Double Enzyme-Catalyzed One-Pot Synthesis of Enantiocomplementary Vicinal Fluoro Alcohols

Article abstract of DOI:10.1021/acs.orglett.0c01825

A double-enzyme-catalyzed strategy for the synthesis of enantiocomplementary vicinal fluoro alcohols through a one-pot, three-step process including lipase-catalyzed hydrolysis, spontaneous decarboxylative fluorination, and subsequent ketoreductase-catalyzed reduction was developed. With this approach, β-ketonic esters were converted to the corresponding vicinal fluoro alcohols with high isolated yields (up to 92percent) and stereoselectivities (up to 99percent). This new cascade process addresses some issues in comparison with traditional methods such as environmentally hazardous reaction conditions and low stereoselectivity outcome.

Full text of DOI:10.1021/acs.orglett.0c01825

pubs.acs.org/OrgLett
Letter
Double Enzyme-Catalyzed One-Pot Synthesis of
Enantiocomplementary Vicinal Fluoro Alcohols
Jiajie Fan,∥ Yongzhen Peng,∥ Weihua Xu, Anlin Wang, Jian Xu,* Huilei Yu, Xianfu Lin, and Qi Wu*
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ABSTRACT: A double-enzyme-catalyzed strategy for the synthesis of
enantiocomplementary vicinal fluoro alcohols through a one-pot, three-
step process including lipase-catalyzed hydrolysis, spontaneous decar-
boxylative fluorination, and subsequent ketoreductase-catalyzed reduc-
tion was developed. With this approach, β-ketonic esters were converted
to the corresponding vicinal fluoro alcohols with high isolated yields (up
to 92%) and stereoselectivities (up to 99%). This new cascade process
addresses some issues in comparison with traditional methods such as
environmentally hazardous reaction conditions and low stereoselectivity
outcome.
in recent years.8 These multistep processes have been
he incorporation of fluorine atoms into organic molecules
Thas a profound effect on their physical, chemical, and conducted under mild reaction conditions without the
isolation of intermediate compounds. For example, Turner
and co-workers have developed several multienzyme cascade
processes to convert alcohols into valuable products, like
enantiopure amines, substituted D-tryptophans, and enantio-
merically pure 2,5-disubstituted pyrrolidine alkaloids.9 Zhao
and Hartwig have reported a cascade process to generate
valuable enantioenriched products combing the isomerization
catalyzed by photocatalysts and the reduction of carbon−
carbon double bonds by ene-reductases.10 In this study, we
describe a novel double-enzyme-catalyzed cascade reaction
providing chiral vicinal fluoro alcohols from β-ketonic esters in
one-pot (Scheme 1). This process consists of three steps: the
β-ketonic esters are initially hydrolyzed by lipase to generate β-
ketonic acids in situ. Subsequently, the β-keto acids undergo
decarboxylative fluorination with Selectfluor reagent through a
spontaneous process. After that, the intermediate fluoro
ketones can be finally reduced by the added (R)- or (S)-
selective ketoreductase respectively, to achieve chiral vicinal
fluoro alcohols with high optical purity and specified
configurations.
biological properties, which play important roles in agro-
chemical, pharmaceutical, and materials science.1 In particular,
vicinal fluoro alcohols are an important class of fluorine
compounds which can be used as the building blocks of natural
product analogues or drug targets, such as steroids or
carbohydrates.2 Thus, the development of general and efficient
methods to achieve fluoro alcohols has received considerable
attention and significant effort in the past decades.
Traditional chemical methods to produce fluoro alcohols
such as fluorination of alkenes or meso-epoxides usually exhibit
limited stereoselectivity, which limits the scope of application.3
To achieve chiral vicinal fluoro alcohols, the most effective
strategy is the reduction of α-fluoro ketones by keto reductases
(KRED).4 However, the requirement of prerequisite prepara-
tion of α-fluoro ketones relies heavily on organometallic
catalysts or hazardous strong oxidants, suffering from high
costs and environmental pollution.5 Deng and co-workers have
developed an alternative process for the synthesis of α-fluoro
ketones through the decarboxylative fluorination of β-ketonic
acids catalyzed by the phase-transfer catalyst in aqueous
media.6 However, as substrates, β-ketonic acids need to be
prepared just before its experimental application due to their
easy decomposition into ketones.7 Because of these limitations
of existing pathways, it is highly desirable to find an efficient,
general, and environment friendly strategy to achieve chiral
vicinal fluoro alcohols.
In the cascade process, the major challenge is the
compatibility of enzymes and chemical catalysts. In this
Received: May 30, 2020
Cascade reaction catalyzed by multiple enzymes or enzymes
in combination with chemical catalysts is an alternative strategy
to achieve chiral compounds, which has gained more attention
https://dx.doi.org/10.1021/acs.orglett.0c01825
© XXXX American Chemical Society
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A

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Letter
Scheme 1. Combination of Lipase and KRED in a Cascade
Reaction
Scheme 2. Substrate Scope of for the Lipase-Catalyzed
a,b
Synthesis of α-Fluoro Ketones
study, the Selectfluor reagent with strong oxidation tends to
denature the enzymes through probable disruption of the
tertiary protein structure.11 Therefore, initial study was
implemented to determine the feasibility of the one-pot
transformation in combination of enzymatic hydrolysis and
decarboxylative fluorination. We selected the decarboxylative
fluorination of ethyl 3-oxo-3-phenylpropanoate (1a) providing
2-fluoro-1phenylethan-1-one as a model reaction. After
screening various reaction parameters, we obtained the desired
product 2a in a good yield (92%) (Table 1, entry 1; see the
a
Table 1. Reaction Optimization for the Cascade Process
Combining Enzymatic Hydrolysis and Decarboxylative
Fluorination
Reaction conditions: 0.05 mmol of β-ketonic ester (1) was dissolved
in 2 mL of buffer (200 mM PBS, pH = 7.4), then 200 μL of Candida
antarctica lipase B (CAL-B, 5000 U/mL) and Selectfluor (1.2 equiv)
were added into the above mixture and shaken for 12 h at 50 °C.
a
b
Conversions were determined by chiral GC.
aromatic ring were also tolerated in the cascade process, which
could not occur in the previous study using β-ketonic acids as
starting materials.6 Heteroaromatic substituted β-ketonic esters
also can be accepted to provide the corresponding α-fluoro
ketones in moderate yield.
The concentration−reaction time curves of lipase-catalyzed
synthesis of fluorination products were investigated and shown
in Figure 1. During the whole process, the residual β-ketonic
b
entry
variation from standard conditions
none
100 mM PBS instead of 200 mM PBS
benzoyl acetic acid instead of 1a
no CAL-B
no Selectfluor
ultrapure water instead of 200 mM PBS
37 °C instead of 50 °C
2a (%)
1
2
3
4
5
6
7
92
55
24
7
0
2
48
a
Reaction conditions: 0.05 mmol of ethyl 3-oxo-3-phenylpropanoate
(1a) was dissolved in 2 mL of buffer (200 mM PBS, pH = 7.4), then
200 μL of CAL-B (5000 U/mL) and Selectfluor (1.2 equiv) were
added to the above mixture and shaken for 12 h at 50 °C.
b
Conversions were determined by chiral GC.
Supporting Information for details). No other additives were
needed in this transformation. Omission of CAL-B or
Selectfluor reagent resulted in a substantial decrease of
conversions (entries 4 and 5). The use of low concentration
of PBS buffer (100 mM) or ultrapure water furnished a
significant loss in reaction conversions or even failed to initiate
the reaction (entries 2 and 6). This observation supported that
the mechanism of the decarboxylative fluorination was a base-
catalyzed process.6 Lastly, experiments with different temper-
atures confirmed 50 °C was the best in this new cascade
reaction (entry 7).
With optimal reaction conditions in hand, we next aimed to
define the scope of the β-ketonic ester precursors. As
illustrated in Scheme 2, the cascade reaction proceeded
smoothly not only for the β-ketonic esters bearing an
electron-withdrawing group on the aryl ring but also for
those substrates having an electron-donating substituent. In
particular, the substrates with a F, Cl, or Br substituent on the
Figure 1. Reaction time curves of lipase-catalyzed synthesis of α-
fluoro ketones.
acid remained at a steadily low concentration level while the
yield of 2a was increasing continuously. The same result was
observed for the p-fluoride-substituted substrate (1h). There-
fore, during the reaction, the concentration of Selectfluor
reagent remained in large excess in comparison with β-ketonic
acid. The excess Selectfluor reagent might shift the equilibrium
to the right and promote the formation of fluorination
products, especially for those products with an electron-
withdrawing substituent on the aromatic ring which cannot be
obtained in the previous reported decarboxylative fluorination
of β-ketoacids.6
B
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Next step was to implement the feasibility of reduction by
KRED in this one-pot protocol. Carbonyl reductase from
Kluyveromyces thermotolerans (KtCR) was first chosen as a
model enzyme for the optimization of the cascade reaction,
which was identified with satisfactory (R)-selectivity for
acetophenone.12 The initial study was performed by adding
KtCR and other cofactors (including NADP+) in one pot after
decarboxylative fluorination. Glucose dehydrogenase (GDH)
was also added to recycle the cofactor. To our delight, the
cascade system in one-pot was proceeded successfully with
high total conversion (92%) and excellent (S)-stereoselectivity
(ee = 99%, the R/S assignment was changed in accordance
with the Cahn−Ingold−Prelog priority rules).
Scheme 3. Substrate Scope of the Cascade Process for the
Production of (S)-Vicinal Fluoro Alcohols
a
However, the high costs of the cofactors motivated us to
seek a more economical way to carry out this transformation.
The whole-cell reaction system was chosen to overcome this
limitation by regenerating the NADPH intracellular.13 Thus,
we performed this whole-cell transformation (Figure 2) by
a
Reaction conditions: 1 mmol of β-ketonic ester (1) and Selectfluor
(30 mM, 1.2 equiv) were dissolved in 40 mL of buffer (200 mM PBS,
pH = 7.4) containing 4 mL of Candida antarctica lipase B (CAL-B,
5000 U/mL). The reaction mixture was shaken vigorously at 50 °C
for 12 h. Then 400 mL of whole-cell culture of KtCR (resuspended in
50 mM sodium phosphate buffer, pH 6.5) with glucose (100 mmol)
was added into the above mixture and shaken at 30 °C overnight. All
yields are isolated yields of products. The ee values were determined
by chiral GC.
Figure 2. Whole-cell reaction system to produce chiral vicinal fluoro
alcohols.
adding 10 mL of the culture medium of KtCR (OD600 ≈ 6)
into the above-mentioned mixture of 1a. As expected, 2a was
able to permeate the cell membrane, and the whole-cell one-
pot reaction successfully provided the product (R)-3a in
excellent total conversion (92%) and selectivity (99%).
Based on the successful one-pot process of 1a, a range of β-
ketonic esters were subjected to the hydrolysis, fluorination
and reduction step by step to yield chiral vicinal fluoro
alcohols. To assess the scalability of these cascade process, we
performed 200 mg scale reactions for all tested substrates (1a−
1l), and isolated yields were obtained for comparison (Scheme
3, Table S1). It can be found that both electron-donating and
electron-withdrawing group substituted substrates afforded the
corresponding products in acceptable isolated yields (20−
92%) and high stereoselectivity (99%). Among them, 3i gave
the best result with 92% isolated yields and 99% ee, while 3e
with the lowest yield. Actually, for all tested substrates, the
conversions of the second step (enzymatic reduction) were
relatively high (Tables S1 and S2), while their activities in the
first step of the lipase-catalyzed hydrolysis and fluorination
were completely different. For example, the conversion of 1e in
the lipase-catalyzed hydrolysis and fluorination was only 23%,
resulting in the lowest isolated yield (20%) for 3e.
Interestingly, the bulky β-ketonic esters (1k) and thienyl-
substituted substrate (1l) were also tolerated with this method
to give the (S)-isomer of 3k and 3l with excellent
enantioselectivity (ee = 99%).
structures on the CAL-B/YtBE-catalyzed cascade process was
also similar to that of the CAL-B/KtCR system. Compound 1i
provided a better result than other substrates, and the isolated
yield of 3e was still the lowest because of the poor conversion
in the first step of lipase-catalyzed hydrolysis and fluorination.
Notably, YtbE showed the same selectivity preference for 3f as
that of KtCR, while they were opposite in the cases of other
products, implying the distinct binding or recognition
mechanism for 3f. For thienyl-substituted substrate (1l),
YtbE showed good activity, but the selectivity is very poor.
These results shown in both Scheme 3 and 4 documented the
synthetic utility of double enzyme-catalyzed one-pot process
for the preparation of enantiocomplementary vicinal fluoro
alcohols.
In summary, we have developed a one-pot, three-step
cascade process combining enzymatic hydrolysis, decarbox-
ylative fluorination, and KRED-catalyzed reduction to achieve
enantiocomplementary vicinal fluoro alcohols. A series of β-
ketonic esters can be successfully converted into the
corresponding chiral vicinal fluoro alcohols with either (R)-
or (S)-configuration in accordance with the selectivity of the
KRED used. This one-pot cascade process was performed in
the aqueous phase under moderate conditions without the
separation of intermediates. A whole-cell system was
implemented to regenerate NADPH in situ to make the
transformation proceed in an economical way. All these
advantages should enable chemoenzymatic transformations
that display great potential in green synthetic chemistry and
sustainable development. However, in the current scale-up
reactions of double enzyme-catalyzed one-pot process, the
The (S)-selective KRED could be replaced by an (R)-
selective KRED; thus, chiral vicinal fluoro alcohols with tailor-
made steteoselectivity were achieved. By using the NADPH-
dependent aldo-keto reductase from Bacillus sp. ECU0013
(YtbE)14 as the KRED, most of the tested aromatic carboxylic
esters could also be converted into corresponding (R)-alcohols
with acceptable isolated yields and high ee values through the
above one-pot, three-step process. The influence of substrate
C
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Letter
Weihua Xu − Department of Chemistry, Zhejiang University,
Hangzhou 310027, P.R. China
Anlin Wang − Institute of Life Sciences, Jiangsu University,
Zhenjiang 212013, P.R. China
Scheme 4. Substrate Scope of the Cascade Process for the
Production of (R)-Vicinal Fluoro Alcohols
a
Huilei Yu − State Key Laboratory of Bioreactor Engineering,
East China University of Science and Technology, Shanghai
200237, P.R. China
Xianfu Lin − Department of Chemistry, Zhejiang University,
Hangzhou 310027, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01825
Author Contributions
∥J.F. and Y.P. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The financial support from National Natural Science
Foundation of China (91956128), Zhejiang Provincial Natural
Science Foundation (LY19B020014), and the Fundamental
Research Funds for the Central Universities (2018QNA3010)
is gratefully acknowledged.
a
Reaction conditions: 1 mmol of β-ketonic ester (1) and Selectfluor
(30 mM, 1.2 equiv) were dissolved in 40 mL of buffer (200 mM PBS,
pH = 7.4) containing 4 mL of Candida antarctica lipase B (CAL-B,
5000 U/mL). The reaction mixture was shaken vigorously at 50 °C
for 12 h. Then 400 mL of whole-cell culture of YtbE (resuspended in
50 mM sodium phosphate buffer, pH 6.5) with glucose (100 mmol)
was added into the above mixture and shaken at 30 °C overnight. All
yields are isolated yields of products. The ee values were determined
by chiral GC.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01825.
Experimental procedures, new compounds character-
1
ization data, H and 13C NMR spectra of all products,
chiral chromatograms (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Jian Xu − Department of Chemistry, Zhejiang University,
Hangzhou 310027, P.R. China; Email: llc123@zju.edu.cn
Qi Wu − Department of Chemistry, Zhejiang University,
Hangzhou 310027, P.R. China; orcid.org/0000-0001-
9386-8068; Email: wuqi1000@163.com
Authors
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Jiajie Fan − Department of Chemistry, Zhejiang University,
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Yongzhen Peng − Department of Chemistry, Zhejiang
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