Asymmetric combinational “metal-biocatalytic system”: One approach to chiral 2-subsituted-tetrahydroquinoline-4-ols towards two-step one-pot processes in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2017.04.074

A novel asymmetric “metal-biocatalytic system”, involving Rh-catalyzed asymmetric transfer hydrogenation and whole cell mediated asymmetric hydroxylation in aqueous buffer, has been achieved. The methodology gives access to 2-subsituted-tetrahydroquinoline-4-ols bearing two stereocenters from 2-subsituted-quinolines in moderate to excellent results (up to 47% yield, 99:1 dr, and >99% ee).

Full text of DOI:10.1016/j.tetlet.2017.04.074

Accepted Manuscript
Asymmetric combinational “metal-biocatalytic system”: one approach to chiral
2-subsituted-tetrahydroquinoline-4-ols towards two-step one-pot processes in
aqueous media
Juxiang Wang, Ke Li, Xiaojian Zhou, Wenyong Han, Nanwei Wan, Baodong
Cui, Huihui Wang, Weicheng Yuan, Yongzheng Chen
PII:
S0040-4039(17)30528-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.074
TETL 48866
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 March 2017
22 April 2017
24 April 2017
Please cite this article as: Wang, J., Li, K., Zhou, X., Han, W., Wan, N., Cui, B., Wang, H., Yuan, W., Chen, Y.,
Asymmetric combinational “metal-biocatalytic system”: one approach to chiral 2-subsituted-tetrahydroquinoline-4-
ols towards two-step one-pot processes in aqueous media, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.04.074
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Graphical Abstract
Asymmetric combinational “metal-
biocatalytic system”: one approach to chiral
2-subsituted-tetrahydroquinoline-4-ols
towards two-step one-pot processes in
aqueous media
Leave this area blank for abstract info.
Juxiang Wang, Ke Li, Xiaojian Zhou, Wenyong Han, Nanwei Wan, Baodong Cui, Huihui Wang, Wei-Cheng
Yuan, Yongzheng Chen*
Generic Drug Research Center of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi
563000, PR China

1
Tetrahedron Letters
Asymmetric combinational “metal-biocatalytic system”: one approach to chiral 2-
subsituted-tetrahydroquinoline-4-ols towards two-step one-pot processes in aqueous
media
Juxiang Wanga, Ke Lia, Xiaojian Zhoua, Wenyong Hana, Nanwei Wana, Baodong Cuia, Huihui Wanga,
Weicheng Yuanb, Yongzheng Chena
a Generic Drug Research Center of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi 563000, PR China
b National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel asymmetric “metal-biocatalytic system”, involving Rh-catalyzed asymmetric transfer
hydrogenation and whole cell mediated asymmetric hydroxylation in aqueous buffer, has been
achieved. The methodology gives access to 2-subsituted-tetrahydroquinoline-4-ols bearing two
stereocenters from 2-subsituted-quinolines in moderate to excellent results (up to 47% yield,
99:1 dr, and >99% ee).
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Combinational catalysis
Asymmetric transfer hydrogenation
Asymmetric hydroxylation
Rhodococcus equi ZMU-LK19
2-Subsituted-tetrahydroquinoline-4-ols
1. Introduction
technology for synthesis of optically active compounds, which
was attributed to its high enantioselectivity, operational
simplicity and broad substrate scope.11 Additionally, biocatalyzed
asymmetric hydroxylation accessing to chiral sec-alcohols by C–
H bond oxidation has been also developed.12 Given that these two
different reactions could be carried out in aqueous medium, so
it’s possible that two successive chemical reactions in one-pot
would be realized by combination of transfer hydrogenation with
hydroxylation. Such step-economic transformations are desirable
and valuable.
Combinational catalysis as one of the most powerful strategies
in asymmetric synthesis has been attracting considerable interest
because of its great potential in the construction of chiral
compounds.1 Obviously, metal catalysis combined with
organocatalysis, organocatalysis combined with biocatalysis as
well as metal catalysis combined with biocatalysis are common
strategies in combinational catalysis.2 In general, biocatalysts are
inactive among the chem-biocatalytic system, which is attributed
to enzymes in biocatalysts are deactivated by chemicals.2
Therefore, the development of highly efficient and compatible
catalytic system between chemical catalysts, especially metal
catalysts, and biocatalysts is a challenge. In the past decade,
asymmetric combinational “metal-biocatalytic system”, including
As a continuation of our ongoing interests in the metal
catalysis and biocatalysis,13 herein we disclose an unprecedented
catalytic strategy combining Rh-catalyzed ATH with whole cell
mediated asymmetric hydroxylation for the construction of a
series of chiral 2-subsituted-tetrahydroquinoline-4-ols (Scheme
1).
Wacker
oxidation/reduction,3
aldol
reaction/reduction,4
Suzuki
Heck/reduction,5
olefinmetathesis/epoxidation,6
reaction/reduction,7 allylic alcohol isomerisation/bioamination,8
amination/Suzuki reaction,9 hydrogenation/hydrolysis,10 have
been developed. Remarkably, metal-biocatalytic asymmetric
reaction has been served as an extra ordinary tool for synthesis of
new chiral compounds which are difficult to obtain by
conventional means.
Transition metal complexes catalyzed asymmetric transfer
hydrogenation (ATH) has emerged as a powerful and practical
Scheme 1. Asymmetric synthesis of 2-subsituted-tetrahydroquinoline-4-ols
through a combinational catalytic process.
———
 Corresponding author. Tel.: +86-851-28642336; fax: +86-851-28609726; e-mail: yzchen@zmc.edu.cn

2
Tetrahedron
2. Results and discussion
17% yield with excellent diastereo- and enantioselectivity (99:1
dr, >99% ee). However, compound 1c with i-Pr group at the C2-
position of the quinoline wasn’t a good substrate, affording 3c in
moderate results (14% yield, 77:23 dr and 99% ee). Interestingly,
the method was compatible with compound 1d, in which R was
represented by cyclopropyl, leading the corresponding chiral
tetrahydroquinoline 3d in 16% yield with 92:8 dr and >99% ee.
To our delight, the diastereo- and enantioselectivity of 3c and 3d
could be further improved after one recrystallization. The
absolute configuration of the product 3d was unambiguously
determined as (C2R, C4R) by X-ray crystallographic analysis
with CuKα radiation= 1.54184 Å (Fig. 1),15 compound 3c in
Scheme 3 was tentatively assigned by analogy.
Scheme 2. Enantioselective synthesis of 3a.
Our studies began with the Rh-catalyzed asymmetric transfer
hydrogenation. 10 mol% of metal-complex prepared via treating
(R, R)-Ts-DPEN and (Cp*RhCl2)2 in situ was applied to catalyze
the ATH of 1a (0.5 mmol, 100 mM). As a result, excellent
conversion (98%) and enantioselectivity (97%) were obtained
using HCO2Na (10.0 equiv.) as hydrogen source in pH 5.0 with
the HOAc/NaOAc system (ABS, 2 M, 5.0 mL) at 40 ºC for 12 h
(Scheme 2).14 After that this mixture was diluted to 83.3 mL
using ABS buffer (50 mM, pH = 5.0), and then the diluted
mixture (83.3 mL) was divided equally into seventeen portions.
Subsequently, cell of Rhodococcus equi ZMU-LK19 prepared via
cell growth and cultivation was suspended in each portion of
mixture (4.9 mL) to a cell density of 50 g dcw/L and the mixture
was incubated at 30 ºC for 24 h.13k To our delight, compound 3a
was obtained in excellent results (99% conv., 47% yield, 99:1 dr
and >99% ee). The absolute configuration of 3a was determined
to be (C2R, C4R) configuration by comparing the HPLC spectra
with the literature known compound.13k
Scheme 4.“Metal-Biocatalytic System” on a large scale quantity.
To examine the utility of the asymmetric “metal-biocatalytic
system”, large scale quantity of 1a (0.5 mmol, 100 mM) was
carried out with 10 mol% of metal-complex in 5.0 mL ABS
buffer (2 M, pH = 5.0) at 40 °C for 12 h (Scheme 4). Afterwards,
the reaction system was diluted to 83.3 mL using ABS buffer (50
mM, pH = 5.0), and then the diluted mixture (83.3 mL) was
directly conducted on Rhodococcus equi ZMU-LK19 mediated
biotransformation. Delightfully, the corresponding product 3a
also could be obtained in an improved yield up to 73% without
any loss of diastereo- (99:1 dr) and enantioselectivity (>99% ee).
3. Conclusions
In conclusion, we have developed a novel combinational
catalyzed asymmetric transfer hydrogenation/regio- and
enantioselective hydroxylation process with 2-substitute
quinolines (1), providing chiral 2-subsituted-tetrahydroquinoline-
4-ols (3) in moderate to excellent results (14-47% yield, 77:23-
99:1 dr and 99->99% ee). Satisfactorily, the diastereo- and
enantioselectivity of some products could be further improved
after recrystallization. The current methodology not only
provides
a
new approach to
chiral 2-subsituted-
tetrahydroquinoline-4-ols, which are contained in numerous
biologically important molecules, but also further illustrates the
potentiality of chemoenzymatic multistep one-pot processes. We
expect that insights gained from our present study are helpful for
opening new opportunities to access chiral 2-subsituted-
tetrahydroquinoline-4-ols.
Scheme 3. Substrate Scope. For the reaction conditions, see the supporting
information. The yield was determined by HPLC analysis of the crude
reaction mixture using external standard, the ee value and dr value were
determined by chiral HPLC analysis. The result in parentheses was obtained
after recrystallization from a mixture of petroleum ether and ethyl acetate.
Acknowledgments
We are grateful for financial support from National Nature
Science Foundation of China (21562054), Science and
Technology Department of Guizhou Province (QKHRC-2016-
4029, QKHRCTD-2014-4002 and QKHPTRC-2016-5801), and
New Century Excellent Talent of the Ministry of Education
(NCET-13-1069).
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4
Tetrahedron
Highlights




Asymmetric “metal-biocatalytic system”.
One-pot conversion of 2-subsituted-quinolines to 2-subsituted-tetrahydroquinoline-4-ols.
Synthesis of chiral 2-subsituted-tetrahydroquinoline-4-ols in moderate to excellent results.
Further illustrates the potentiality of chemoenzymatic multistep one-pot processes.