Biomimetic Oxidative Deamination Catalysis via ortho-Naphthoquinone-Catalyzed Aerobic Oxidation Strategy

Article abstract of DOI:10.1021/acscatal.8b00992

An ortho-naphthoquinone-catalyzed oxidative deamination reaction has been developed where the molecular oxygen and water serve as the sole oxidant and nucleophile. The current aerobic deamination reaction proceeds via the ketimine formation between ortho-naphthoquinones and amines followed by the prototropic rearrangement and hydrolysis by water, representing a biomimetic oxidative deamination of amine species in the human body by the liver and kidneys. The compatibility of ortho-naphthoquinone organocatalysts with molecular oxygen and water opens up a new biomimetic catalyst system that can function as versatile deaminases for a variety of amine-containing molecules such as amino acids and DNA nuclear bases.

Full text of DOI:10.1021/acscatal.8b00992

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Letter
Biomimetic Oxidative Deamination Catalysis via ortho-
Naphthoquinone-Catalyzed Aerobic Oxidation Strategy
Gangadhararao Golime, Ganganna Bogonda, Hun Young Kim, and Kyungsoo Oh
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00992 • Publication Date (Web): 27 Apr 2018
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Biomimetic Oxidative Deamination Catalysis via ortho-
Naphthoquinone-Catalyzed Aerobic Oxidation Strategy
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Gangadhararao Golime, Ganganna Bogonda, Hun Young Kim* and Kyungsoo Oh*
Center for Metareceptome Research, College of Pharmacy, ChungꢀAng University, 84 Heukseokꢀro, Dongjak, Seoul 06974,
Republic of Korea
KEYWORDS: aerobic oxidation, deamination, organocatalysis, ortho-naphthoquinone, prototropic rearrangement
ABSTRACT: An orthoꢀnaphthoquinoneꢀcatalyzed oxidative deamination reaction has been developed where the molecular oxygen
and water serve as the sole oxidant and nucleophile. The current aerobic deamination reaction proceeds via the ketimine formation
between orthoꢀnaphthoquinones and amines followed by the prototropic rearrangement and hydrolysis by water, representing a
biomimetic oxidative deamination of amine species in the human body by liver and kidneys. The compatibility of orthoꢀ
naphthoquinone organocatalysts with molecular oxygen and water opens up a new biomimetic catalyst system that can function as
versatile deaminases for a variety of amineꢀcontaining molecules such as amino acids and DNA nuclear bases.
Amine dehydrogenases are periplasmic quinoproteins inꢀ
volving the bacterial growth on primary amines as a source of
carbon and nitrogen.1 Aromatic amine dehydrogenase
(AADH) is specific for primary amines while methylamine
dehydrogenase (MADH) displays its specificity for smaller
amines such as methylamine and ethylamine.2 These enzymes
are tryptophan tryptophyquinone (TTQ)ꢀdependant and cataꢀ
lyze the deamination of primary amines to aldehydes and amꢀ
monia (Scheme 1A). Another class of enzymes that perform
the oxidation of primary amines to aldehydes is periplasmic as
well as human copper amine oxidases (CuAOs) that utilize a
redox cofactor, topaquinone (TPQ), and molecular oxygen in a
variety of biological processes such as the oxidation of neuroꢀ
transmitters in animals, thus leading to the formation of amꢀ
monia and hydrogen peroxide as byproducts.3 Recently, treꢀ
mendous research efforts have been made to the development
of CuAOsꢀlike biomimetic catalysts that could bring the sigꢀ
nificant substrate scope that natural enzymes can not offer
(Scheme 1B).4 Thus, the synthetic orthoꢀquinone catalysts
enabled the aerobic oxidation of αꢀbranched primary benzylic
amines5 and secondary amines.6 However, the current CuAOsꢀ
like biomimetic catalyst systems convert primary and secondꢀ
ary amines to imines and ketimines, respectively. A subseꢀ
quent hydrolysis of imines and ketimines will be required to
obtain the true enzymatic oxidation products, aldehydes or
ketones, and also lead to the recovery of amine starting mateꢀ
rials up to 50% yields. This means that the CuAOsꢀlike bioꢀ
mimetic catalysts scavenge the 50% of amine substrates, only
leading to the maximum yield of 50% of aldehyde/ketone
products. Previously, the Corey group demonstrated the transꢀ
amination reaction protocol that combined the amines
(R2CHNH2) and mesitylglyoxals (ArꢀCH2CHO) to form Schiff
bases which underwent prototropic rearrangement to isomeric
Schiff bases. The subsequent acid hydrolysis of the newly
formed Schiff bases led to the desired ketones.7 Recently, the
group of Srogl reported the aerobic oxidation of ascorbic acid
to dehydroascorbic acid that condensed with amines to give
aldehydes and ketones upon acid hydrolysis.8 At the present
time there exist no practical catalytic systems that perform the
direct aerobic oxidation of amines to aldehydes and ketones
without using the separate hydrolysis step and the stoichioꢀ
metric amount of oxidants.9 As a consequence, the developꢀ
ment of oneꢀpot catalytic aerobic oxidation of primary amines
to aldehydes and ketones, the true enzyme-mimetic catalyst
system, remains significant unmet need in aerobic oxidation
protocols.10 Herein, we report the development of an unpreceꢀ
dented promiscuous enzymeꢀmimetic organocatalyst system
that skillfully promotes the ADHꢀlike oxidation of primary
amines, the CuAOsꢀlike oxidation of αꢀbranched primary
amines, and the deaminaseꢀlike reactivity for DNA nuclear
bases.
SCHEMES 1. (A) Amine Dehydrogenases and Cupper
Amine Oxidases. (B) Proposed Enzyme-mimetic Catalytic
System
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NQ1, the reaction temperature was investigated (entry 19ꢀ20),
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where the optimal reaction temperature of 80 °C provided the
ketone 2d and the ketimine 3d in 72 % yield and 7 % yield,
respectively. The reaction conversion was clearly catalyst
loadingꢀdependant, thus the optimal loading of o-NQ1 was set
as 15 mol % (entry 21). The control experiments confirmed
that the molecular oxygen in air was enough to induce the
direct oxidation of amine without an oxygen balloon (entry
22) and the reaction required molecular oxygen to render the
catalyst turnover (entry 23). Interestingly, the Stahl’s catalyst
system,12 tertꢀbutylꢀ2ꢀyydoxybenzoquinone (TBHBQ), under
our optimized conditions provided the ketone 2d and the
ketimine 3d in 56 % yield and 14 % yield, respectively.
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Table 1. Optimization of the Direct Aerobic Oxidation of
Amines to Aldehydes/Ketonesa
With an aim of developing an enzymeꢀmimetic catalyst sysꢀ
tem that can utilize water (like ADHs) and molecular oxygen
(like CuAOs), we envisioned the orthoꢀnaphthoquinoneꢀ
catalyzed direct aerobic oxidation of amines to aldehydes and
ketones. Previously, we had shown that the aerobic oxidations
of amines were possible via the modular catalyst systems of
orthoꢀnaphthoquinone with Cu(OAc)2 for homoꢀcoupled
imines, with TFA for crossꢀcoupled imines, and with Ag2CO3
for the oxidation of secondary amines.11 Encouraged by the
fact that the orthoꢀnaphthoquinone catalyst displays robust
stability with acidic and basic conditions, we investigated the
compatibility of the catalyst system with water (Table 1) as the
initial condensation reaction between catalysts and amines
produce water molecules during the catalytic cycle. Thus, benꢀ
zylamine 1a was treated with a catalytic amount of o-NQ1 (15
Entry
1
Cat (mol %)
Solvent
Yield 2
Yield 3
(%)b
(%)b
T (°C)
1
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
o-NQ1 (15)
o-NQ1 (15)
o-NQ1 (15)
o-NQ1 (5)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
80
80
80
23
23
23
23
23
23
23
23
23
23
23
23
23
23
23
60
80
80
80
80
80
2a, 67c
2b, 79c
2c, 84c
2d, 4
3a, 0
2
3b, 0
3
3c, 0
4
3d, 32
3d, 46
3d, 36
3d, 44
3d, 11
3d, 40
3d, 21
3d, 8
5
o-NQ1 (10)
o-NQ2 (10)
o-NQ3 (10)
o-NQ4 (10)
o-NQ5 (10)
o-NQ6 (10)
o-NQ7 (10)
o-NQ8 (10)
o-NQ9 (10)
o-NQ10 (10)
o-NQ1 (10)
o-NQ1 (10)
o-NQ1 (10)
o-NQ1 (10)
o-NQ1 (10)
o-NQ1 (10)
o-NQ1 (15)
o-NQ1 (15)
o-NQ1 (15)
TBHBQ (15)
2d, 25
2d, 6
6
7
2d, 20
2d, 2
8
1
9
2d, 1
mol%) in CH3CN/H2O at ambient temperature. The H NMR
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22d
23e
24
2d, 1
analysis of the reaction mixture revealed the formation of
imine intermediate 3a in > 90 % yields within 48 h. The imine
intermediate was stable under the reaction conditions with
intact o-NQ1. However, upon increasing the reaction temperaꢀ
ture to 80 °C, the imine 3a was hydrolyzed by the residual
water in CH3CN to give benzaldehyde 2a and benzylamine 1a
where the catalyst o-NQ1 quickly converted benzylamine 1a
to benzaldehyde 2a (entry 1). While the crude reaction mixture
showed the exclusive formation of 2a, the isolated yield was
67 % due to the volatile nature of benzaldehyde 2a. The use of
other benzylamines with higher molecular masses led to the
improved isolated yields of aldehydes 2bꢀ2c in 79ꢀ84 % yields
(entry 2ꢀ3). After gaining the valuable reaction profile, we
turned our attention to secꢀprimary amine, 1ꢀ
phenylethylamine, as substrate for the direct oxidation of
amines. At ambient temperature, the use of 5 mol % o-NQ1
only led to the formation of ketimine 3d in 32 % yield alongꢀ
side 4 % yield of ketone 2d (entry 4). Increasing the catalyst
loading to 10 % mol improved the yields of ketone 2d and
ketimine 3d to 25 % and 46 %, respectively (entry 5). Screenꢀ
ing of other orthoꢀnaphthoquinone catalysts (o-NQ) was perꢀ
formed (entry 6ꢀ14), but only o-NQ3 possessed the similar
catalytic activity as o-NQ1 (entry 7). The solvent screening
also confirmed that CH3CN was the optimal reaction solvent
(entry 15ꢀ18). To further optimize the catalytic activity of o-
2d, 2
2d, 2
3d, 17
3d, 37
3d, 21
3d, 44
3d, 54
3d, 45
3d, 36
3d, 21
3d, 7
2d, 5
2d, 1
2d, 6
PhCH3
CH2Cl2
EtOH
2d, 12
2d, 14
2d, 5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
2d, 52
2d, 72
2d, 100
2d, 98
2d, 18
2d, 56
3d, 0
3d, 2
3d, 4
3d, 14
aReaction conditions: 1 (0.4 mmol), o-NQ catalyst (mol %) in solvent (0.4 M)
for 36-48 h. bUnless stated otherwise, yield was determined by 1H NMR.
cIsolated yields using a mixture of CH3CN:H2O (3:1). dReaction using oxygen
balloon. eReaction under argon. TBHBQ = tert-Butyl-2-hydroxybenzoquinone.
With the optimized reaction conditions in place, the subꢀ
strate scope of the o-NQ1ꢀcatalyzed direct oxidation of amines
to ketones was studied using a variety of secꢀprimary amines
with different electronic and steric characters (Scheme 2). 1ꢀ
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Phenylethyl derivatives with different electronic character
tical aerobic oxidation protocol for ketimine synthesis from
the secꢀprimary amines.
1
were all suitable substrates, providing excellent isolated yields
of ketones (2dꢀ2o) in 79ꢀ97 % yield. The sole formation of
products was observed, and the analytically pure products
were obtained after filtering through a short pad of silica to
remove the catalyst o-NQ1. Upon scaling up the reaction, the
recovery of catalyst o-NQ1 was attempted. However, the reꢀ
covered o-NQ1 remained < 5 % yields due to the formation of
several polar byꢀproducts including diacid derivatives.13 Also,
the workꢀup procedure required phase separation, leading to
somewhat diminished isolated yields of ketone products. The
slight loss of isolated products was mainly due to the volatile
nature of ketones. 1ꢀ(Naphthalenꢀ1ꢀyl)ethylamine 1p required
20 mol % catalyst loading to provide the corresponding ketone
2p in 74 % yield. The use of 1ꢀ(thiophenꢀ2ꢀyl)ethylamine 1q
also provide an excellent yield of ketone 2q in 94 %. Another
secꢀprimary amine, diphenylmethanamine 1r, also underwent
the desired oxidation to give ketone 2r in 65 % yield. The
current catalyst system failed to show the catalytic activity for
1ꢀphenylpropanꢀ1ꢀamine 1s, where the ketone 2s was isolated
in 20 % yield. Interestingly, a cyclic secꢀprimary amine 1t was
directly oxidized under the reaction conditions to give ketone
2t in 60 % yield. Based on the structural feature of 1s and 1t, it
could be concluded that the flexible conformation of the ethyl
group in 1s rendered the steric repulsion that prevented the
catalyst turnꢀover activity. The aryl group in secꢀprimary
amines turned out to be not required since 1ꢀ(adamantanꢀ1ꢀ
yl)ethylamine 1u smoothly underwent the oxidation to give
the ketone 2u in 56 % yield.
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SCHEMES 3. Scope of o-NQ1-Catalyzed Aerobic Oxida-
tion of Amines to Ketimines
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b
aNMR yield of 96 %. 15 mol% catalyst loading at 80 °C. cReꢀ
action at 60 °C. d100 mol % catalyst loading.
The o-NQ1ꢀcatalyzed direct oxidations of amines to ketones
mimic amine dehydrogenases as well as amine oxidases that
use water molecule and molecular oxygen, respectively, for
their catalytic activities. While the employment of alkenyl and
alkynyl amines, 4a and 4b, was partially successful in the diꢀ
rect deamination protocol, due to the nucleophilic character of
water and byꢀproduct, H2O2 at elevated reaction temperature
the formation of ketimines 7a and 7b instead of the correꢀ
sponding ketone products was observed in 79ꢀ88% yields
(Scheme 4). Also, the reaction under an oxygen balloon
helped the catalyst turnꢀover at 23 °C, possibly facilitating the
redox process between orthoꢀnaphthoquinone and 2ꢀ
aminonaphthalenꢀ1ꢀol.16 In addition, the decarboxylative deꢀ
amination of amino acids revealed the importance of a neighꢀ
boring aryl group for the catalyst turnꢀover number, where
phenylglycine 8 was converted to benzaldehyde in 92%
yield.17 To explore the possibility of o-NQ1 as deaminaseꢀ
mimetics18 that removes amino groups from DNA nuclear
bases, we investigated the conversion of cytosines 9 to uracils
10.19 After some experimentation, we found that a stoichioꢀ
metric amount of o-NQ1 could exert the formation of uracils
10 in 63ꢀ71% yields.
SCHEMES 2. Scope of sec-Primary Amines in the o-NQ1-
Catalyzed Direct Oxidation of Amines to Ketones
a20 mol % catalyst.
The fact that the catalyst o-NQ1 enables the direct oxidation
of secꢀprimary amines to ketones through the formation of
ketimine intermediate led us to reꢀoptimize the reaction condiꢀ
tions to selectively obtain ketimines 3 (see Supporting Inforꢀ
mation for detail). Scheme 3 lists the scope of o-NQ1ꢀ
catalyzed aerobic oxidation of secꢀprimary amines to
ketimines. Thus, with the cooperative action of o-NQ1 and
acetic acid the oxidation reaction was interrupted at the
ketimine stage thanks to the dehydrating effect of 3 Å molecuꢀ
lar sieves.14 The optimized reaction condition was widely apꢀ
plicable to secꢀprimary amines, leading to excellent isolated
yields of ketimines (3dꢀ3r). However, the corresponding
ketimines of 1ꢀ(naphthalenꢀ1ꢀyl)ethylamine 1p and 1ꢀ
(adamantanꢀ1ꢀyl)ethylamine 1u could not be identified, where
the ketones 2p and 2u were the only observed products. This
result may signify the steric requirement for the ketimine forꢀ
mation. 1ꢀPhenylpropanꢀ1ꢀamine 1s and cyclic secꢀprimary
amine 1t were not oxidized, instead the catalyst o-NQ1 was
captured by the substrates as benzooxazine derivatives (3sꢀ
3t).15 Nevertheless, the results in Scheme 3 represent the pracꢀ
SCHEMES 4. o-NQ1-Mediated Direct Deamination of
Various Amines (Yields using internal standard)
A proposed reaction mechanism for the direct aerobic deamꢀ
ination is depicted in Scheme 5 based on the HRMSꢀESI analꢀ
ysis of the reaction mixture. The orthoꢀnaphthoquinone cataꢀ
lyst, o-NQ1, condenses with amine 1 to give water and o-NQ-
ketimine. While there are two ketone moieties that amine 1
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can condense with, the crystallographic evidence of benzooxaꢀ
Supporting Information
1
2
3
4
5
6
7
8
zine derivative 3t clearly demonstrates the site of attack being
the 2ꢀcarbon position of o-NQ1. The prototropic rearrangeꢀ
ment then occurs to give Naphthol-ketimine. Our mass specꢀ
tra analysis revealed the peak corresponding to either o-NQ-
ketimine or Naphthol-ketimine as [M+H]+. Naphthol-
aminal should be derived from the reaction of the Naphthol-
ketimine with another molecule of amine 1. Alternatively, the
Naphthol-ketimine can isomerize to Naphthol-enamine in
such cases the catalyst arrest happens to give benzooxazine
derivatives such as 3s and 3t. The Naphthol-aminal underꢀ
goes the equilibriumꢀdriven dissociation of ketimine 3 to give
Naphthol-amine that on exposure to air spontaneously oxiꢀ
dizes to regenerate catalytically active species to reꢀenter the
catalytic cycle.11 The formations of Naphthol-amine as well
as the reduced form of o-NQ1, Catechol, were also estabꢀ
lished from the MS analysis of the reaction mixture. Ketimine
3 is hydrolyzed to give ketone 2, and amine 1 reꢀenters the
catalytic cycle. From the MS analysis of the reaction mixture
we also identified the formation of unsubstituted Ketimine,
possibly from the reaction between the ketone 2 and NH3 byꢀ
product. Also, we observed the formation of Catechol-
product complex, representing the resting state of Catechol
intermediate (see Supporting Information for HRMSꢀESI daꢀ
ta).
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and characterization data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
9
*Eꢀmail: kyungsoooh@cau.ac.kr.
*Eꢀmail: hunykim@cau.ac.kr
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the National Research Foundation
of Korea (NRF) grants funded by the Korean government (MSIP)
(NRFꢀ2015R1A5A1008958 and NRFꢀ2015R1C1A2A01053504).
REFERENCES
(1) For reviews, see: (a) Principles and Application of Quinopro-
teins; Davidson. V. L., Ed.; Marcel Dekker, Inc., New York, 1993. (b)
Davidson, V. L. Electron Transfer in Quinoproteins. Arch. Biochem.
Biophys. 2004, 428, 32ꢀ40.
SCHEMES 5. A Proposed Catalytic Cycle for the Aerobic
Deamination Based on HRMS-ESI Analysis
(2) (a) Eady, R. R.; Large, P. J. Microbial Oxidation of Amines.
Spectral and Kinetic Properties of the Primary Amine Dehydrogenase
of Pseudomonas AM 1. Biochem. J. 1971, 123, 757ꢀ768. (b) de Beer,
R.; Duine, J. A.; Frank Jzn, J.; Large, P. J. The Prosthetic Group of
Methylamine Dehydrogenase from Pseudomonas AM1: Evidence for
a Quinone Structure. Biochim. Biophys. Acta 1980, 622, 370ꢀ374. (c)
Hyun, Y. L.; Davidson, V. L. Mechanistic Studies of Aromatic Amine
Dehydrogenase, a Tryptophan Tryptophylquinone Enzyme. Biochem-
istry 1995, 34, 816ꢀ823. (d) Roujeinikova, A.; Hothi, P.; Masgrau, L.;
Sutcliffe, M. J.; Scrutton, N. S.; Leys, D. New Insights into the Reꢀ
ductive Halfꢀreaction Mechanism of Aromatic Amine Dehydrogenase
Revealed by Reaction with Carbinolamine Substrates. J. Biol. Chem.
2007, 282, 23766ꢀ23777.
(3) For reviews, see: (a) Mure, M.; Mills, S. A.; Klinman, J. P.
Catalytic Mechanism of the Topa Quinone Containing Copper Amine
Oxidases. Biochemistry 2002, 41, 9269ꢀ9278. (b) Mure, M. Tyroꢀ
sineꢀDerived Quinone Cofactors. Acc. Chem. Res. 2004, 37, 131ꢀ139.
(c) Klinman, J. P.; Bonnot, F. Intrigues and Intricacies of the Biosynꢀ
thetic Pathways for the Enzymatic Quinocofactors: PQQ, TTQ, CTQ,
TPQ, and LTQ.Chem. Rev. 2014, 114, 4343ꢀ4365.
(4) For recent reviews, see: (a) Chen, B.; Wang, L.; Gao, S. Recent
Advances in Aerobic Oxidation of Alcohols and Amines to Imines.
ACS Catal. 2015, 5, 5851ꢀ5876. (b) Wendlandt, A. E.; Stahl, S. S.
QuinoneꢀCatalyzed Selective Oxidation of Organic Molecules. An-
gew. Chem. Int. Ed. 2015, 54, 14638ꢀ14658. (c) Largeron M. Aerobic
Catalytic Systems Inspired by Copper Amine Oxidases: Recent Deꢀ
velopments and Synthetic Applications. Org. Biomol. Chem. 2017,
15, 4722ꢀ4730.
(5) Qin, Y.; Zhang, L.; Lv, J.; Luo, S.; Cheng J.ꢀP. Bioinspired Orꢀ
ganocatalytic Aerobic C–H Oxidation of Amines with an orthoꢀ
Quinone Catalyst. Org. Lett. 2015, 17, 1469ꢀ1472.
(6) For examples, see: (a) Yuan, H.; Yoo, W.ꢀJ.; Miyamura, H.;
Kobayashi, S. Discovery of a Metalloenzymeꢀlike Cooperative Cataꢀ
lytic System of Metal Nanoclusters and Catechol Derivatives for the
Aerobic Oxidation of Amines. J. Am. Chem. Soc. 2012, 134, 13970ꢀ
13973. (b) Jawale, D. V.; Gravel, E.; Shah, N.; Dauvois, V.; Li, H.;
Namboothiri, I. N. N.; Doris, E. Cooperative Dehydrogenation of Nꢀ
In summary, we have developed a novel aerobic deaminaꢀ
tion reaction to directly access to ketones and ketimines from
αꢀbranched primary amines. The direct formation of ketones
from amines has been, for the first time, achieved in good to
excellent yields thanks to the mild organocatalyst, orthoꢀ
naphthoquinone, with a distinctive amine activation mode.
Another key feature of the deamination catalyst is its applicaꢀ
bility to a diverse array of amineꢀcontaining molecules, where
the unprecedented deamination activity for amino acids and
DNA nuclear bases has been demonstrated with the specific
substrate dependency. Further extension of the aerobic deamiꢀ
nation reactions is currently underway, and our results will be
reported in due course.
Heterocycles Using
a Carbon Nanotube–Rhodium Nanohybrid.
Chem. – Eur. J. 2015, 21, 7039ꢀ7042. (c) Wendlandt, A. E.; Stahl, S.
S. Bioinspired Aerobic Oxidation of Secondary Amines and Nitrogen
Heterocycles with a Bifunctional Quinone Catalyst. J. Am. Chem.
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Soc. 2014, 136, 506ꢀ512. (d) Wendlandt, A. E.; Stahl, S. S. Modular
nism of C−C Cleavage of Cyclic 1,2ꢀDiketones with Alkaline Hydroꢀ
gen Peroxide. The Acyclic Mechanism and Its Application to the
Basic Autooxidation of Pyrogallol. J. Am. Chem. Soc. 1983, 105,
5035ꢀ5040.
oꢀQuinone Catalyst System for Dehydrogenation of Tetrahydroquinoꢀ
lines under Ambient Conditions. J. Am. Chem. Soc. 2014, 136,
11910ꢀ11913.
1
2
3
4
5
6
7
8
9
(7) (a) Corey, E. J.; Achiwa, K. Oxidation of Primary Amines to
Ketones. J. Am. Chem. Soc. 1969, 91, 1429ꢀ1432. (b) Buckley, T. F.;
Rapoport, H. Mild and Simple Biomimetic Conversion of Amines to
Carbonyl Compounds. J. Am. Chem. Soc. 1982, 104, 4446ꢀ4450.
(8) Srogl, J.; Voltrova, S. Copper/Ascorbic Acid Dyad as a Catalytꢀ
ic System for Selective Aerobic Oxidation of Amines. Org. Lett.
2009, 11, 843ꢀ845.
(9) (a) Matsuo, J.; Kawana, A.; Fukuda, Y.; Mukaiyama, T. Oxidaꢀ
tive Deamination of Various Primary Amines to the Corresponding
Carbonyl Compounds by Using NꢀtertꢀButylphenylsulfinimidoyl
Chloride. Chem. Lett. 2001, 712ꢀ713. (b) Nicolaou, K. C.; Mathison,
C. J. N.; Montagnon, T. oꢀIodoxybenzoic Acid (IBX) as a Viable
Reagent in the Manipulation of Nitrogenꢀ and SulfurꢀContaining
Substrates: Scope, Generality, and Mechanism of IBXꢀMediated
Amine Oxidations and Dithiane Deprotections. J. Am. Chem. Soc.
2004, 126, 5192ꢀ5201. (c) Hamamoto, H.; Suzuki, Y.; Takahashi, H.;
Ikegami, S. Direct Transformation of Benzilic Amines to Carbonyls
Using Polyacrylamideꢀbound Tungstate under PhaseꢀTransfer Catalyꢀ
sis Conditions. Tetrahedron Lett. 2007, 48, 4239ꢀ4242. (d) Galletti,
P.; Funiciello, F.; Soldati, R.; Giacomini, D. Selective Oxidation of
Amine to Aldehydes or Imines using LaccaseꢀMediated Bioꢀ
Oxidation. Adv. Synth. Catal. 2015, 357, 1840ꢀ1848.
(10) For the earlier attempts with low yields of 10ꢀ40 %, see: (a)
Yoneda, F.; Sakuma, Y.; Kadokawa, Y. Koshiro, A. Oxidation of
Amines to Carbonyl Compounds by Pyrimido[4,5ꢀb]quinolineꢀ2,4ꢀ
(3H,10H)ꢀdione (5ꢀDeazaflavin). Chem. Lett. 1979, 8, 1467ꢀ1468. (b)
Yoneda, F.; Kakagawa, K. Autorecylcling in the Oxidation of Alcoꢀ
hols and Amines by 1,6ꢀDimethylpyrimidoꢀ[4,5ꢀc]pyridazineꢀ
5,7(1H,6H)ꢀdione (4ꢀDeazatoxoflavins). J. Chem. Soc., Chem. Com-
mun. 1980, 878ꢀ879. (c) Yoneda, F.; Nakagawa, K.; Noguchi, M.;
Higuchi, M. Syntheses of 1, 6ꢀDimethylpyrimido [4,5ꢀc] pyridazineꢀ
5, 7(1H,6H)ꢀdiones (4ꢀDeazatoxoflavins) and Their Use in the Autoꢀ
recycling Oxidation of Alcohols and Amines. Chem. Pharm. Bull.
1981, 29, 379ꢀ385. (d) Nagamatsu, T.; Hashiguchi, Y.; Sakuma, Y.;
Yoneda, F. Autorecycling Oxidation of Amines to Carbonyl Comꢀ
pounds Catalyzed by 3,4ꢀDisubstituted 4ꢀDeazatoxoflavin Derivaꢀ
tives. Chem. Lett. 1982, 11, 1309ꢀ1312. (d) Ohshiro, Y.; Itoh, S.;
Kurokawa, K.; Kato, J.; Hirao, T.; Agawa, T. Micelle Enhanced Oxiꢀ
dation of Amines by Coenzyme PQQ. Tetrahedron Lett. 1983, 24,
3465ꢀ3468.
(14) For selected examples, see: (a) Wanner, M. J.; van der Haas,
R. N. S.; de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H. Cataꢀ
lytic Asymmetric Pictet–Spengler Reactions via Sulfenyliminium
Ions. Angew. Chem. Int. Ed. 2007, 46, 7485ꢀ7487. (b) Lou, S.;
Moquist, P. N.; Schaus, S. E. Asymmetric Allylboration of Acyl
Imines Catalyzed by Chiral Diols. J. Am. Chem. Soc. 2007, 129,
15398ꢀ15404. (c) Itoh, J.; Fuchibe, K.; Akiyama, T. Chiral Phosphorꢀ
ic Acid Catalyzed Enantioselective Friedel–Crafts Alkylation of Inꢀ
doles with Nitroalkenes: Cooperative Effect of 3 Å Molecular Sieves.
Angew. Chem. Int. Ed. 2008, 47, 4016ꢀ4018. (d) Li, N.; Song, J.; Tu,
X.ꢀF.; Liu, B.; Chen, X.ꢀH.; Gong, L.ꢀZ. Organocatalytic Asymmetric
Intramolecular [3+2] Cycloaddition: A Straightforward Approach to
Access Multiply Substituted Hexahydrochromeno[4,3ꢀb]pyrrolidine
Derivatives in High Optical Purity. Org. Biom. Chem. 2010, 8, 2016ꢀ
2019. (e) Takizawa, S.; Kiriyama, K.; Ikeki, K.; Sasai, H. A Bifuncꢀ
tional Spiroꢀtype Organocatalyst with High Enantiocontrol: Applicaꢀ
tion to the AzaꢀMorita–Baylis–Hillman Reactions. Chem. Commun.
2011, 47, 9227ꢀ9229.
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12
13
14
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20
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30
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(15) CCDC 1826024 contains the supplementary crystallographic
data for 3t. These data can be obtained free of charge from The Camꢀ
bridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
(16) For the aerobic oxidation of naphthaleneꢀ1,2ꢀdiols, see: Kim,
H. Y.; Takizawa, S.; Oh, K. Copperꢀcatalyzed Divergent Oxidative
Pathways of 2ꢀNaphthol Derivatives: orthoꢀNaphthoquinone versus 2ꢀ
BINOLs. Org. Biomol. Chem. 2016, 14, 7191ꢀ7196.
(17) The use of o-NQ1 for phenylalanine and leucine did not show
the catalytic activity, only leading to the corresponding aldehydes in
10ꢀ20% yields. For the pioneering deamination attempts of carboxylic
acids, see: a) Itoh, S.; Kato, N.; Ohshiro, Y.; Agawa, T. Oxidative
Decarboxylation of αꢀAmino Acids with Coenzyme PQQ. Tetrahe-
dron Lett. 1984, 25, 4753ꢀ4756. (b) Mure, M.; Suzuki, A.; Itoh, S.;
Ohshiro, Y. Oxidative C−C Fission (Dealdolation) of βꢀHydroxy
Amino Acids by Coenzyme PQQ. J. Chem. Soc., Chem. Commun.
1990, 1608ꢀ1612.
(18) For the cytosine deaminase activity, see: (a) Kream, J.; Charꢀ
gaff, E. On the Cytosine Deaminase of Yeast. J. Am. Chem. Soc.
1952, 74, 5157ꢀ5160. (b) Cohen, S. S.; Barner, H. D. The Conversion
of 5ꢀMethyldeoxycytidine to Thymidine in vitro and in vivo. J. Biol.
Chem. 1957, 226, 631ꢀ642. (c) Ipata, P. L.; Marmocchi, F.; Magni,
G.; Felicioli, R.; Polidoro, G. Baker's Yeast Cytosine Deaminase.
Enzymic Properties and Allosteric Inhibition by Nucleosides and
Nucleotides. Biochemistry, 1971, 10, 4270ꢀ4276. (d) Hitchcock, D.
S.; Fedorov, A. A.; Fedrov, E. V.; Almo, S. C.; Raushel, F. M. Disꢀ
covery of a Bacterial 5ꢀMethylcytosine Deaminase. Biochemistry,
2014, 53, 7426ꢀ7435.
(11) Goriya, Y.; Kim, H. Y.; Oh, K. oꢀNaphthoquinoneꢀCatalyzed
Aerobic Oxidation of Amines to (Ket)imines: A Modular Catalyst
Approach. Org. Lett. 2016, 18, 5174ꢀ5177.
(12) A single example of secꢀprimary amine oxidation by TBHBQ
to imine in 69% yield was described, see: Wendlandt, A. E.; Stahl, S.
S. Chemoselective Organocatalytic Aerobic Oxidation of Primary
Amines to Secondary Imines. Org. Lett. 2012, 14, 2850ꢀ2853.
(13) After the reaction, the formation of diacid derivatives, possiꢀ
bly formed by the H2O2ꢀpromoted cleavage of o-NQ1, was confirmed
from the MS analysis. For the formation of diacids from the oxidation
of orthoꢀquinones, see: (a) Speier, G.; Tyeklar, Z. Kinetics and Mechꢀ
anism of the Oxidation of 3,5ꢀDiꢀtꢀbutylꢀoꢀbenzoquinone with Hyꢀ
drogen Peroxide in Aqueous Methanol Solution. J. Chem. Soc., Per-
kin Trans 2, 1981, 1176ꢀ1179. (b) Sawaki, Y.; Foote, C. S. Mechaꢀ
(19) The chemical conversion of cytosine to uracil requires nitrous
acid followed by strong basic conditions, see: Swigor, J. E.; Pittman,
K. A. Synthesis of 1ꢀ(2ꢀDeoxyꢀ2ꢀfluoroꢀβꢀDꢀarabinofuranosyl)ꢀ5ꢀiodo
[2ꢀ14C]uracil. J. Label. Compd. Radiopharm, 1985, 22, 931ꢀ937.
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