron-donating groups.
Based on the formed products, reaction condition, and the
tested substrates, we proposed that the reaction most likely
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 5
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
instances, the 3-aminopyridin-2-one motif has the potential
ability to form multiple hydrogen bonds or to act as a
chelating ligand. Bioactive compounds including this
(4) Severina, I. S.; Pyatakova, N. V.; Postnikov, A. B.; Preobrazhenskaya,
M. N.; Khropov, Y. V. Eur. J. Pharmacol. 2004, 483, 127-132.
5) Xu, F.; Kong, D. K.; He, X. Y.; Zhang, Z.; Han, M.; Xie, X. Q.; Wang,
P.; Cheng, H. R.; Tao, M. F.; Zhang, L. P.; Deng, Z. X.; Lin, S. J. J. Am.
Chem.Soc. 2013, 135, 1739-1748.
(
1
9
important building block include a thrombin inhibitor, an
2
0
interleukin-2 inducible T-cell kinase inhibitor and the human
immunodeficiency virus type reverse transcriptase
Furthermore, a series of substituted 3-hydroxy
(6) (a) Chan, B. K.; Ciufolini, M. A. J. Org. Chem. 2007, 72, 8489-8495;
(b) Boger, D. L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem. Soc. 1993,
1
2
1
1
15, 10733-10741; (c) Preobrazhenskaya, M. N.; Holpnekozlova, N. V.;
inhibitor.
Lazhko, E. I. J. Antibiot. 1992, 45, 227-234.
(7) (a) Katagiri, M.; Yamamoto, S.; Hayaishi, O. J. Biol. Chem. 1962, 237,
pridin-2(1H)-ones, 5-hydroxy-pyrimidin -4(3H)-ones and 3-
hydroxyquinolin-2(1H)-ones are effective inhibitors of
influenza endonuclease by acting as bimetal chelating ligands
2
413-2414; (b) Nakano, H.; Wieser, M.; Hurh, B.; Kawai, T.; Yoshida, T.;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Yamane, T.; Nagasawa, T. Eur. J. Biochem. 1999, 260, 120-126; (c)
Jimenez, J. I.; Canales, A.; Jimenez-Barbero, J.; Ginalski, K.; Rychlewski,
L.; Garcia, J. L.; Diaz, E. Proc. Natl. Acad. Sci. USA 2008, 105, 11329-
11334.
22
at the active site of the enzyme. In addition, a number of
functionalized 5-aminopyrimidin-4(3H)-ones are orally active
23
inhibitors of human neutrophil elastase.
(8) (a) Niviere, V.; Fieschi, F.; Decout, J. L.; Fontecave, M. J. Biol. Chem.
In conclusion, an efficient and environmentally friendly
electrophilic aromatic hydroxylation of picolinic acids with
ipso-decarboxylation has been developed and applied to the
conversion of streptonigrin to streptonigrone. The reaction
utilizes atmospheric oxygen as the terminal oxidant which is
activated by the reduced form of natural flavins in an aqueous
solution. The reaction not only works for streptonigrin
analogues, but can also be applied to other activated picolinic
acid derivatives with electron donating groups to produce
useful building blocks for bioactive compounds.
1999, 274, 18252-18260; (b) Lin, S. J.; Van Lanen, S. G.; Shen, B. J. Am.
Chem. Soc. 2008, 130, 6616-6623.
(9) (a) Ball , S.; Bruice , T. C. J. Am. Chem. Soc. 1979, 101, 4017 –4019;
(b) Minidis, A. B.; Backvall, J. E. Chem. Eur. J. 2001, 7, 297-302; (c)
Murahashi, S. I.; Oda, T.; Masui, Y. J. Am. Chem. Soc. 1989, 111, 5002-
5
003; (d) Imada, Y.; Iida, H.; Ono, S.; Murahashi, S. J. Am. Chem. Soc.
2003, 125, 2868-2869.
(10) (a) Mazzini , C.; Lebreton , J.; Furstoss , R. J. Org. Chem. 1996, 61, 8
–9; (b) Murahashi, S.; Ono, S.; Imada, Y. Angew. Chem. Int. Ed. 2002,
1
14, 2472-2474; (c) Imada, Y.; Iida, H.; Murahashi, S.; Naota, T. Angew.
Chem. Int. Ed. 2005, 44, 1704-1706.
11) Chen, S.; Hossain, M. S.; Foss, F. W. Acs Sustain. Chem. Eng. 2013,
(
1, 1045-1051.
ASSOCIATED CONTENT
(12) (a) Imada, Y.; Osaki, M.; Noguchi, M.; Maeda, T.; Fujiki, M.;
Kawamorita, S.; Komiya, N.; Naota, T. Chemcatchem 2015, 7, 99-106; (b)
Smit, C.; Fraaije, M. W.; Minnaard, A. J. J. Org. Chem. 2008, 73, 9482-
Supporting Information. Reaction procedures and analytical
data are available free of charge via the Internet at
http://pubs.acs.org..
9
485; (c) Imada, Y.; Kitagawa, T.; Ohno, T.; Iida, H.; Naota, T. Org. Lett.
2010, 12, 32-35; (d) Marsh, B. J.; Heath, E. L.; Carbery, D. R. Chem.
Commun. 2011, 47, 280-282.
(13) (a) Murray, A. T.; Matton, P.; Fairhurst, N. W. G.; John, M. P.;
Carbery, D. R. Org. Lett. 2012, 14, 3656-3659; (b) Chen, S.; Hossein, M.
S.; Foss, F. W. Org. Lett. 2012, 14, 2806-2809; (c) Chen, S.; Foss, F. W.
Org. Lett. 2012, 14, 5150-5153.
AUTHOR INFORMATION
Corresponding Author
*
linsj@sjtu.edu.cn
(
14) (a) Imada, Y.; Naota, T., Chem. Rec. 2007, 7, 354-361; (b) Iida, H.;
Imada, Y.; Murahashi, S. I. Org. Biomol. Chem. 2015, 13 (28), 7599-7613;
c) Gelalcha, F. G. Chem. Rev. 2007, 107, 3338-3361; (d) de Gonzalo, G.;
Funding Sources
(
This work is financially supported by the National Natural Sci-
ence Foundation of China (NNSFC, 31425001 for SL; 31370082
for ZD) and the research grants from MOE of China, and the Leo-
poldina Fellowship Program (German National Academy of Sci-
ences Leopoldina, LPDS 2013-12 for NLB).
Fraaije, M. W. Chemcatchem 2013, 5, 403-415; (e) Cibulka, R. Eur. J.
Org. Chem. 2015, 2015, 915-932.
(15) (a) Lowe, H. J.; Clark,. W. M. J. Biol. Chem. 1956, 221 (2), 983-992;
(b) Loechler, E. L.; Hollocher,. T. C. J. Am. Chem. Soc. 1980, 102, 7312-
7321.
(16) (a) Zhou, L.; Liu, X.; Ji, J.; Zhang, Y.; Hu, X.; Lin, L.; Feng, X. J.
Am. Chem. Soc. 2012, 134, 17023-17026; (b) Renz, M.; Meunier, B. Eur.
J. Org. Chem. 1999, 737-750; (c) Brink, t., G.-J.; Arends, I. W. C. E.;
Sheldon, R. A. Chem. Rev. 2004, 104, 4105–4124; (d) Matsumoto, M.;
Kobayashi, K.; Hotta, Y. J. Org. Chem. 1984, 49, 4740–4741.
(17) Massey V. J. Biol. Chem. 1994, 269, 69-83.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We would like to thank the instrumental analysis center of SJTU
and Professor Kaifeng Hu at Kunming Institute of Botany for
assistance with NMR spectroscopy. We also thank Professor Ang
Li at Shanghai Institute of Organic Chemistry for helpful discus-
sion about the catalytic mechanism.
(18) Quarroz, D. Swiss Patent CH644847, 1984.
(19) Lu, T. B.; Markotan, T.; Ballentine, S. K.; Giardino, E. C.; Spurlino,
J.; Brown, K.; Maryanoff, B. E.; Tomczuk, B. E.; Damiano, B. P.; Shukla,
U.; End, D.; Andrade-Gordon, P.; Bone, R. F.; Player, M. R.. J. Med.
Chem. 2010, 53, 1843-1856.
(20) Charrier, J. D.; Miller, A.; Kay, D. P.; Brenchley, G.; Twin, H. C.;
REFERENCES
Collier, P. N.; Ramaya, S.; Keily, S. B.; Durrant, S. J.; Knegtel, R. M. A.;
Tanner, A. J.; Brown, K.; Curnock, A. P.; Jimenez, J. M. J. Med. Chem.
2011, 54, 2341-2350.
(1) (a) Herlt, A. J.; Rickards, R. W.; Wu, J. P. J. Antibiot. 1985, 38, 516-
5
18; (b) Chiu, Y. Y.; Lipscomb, W. N. J. Am. Chem. Soc. 1975, 97, 2525-
(21) Saari, W. S.; Wai, J. S.; Fisher, T. E.; Thomas, C. M.; Hoffman, J. M.;
2530; (c) Doyle, T. W.; Balitz, D. M.; Grulich, R. E.; Nettleton, D. E.;
Gould, S. J.; Tann, C. H.; Moews, A. E. Tetrahedron Lett. 1981, 22, 4595-
Rooney, C. S.; Smith, A. M.; Jones, J. H.; Bamberger, D. L.; Goldman, M.
E.; Obrien, J. A.; Nunberg, J. H.; Quintero, J. C.; Schleif, W. A.; Emini, E.
A.; Anderson, P. S. J. Med. Chem. 1992, 35, 3792-3802.
(22) Sagong, H. Y.; Bauman, J. D.; Patel, D.; Das, K.; Arnold, E.; LaVoie,
E. J. J. Med. Chem. 2014, 57, 8086-8098.
4
598; (d) Wang, H. S.; Yeo, S. L.; Xu, J.; Xu, X. L.; He, H.; Ronca, F.;
Ting, A. E.; Wang, Y.; Yu, V. C.; Sim, M. M. J. Nat. Prod. 2002, 65 (5),
21-724; (e) Ciufolini, M. A.; Bishop, M. J. J. Chem. Soc. Chem. Comm.
1993, 1463-1464.
2) (a) White, H. L.; White, J. R. Mol. Pharmacol. 1968, 4, 549-565; (b)
7
(23) Ohmoto, K.; Yamamoto, T.; Okuma, M.; Horiuchi, T.; Imanishi, H.;
(
Odagaki, Y.; Kawabata, K.; Sekioka, T.; Hirota, Y.; Matsuoka, S.; Nakai,
H.; Toda, M.; Cheronis, J. C.; Spruce, L. W.; Gyorkos, A.; Wieczorek, M.
J. Med. Chem. 2001, 44, 1268-1285.
Beall, H. D.; Mulcahy, R. T.; Siegel, D.; Traver, R. D.; Gibson, N. W.;
Ross, D. Cancer Res. 1994, 54, 3196-3201; (c) McBride, T. J.; Oleson, J.
J.; Woolf, D. Cancer Res. 1966, 26, 727-732.
(3) Bolzan, A. D.; Bianchi, M. S. Mutat. Res. 2001, 488, 25-37.
ACS Paragon Plus Environment

Page 5 of 5
ACS Catalysis
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
TOC
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment