Synergistic Chemo/Biocatalytic Synthesis of Alkaloidal Tetrahydroquinolines

Article abstract of DOI:10.1021/acscatal.8b01220

The power of complementary chemocatalytic and biocatalytic transformations is demonstrated in the asymmetric synthesis of 2-substituted tetrahydroquinolines. A series of racemic tetrahydroquinolines were synthesized through a convergent one-pot Rh(I)-catalyzed addition/condensation sequence of alkyl vinyl ketones and aminophenylboronic acids. The resulting tetrahydroquinolines were thereafter shown to be substrates for the flavin-dependent enzyme cyclohexylamine oxidase, and preparative-scale deracemizations have been demonstrated on these high-value targets.

Full text of DOI:10.1021/acscatal.8b01220

Subscriber access provided by Kaohsiung Medical University
Letter
Synergistic chemo/biocatalytic synthesis of alkaloidal tetrahydroquinolines
Sebastian Cronin Cosgrove, Shahed Hussain, Nicholas J Turner, and Stephen Philip Marsden
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01220 • Publication Date (Web): 14 May 2018
Downloaded from http://pubs.acs.org on May 14, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
ACS Catalysis
1
2
3
4
5
6
7
8
9
Synergistic chemo/biocatalytic synthesis of alkaloidal tetrahydro-
quinolines
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
1,2
1†
1
2
Sebastian C. Cosgrove, Shahed Hussain, Nicholas J. Turner* and Stephen P. Marsden*
1School of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester
M1 7DN, United Kingdom
2
Institute of Process Research and Development and School of Chemistry, University of Leeds, Leeds, LS2 9JT, United
Kingdom
ABSTRACT: The power of complementary chemoꢀ and biocatalytic transformations is demonstrated in the asymmetric synthesis
of 2ꢀsubstituted tetrahydroquinolines. A series of racemic tetrahydroquinolines were synthesized through a convergent oneꢀpot
Rh(I)ꢀcatalysed addition/condensation sequence of alkyl vinyl ketones and aminophenylboronic acids. The resulting tetrahydroꢀ
quinolines were thereafter shown to be substrates for the flavinꢀdependent enzyme cyclohexylamine oxidase, and preparativeꢀscale
deracemizations have been demonstrated on these highꢀvalue targets.
KEYWORDS: rhodium catalysis, biocatalysis, amine oxidase, alkaloidal tetrahydroquinoline, enzymatic deracemization
Introduction
Amines are an important class of molecule that are present
in many biologicallyꢀrelevant compounds. A recent analysis of
FDA registered pharmaceuticals revealed that 84% contained
1
an amine moiety, with 59% of these being cyclic. Particularly
relevant are chiral amines, which are subunits of ca. 40% of
all pharmaceuticals. A variety of strategies have been develꢀ
Figure 1. Alkaloids isolated from Galipea officinalis
2
oped for the preparation of enantiopure amines, from classical
resolution through to asymmetric chemocatalysis.
While many cyclic amines have been deracemised by AOx
enzymes, studies on deracemization of THQs have been limꢀ
3
,4
25–27
ited.
Lau engineered CHAO using iterative mutagenesis,
Biocatalysis has found numerous applications in chiral
5
producing a mutant which fully deracemized 2ꢀmethylTHQ on
a preparative scale, but no activity was seen against other
amine synthesis and the toolbox of enzymes that can be used
6
to synthesise chiral amines includes transaminase, amino acid
26
7
–9
10,11
12
THQ substrates. More recently this group demonstrated that
the selectivity of CHAO could be reversed through a single
point mutation of the wildꢀtype, and showed an improved subꢀ
dehydrogenase,
imine reductase,
reductive aminase
1
3
and phenylalanine ammoniaꢀlyase. In addition, amine oxiꢀ
dase (AOx) has been applied by many groups in biocatalytic
deracemization reactions.
28
1
4,15
strate scope of the enzyme. Deng found that a novel AOx
Several flavinꢀdependent AOx
from Pseudomonas monteilii could catalyse selective oxidaꢀ
tion of THQ derivatives to the respective quinolines, and
demonstrated mutants that could be used for a traditional kiꢀ
enzymes have been used in the deracemization of racemic
amines including the Sꢀselective monoamine oxidase from
16,17
Aspergillus niger (MAOꢀN)
(
and cyclohexylamine oxidase
29
18
19
netic resolution of 2ꢀmethylTHQs.
CHAO), and 6ꢀhydroxyꢀDꢀnicotine oxidase (6ꢀHDNO)
which demonstrates complementary Rꢀselectivity and has also
been engineered to generate a more active mutant.
For these deracemisation studies, the majority of the raceꢀ
mic THQs were prepared by reduction of the corresponding
quinolines and they are therefore contingent upon the availaꢀ
bility of these compounds. A more direct and modular apꢀ
proach would be attractive. A powerful emerging synthetic
strategy is the union of chemoꢀ and biocatalysis to achieve
cascade or sequential transformations. This approach is parꢀ
ticularly powerful when harnessing metalꢀcatalysed CꢀC bond
forming processes for which there are no direct biocatalytic
2
0–22
Tetrahydroquinolines (THQs) are an important class of bioꢀ
logicallyꢀactive amines, found in a range of synthetic pharmaꢀ
2
3
ceuticals and naturallyꢀoccurring alkaloids. As typical examꢀ
ples, a family of 2ꢀsubstituted THQs 1ꢀ4 isolated from Galipea
officinalis are shown in Figure 1, several of which have bioꢀ
30
24
logical activity against certain malarial strains (Figure 1).
Methods for the asymmetric synthesis of THQs are therefore
of interest in medicinal chemistry.
equivalents, hence greatly expanding the range of substrates
31–37
for the biocatalytic transformation.
Herein we show that
the synergistic application of a chemocatalytic oneꢀpot, twoꢀ
component condensation and biocatalytic deracemisation enaꢀ
bles the efficient asymmetric synthesis of THQ natural prodꢀ
ucts.
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 5
Results
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
Previously, we have demonstrated a formal [4+2] approach
to the assembly of nitrogen heterocycles through rhodiumꢀ
catalysed conjugate addition/condensation of orthoꢀ
aminophenylboronic acids with Michael acceptors.
case of enone acceptors, the addition/condensation generates
unstable dihydroquinoline intermediates which can be reduced
in the same pot to give tetrahydroquinolines. Chemocatalytic
asymmetric addition to betaꢀsubstituted enones (using a chiral
phosphine/rhodium complex) followed by a diastereoselective
synꢀreduction allowed access to highly enantioenriched 2,4ꢀ
3
8–40
In the
4
0
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
4
0
disubstituted THQ products. However, many valuable prodꢀ
ucts (including alkaloids 1ꢀ4) feature stereocentres only at the
2
ꢀposition, which cannot be accessed asymmetrically through
this approach.
The approach to simple 2ꢀsubstituted THQs requires the use
of highly reactive unsubstituted vinyl ketones, and modificaꢀ
tion of the previously disclosed conjugate addition conditions
was required for good conversion. Specifically, we found that
introduction of the phenylboronic acid as its HCl salt rather
o
than the free base and operating at elevated (90 C) rather than
room temperature gave the optimal results. Initially, we examꢀ
ined the use of imine reductases to reduce the prochiral dihyꢀ
droquinoline intermediates 5; however exposure of the crude
reaction mixture following filtration to both (R) and (S)ꢀIREDs
failed to give any observable THQ product. The racemic 2ꢀ
substituted THQ was therefore produced in a oneꢀpot process
by addition of sodium tri(acetoxy)borohydride to the reaction
mixture on completion of the conjugate addition. Under these
conditions, the model 2ꢀ(2ꢀphenylethyl)THQ 6a could be asꢀ
sembled efficiently (Scheme 1).
Scheme 2. Synthesis of 2-substituted tetrahydroquinolines
a
TBAF, THF, rt., 16h
We then turned to the AOxꢀmediated deracemisation of the
THQs 6aꢀf in order to complete formal asymmetric syntheses
of the alkaloids. The analytical scale biotransformations were
run using whole E. coli cells expressing three AOx enzymes
15
described previously: MAOꢀN D9, the CHAO variant deꢀ
26
20
scribed by Lau et al., and 6ꢀHDNO which was engineered
previously in the Turner group. On an analytical scale almost
full deracemization of 6a was observed with the CHAO variꢀ
ant, with an ee of 94% after 96 h. With MAOꢀN D9 only trace
activity was observed, and 6ꢀHDNO gave no activity towards
this substrate. Pleasingly, CHAO also displayed good activity
towards the natural product substrates 6bꢀf, with cuspareine
precursor 6c giving 90% ee, galipinine precursor 6c being
converted to a lower ee of 70%, galipeine substrate 6e also
giving an ee of 70% and the isomeric substrate 6f was fully
deracemized in only 48h. Interestingly, when the angustureine
precursor 6b was subjected to deracemization by CHAO, an ee
of only 47% was observed, but inspection of the HPLC trace
showed a new peak not corresponding to either enantiomer
which was subsequently shown to be the fully oxidised 2ꢀ
pentylquinoline (see below). The THQ 6b was however a suitꢀ
able substrate for the MAOꢀN D9 enzyme, giving an ee of
Scheme 1. Conditions for Rh(I)-catalysed 2-substituted-
tetrahydroquinoline synthesis
We next used these optimized conditions to extend the subꢀ
strate scope to encompass the 2ꢀsubstituents found in alkaloids
1ꢀ4 (Scheme 2). Pleasingly, incorporation of a simple pentyl
substituent gave 6b in good yield, while (3,4ꢀ
dimethoxyphenyl)ꢀ and (3,4ꢀmethylenedioxyphenyl)ethyl subꢀ
stituents were also tolerated in 6c/d. Galipeine 4 features both
hydroxyl and methoxy substitutents on the phenyl ring; the
natural product was originally assigned the 3ꢀhydroxyꢀ4ꢀ
8
5% after 96 h. Interestingly, it also showed limited activity
towards 6ꢀHDNO, with selectivity shown for the opposite
enantiomer (Table 1).
41
methoxy substitution but this has recently been revised. We
prepared both isomeric forms, with the phenolic function inꢀ
troduced as the TBS ether, which was readily deprotected to
give 6e/f. The Nꢀmethylations of compounds 6bꢀe are known
41,42
in the literature
and were repeated here (Supporting Inforꢀ
mation), thus completing racemic total syntheses of all four
alkaloids 1ꢀ4 along with the regioisomeric analogue derived
from 6f.
ACS Paragon Plus Environment

Page 3 of 5
ACS Catalysis
Table 1. Analytical scale MAO deracemizations of THQ
bic oxidation, dihydroquinoline disproportionation, or an enꢀ
29
1
2
3
4
5
6
7
8
9
substrates
zymaticallyꢀmediated oxidation step. Work is currently unꢀ
derway to establish the mechanism of this aromatization.
Conclusions
In
tion/condensation sequence allows for the oneꢀpot synthesis of
ꢀsubstituted THQs, including desꢀmethyl variants of a range
conclusion,
Rh(I)ꢀcatalysed
conjugate
addiꢀ
2
a
of Galipea alkaloids. We have also demonstrated application
of AOx enzymes in the deracemization of these highꢀvalue
products on preparative scale. The synergies between CꢀC
bond forming chemocatalysis and biocatalysis for the rapid
assembly of enantioenriched products are thus further demonꢀ
strated and provide inspiration for future studies.
Substrate
CHAO ee
MAO-N D9 ee 6-HDNO ee
b
6
6
a
94%
trace
85%
0%
0%
13%
0%
0%
0%
0%
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
c
b
47%
6
c
90%
70%
70%
6
d
0%
6e
0%
ASSOCIATED CONTENT
d
6
f
>99%
0%
Supporting Information available: experimental procedures, specꢀ
1
13
troscopic data for all new compounds, including H and C NMR
spectra, HPLC conditions and traces for all chiral compounds, and
procedures for bacterial culture growth. This material is available
free of charge via the Internet at http://pubs.acs.org.
Standard Conditions: THQ (5 mM), NH ·BH (50 mM), E. coli
3
3
ꢀ
1
cells (100 mg mL ), 1 M phosphate buffer (pH 7.4), 500 μL total
a
b
vol. Enantiomeric excess determined by chiral phase HPLC 72
c
h instead of 96 h Contained additional peak in HPLC trace when
compared with racemic standard 48 h instead of 96 h
d
AUTHOR INFORMATION
Corresponding Authors
We then examined the preparative scale deracemisation of
several substrates (Table 2). The model substrate 6a delivered
the Rꢀenantiomer (determined by comparison of the optical
rotation with the literature value) with an ee of 94% and an
isolated yield of 84% on a 50 mg scale. Deracemisation of the
alkaloidal precursors 6c and 6e stalled at around 50% ee, howꢀ
ever. Interestingly, the isomeric 3ꢀhydroxyꢀ4ꢀmethoxyphenyl
variant 6f gave complete deracemisation, delivering a single
enantiomer in 65% yield, so it is possible the 3ꢀmethoxy subꢀ
stituent in 6c and 6e is responsible for the limited activity. The
configuration of deracemized 6f was based on the assignement
of 6a and that of literature precedents for the genuine natural
* S.P.Marsden@leeds.ac.uk
* Nicholas.turner@manchester.ac.uk
Present Addresses
†
S. Hussain: Dr.Reddy's, Cambridge Science Park Milton Rd,
Milton, Cambridge CB4 0WW
Author Contributions
All authors have given approval to the final version of the manuꢀ
script.
43
product. This limitation could potentially be addressed
ACKNOWLEDGMENT
through protein engineering of CHAO to create more tolerant
mutants.
We are grateful to the EPSRC for funding to SCC (DTA studentꢀ
ship at University of Leeds; Doctoral Prize Fellowship at Univerꢀ
sity of Manchester). Thanks to Reynard Spiess for mass spec serꢀ
vices.
Table 2. Preparative-scale deracemization reactions using
CHAO
REFERENCES
(
1)
Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
Structural Diversity, Substitution Patterns, and Frequency of
Nitrogen Heterocycles among U.S. FDA Approved
Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274.
Jarvis, L. M. The Year In New Drugs. Chem. Eng. News 2016,
94, 12–17.
(
2)
3)
1
2
a
b
Substrate
R
R
Time
96h
96h
96h
48h
Yield
84%
64%
80%
65%
ee
(
Nugent, T. C. Chiral Amine Synthesis: Methods, Developments
and Applications; WILEYꢀVCH Verlag: Weinheim, Germany,
6
a
c
H
H
94%
52%
50%
>99%
2
010.
6
OMe
OMe
OH
OMe
OH
(4)
(5)
Nugent, T. C.; ElꢀShazly, M. Chiral Amine Synthesis ꢀ Recent
Developments and Trends for Enamide Reduction, Reductive
Amination, and Imine Reduction. Adv. Synth. Catal. 2010, 352,
6e
6f
OMe
7
53–819.
Ghislieri, D.; Turner, N. J. Biocatalytic Approaches to the
Synthesis of Enantiomerically Pure Chiral Amines. Top. Catal.
Standard conditions: THQ (5 mM), NH ·BH (50 mM), E. coli
3
3
ꢀ1
a
cells (100 mg mL ), 1 M phosphate buffer (pH 7.4) Isolated
2
014, 57, 284–300.
b
yield Enantiomeric excess determined by chiral HPLC
(
6)
7)
Fuchs, M.; Farnberger, J. E.; Kroutil, W. The Industrial Age of
Biocatalytic Transamination. European J. Org. Chem. 2015,
6965–6982.
Mutti, F. G.; Knaus, T.; Scrutton, N. S.; Breuer, M.; Turner, N.
J. Conversion of Alcohols to Enantiopure Amines through Dualꢀ
Enzyme HydrogenꢀBorrowing Cascades. Science 2015, 349,
1525–1529.
Attempted preparativeꢀscale deracemisation of the anꢀ
gustureine precursor 6b with CHAO showed almost full conꢀ
version to the fully oxidized 2ꢀpentylquinoline, allowing conꢀ
firmation that this was the additional peak observed on the
analytical scale HPLC trace (See SI). At this stage it is unclear
whether the second oxidation is a result of nonꢀcatalysed aeroꢀ
(
(8)
Knaus, T.; Böhmer, W.; Mutti, F. G. Amine Dehydrogenases:
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 5
Efficient Biocatalysts for the Reductive Amination of Carbonyl
Compounds. Green Chem. 2017, 19, 453–463.
Biocatalytic Potential in Deracemization of Racemic Amines.
Appl. Microbiol. Biotechnol. 2014, 98, 1681–1689.
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
(
9)
Nestl, B. M.; Hammer, S. C.; Nebel, B. A.; Hauer, B. New
Generation of Biocatalysts for Organic Synthesis. Angew. Chem.
Int. Ed. 2014, 53, 3070–3095.
Grogan, G.; Turner, N. J. InspIRED by Nature: NADPHꢀ
Dependent Imine Reductases (IREDs) as Catalysts for the
Preparation of Chiral Amines. Chem. Eur. J. 2016, 22, 1900–
(28)
(29)
Yao, P.; Cong, P.; Gong, R.; Li, J.; Li, G.; Ren, J.; Feng, J.; Lin,
J.; Lau, P.; Wu, Q.; Zhu, D. Biocatalytic Route to Chiral 2ꢀ
Substitutedꢀ1,
2,
3,
4ꢀTetrahydroquinolines
Using
(10)
Cyclohexylamine Oxidase Muteins. ACS Catal. 2018, 8, 1648–
1652.
Deng, G.; Wan, N.; Qin, L.; Cui, B.; An, M.; Han, W.; Chen, Y.
Deracemisation of Phenyl Substituted 2ꢀMethylꢀ1,2,3,4ꢀ
Tetrahydroquinolines by a Recombinant Monoamine Oxidase
from Pseudomonas Monteilii ZMUꢀT01. ChemCatChem 2018,
10, doi: 10.1002/cctc.201701995
Gröger, H.; Hummel, W. Combining the “two Worlds” of
Chemocatalysis and Biocatalysis towards MultiꢀStep OneꢀPot
Processes in Aqueous Media. Curr. Opin. Chem. Biol. 2014, 19,
171–179.
Boffi, A.; Cacchi, S.; Ceci, P.; Cirilli, R.; Fabrizi, G.; Prastaro,
A.; Niembro, S.; Shafir, A.; Vallribera, A. The Heck Reaction of
Allylic Alcohols Catalyzed by Palladium Nanoparticles in
Water: Chemoenzymatic Synthesis of (R)ꢀ(−)ꢀRhododendrol.
ChemCatChem 2011, 3, 347–353.
Latham, J.; Henry, J.ꢀM.; Sharif, H. H.; Menon, B. R. K.;
Shepherd, S. A.; Greaney, M. F.; Micklefield, J. Integrated
Catalysis Opens New Arylation Pathways via Regiodivergent
Enzymatic C–H Activation. Nat. Commun. 2016, 7, 11873.
Denard, C. A.; Huang, H.; Bartlett, M. J.; Lu, L.; Tan, Y.; Zhao,
H.; Hartwig, J. F. Cooperative Tandem Catalysis by an
Organometallic Complex and a Metalloenzyme. Angew. Chem.
Int. Ed. 2014, 53, 465–469.
Burda, E.; Hummel, W.; Gröger, H. Modular Chemoenzymatic
OneꢀPot Syntheses in Aqueous Media: Combination of a
PalladiumꢀCatalyzed CrossꢀCoupling with an Asymmetric
Biotransformation. Angew. Chem. Int. Ed. 2008, 47, 9551–9554.
Scalacci, N.; Black, G. W.; Mattedi, G.; Brown, N. L.; Turner,
N. J.; Castagnolo, D. Unveiling the Biocatalytic Aromatizing
Activity of Monoamine Oxidases MAOꢀN and 6ꢀHDNO:
Development of Chemoenzymatic Cascades for the Synthesis of
Pyrroles. ACS Catal. 2017, 7, 1295–1300.
Gómez Baraibar, Á.; Reichert, D.; Mügge, C.; Seger, S.; Gröger,
H.; Kourist, R. A OneꢀPot Cascade Reaction Combining an
Encapsulated Decarboxylase with a Metathesis Catalyst for the
Synthesis of BioꢀBased Antioxidants. Angew. Chem. Int. Ed.
2016, 55, 14823–14827.
Tenbrink, K.; Seßler, M.; Schatz, J.; Gröger, H. Combination of
Olefin Metathesis and Enzymatic Ester Hydrolysis in Aqueous
Media in a OneꢀPot Synthesis. Adv. Synth. Catal. 2011, 353,
2363–2367.
Horn, J.; Marsden, S. P.; Nelson, A.; House, D.; Weingarten, G.
G. Convergent , Regiospecific Synthesis of Quinolines from Oꢀ
Aminophenylboronates. Org. Lett. 2008, 10, 4117–4120.
Horn, J.; Li, H. Y.; Marsden, S. P.; Nelson, A.; Shearer, R. J.;
Campbell, A. J.; House, D.; Weingarten, G. G. Convergent
Synthesis of Dihydroquinolones from OꢀAminoarylboronates.
Tetrahedron 2009, 65, 9002–9007.
1
907.
(11)
(12)
(13)
MangasꢀSanchez, J.; France, S. P.; Montgomery, S. L.; Aleku,
G. A.; Man, H.; Sharma, M.; Ramsden, J. I.; Grogan, G.; Turner,
N. J. Imine Reductases (IREDs). Curr. Opin. Chem. Biol. 2017,
3
7, 19–25.
(30)
(31)
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
Aleku, G. A.; France, S. P.; Man, H.; MangasꢀSanchez, J.;
Montgomery, S. L.; Sharma, M.; Leipold, F.; Hussain, S.;
Grogan, G.; Turner, N. J.
A Reductive Aminase from
Aspergillus Oryzae. Nat. Chem. 2017, 9, 961–969.
Parmeggiani, F.; Weise, N. J.; Ahmed, S. T.; Turner, N. J.
Synthetic and Therapeutic Applications of AmmoniaꢀLyases
and Aminomutases. Chem. Rev. 2018, 118, 73–118.
Alexeeva, M.; Enright, A.; Dawson, M. J.; Mahmoudian, M.;
Turner, N. J. Deracemization of AlphaꢀMethylbenzylamine
Using an Enzyme Obtained by in Vitro Evolution. Angew.
Chem. Int. Ed. 2002, 41, 3177–3180.
Ghislieri, D.; Green, A. P.; Pontini, M.; Willies, S. C.; Rowles,
I.; Frank, A.; Grogan, G.; Turner, N. J. Engineering an
Enantioselective Amine Oxidase for the Synthesis of
Pharmaceutical Building Blocks and Alkaloid Natural Products.
J. Am. Chem. Soc. 2013, 135, 10863–10869.
Schilling, B.; Lerch, K. Amine Oxidases from Aspergillus
Niger: Identification of a Novel FlavinꢀDependent Enzyme.
Biochim. Biophys. Acta - Gen. Subj. 1995, 1243, 529–537.
Sablin, S. O.; Yankovskaya, V.; Bernard, S.; Cronin, C.; Singer,
T. P. Isolation and Characterization of an Evolutionary
Precursor of Human MAO A and B. Eur. J. Biochem. 1997, 43,
(
14)
15)
(32)
(33)
(34)
(35)
(
(
16)
17)
(
4
55–456.
(18)
Iwaki, H.; Shimizu, M.; Tokuyama, T.; Hasegawa, Y.
Biodegradation of Cyclohexylamine by Brevibacterium
Oxydans IHꢀ35A. Appl. Environ. Microbiol. 1999, 65, 2232–
2234.
(36)
(37)
(
19)
20)
Decker, K.; Dai, V. D. Mechanism and Specificity of Lꢀ and Dꢀ
6
ꢀHydroxynicotine Oxidase. Eur. J. Biochem. 1967, 3, 132–138.
(
Heath, R. S.; Pontini, M.; Bechi, B.; Turner, N. J. Development
of an RꢀSelective Amine Oxidase with Broad Substrate
Specificity and High Enantioselectivity. ChemCatChem 2014, 6,
9
96–1002.
(
21)
22)
Heath, R. S.; Pontini, M.; Hussain, S.; Turner, N. J. Combined
Imine Reductase and Amine Oxidase Catalyzed Deracemization
of Nitrogen Heterocycles. ChemCatChem 2016, 8, 117–120.
Yasukawa, K.; Nakano, S.; Asano, Y. Tailoring DꢀAmino Acid
Oxidase from the Pig Kidney to RꢀStereoselective Amine
Oxidase and Its Use in the Deracemization ofꢁαꢀ
Methylbenzylamine. Angew. Chem. Int. Ed. 2014, 53, 4428–
(38)
(39)
(
4
431.
(
23)
24)
Sridharan, V.; Suryavanshi, P. A.; Menéndez, J. C. Advances in
the Chemistry of Tetrahydroquinolines. Chem. Rev. 2011, 111,
7157–7259.
JacquemondꢀCollet, I.; Hannedouche, S.; Fabre, N.; Fourasté, I.;
Moulis, C. Two Tetrahydroquinoline Alkaloids from Galipea
Officinalis. Phytochemistry 1999, 51, 1167–1169.
Leisch, H.; Grosse, S.; Iwaki, H.; Hasegawa, Y.; Lau, P. C. K.
Cyclohexylamine Oxidase as a Useful Biocatalyst for the
Kinetic Resolution and Dereacemization of Amines. Can. J.
Chem. 2012, 90, 39–45.
Li, G.; Ren, J.; Yao, P.; Duan, Y.; Zhang, H.; Wu, Q.; Feng, J.;
Lau, P. C. K.; Zhu, D. Deracemization of 2ꢀMethylꢀ1,2,3,4ꢀ
Tetrahydroquinoline Using Mutant Cyclohexylamine Oxidase
Obtained by Iterative Saturation Mutagenesis. ACS Catal. 2014,
(40)
Li, H. Y.; Horn, J.; Campbell, A.; House, D.; Nelson, A.;
Marsden, S. P. A Convergent RhodiumꢀCatalysed Asymmetric
Synthesis of Tetrahydroquinolines. Chem. Commun. 2014, 50,
10222–10224.
Davies, S. G.; Fletcher, A. M.; Houlsby, I. T. T.; Roberts, P. M.;
Thomson, J. E. Structural Revision of the Hancock Alkaloid (−)ꢀ
Galipeine. J. Org. Chem. 2017, 82, 10673–10679.
DiazꢀMuñoz, G.; Isidorio, R. G.; Miranda, I. L.; de Souza Dias,
G. N.; Diaz, M. A. N. A Concise and Efficient Synthesis of
Tetrahydroquinoline Alkaloids Using the Phase Transfer
Mediated Wittig Olefination Reaction. Tetrahedron Lett. 2017,
58, 3311–3315.
Taylor, L. L.; Goldberg, F. W.; Hii, K. K. (Mimi). Asymmetric
Synthesis of 2ꢀAlkylꢀSubstituted Tetrahydroquinolines by an
Enantioselective AzaꢀMichael Reaction. Org. Biomol. Chem.
2012, 10, 4424–4432.
(
(41)
(42)
(25)
(26)
(43)
4
, 903–908.
(27)
Li, G.; Ren, J.; Iwaki, H.; Zhang, D.; Hasegawa, Y.; Wu, Q.;
Feng, J.; Lau, P. C. K.; Zhu, D. Substrate Profiling of
Cyclohexylamine Oxidase and Its Mutants Reveals New
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
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
5
ACS Paragon Plus Environment