Easy Access to Enantiopure (S)- and (R)-Aryl Alkyl Alcohols by a Combination of Gold(III)-Catalyzed Alkyne Hydration and Enzymatic Reduction

Article abstract of DOI:10.1002/cctc.201701752

Chemoenzymatic one-pot processes based on the combination of metal catalysis and biocatalysis open up highly attractive perspectives regarding the production of enantiopure compounds. By combining a gold-catalyzed hydration reaction with an enzymatic reduction, we present a straightforward and atom-economical chemoenzymatic method for the synthesis of secondary alcohols with excellent optical purity. Efficient cofactor recycling exploits the solvent of the metal-catalyzed step as an auxiliary substrate for the enzymatic step.

Full text of DOI:10.1002/cctc.201701752

DOI: 10.1002/cctc.201701752
Communications
Easy Access to Enantiopure (S)- and (R)-Aryl Alkyl Alcohols
by a Combination of Gold(III)-Catalyzed Alkyne Hydration
and Enzymatic Reduction
Patricia Schaaf, Vladimir Gojic, Thomas Bayer, Florian Rudroff, Michael Schnꢀrch, and
Marko D. Mihovilovic*[a]
Chemoenzymatic one-pot processes based on the combination
of metal catalysis and biocatalysis open up highly attractive
perspectives regarding the production of enantiopure com-
pounds. By combining a gold-catalyzed hydration reaction
with an enzymatic reduction, we present a straightforward and
atom-economical chemoenzymatic method for the synthesis of
secondary alcohols with excellent optical purity. Efficient cofac-
tor recycling exploits the solvent of the metal-catalyzed step
as an auxiliary substrate for the enzymatic step.
There are only very few examples without any form of com-
partmentalization; for example, a recent concurrent rutheni-
um-catalyzed allylic alcohol isomerization and asymmetric bio-
reduction[26] and the combination of metathesis with the bio-
catalytic aromatizing activity of monoamine oxidases.[27] Fur-
thermore, an iridium-catalyzed oxidation was combined con-
currently to an asymmetric biocatalytic reduction,[28] and the
combination of biocatalysts with artificial metalloenzymes ena-
bled synthetic cascades.[29,30] Thus, the most challenging task is
to arbitrate the reaction environments of the individual steps
by identifying consensus conditions with minimal detrimental
effects. In addition to spatial separation, temporal separation
provides a simple alternative; the addition of the biocatalyst at
a later stage may avoid temperature issues and limits problems
associated with solvent and metal compatibility. Nevertheless,
the choice of the catalytic metal species is crucial for a success-
ful chemoenzymatic one-pot process. Gold as an inert metal
species is known to be well tolerated by microorganisms to a
certain amount.[31–33] Gold salts, on the other hand, are often
exploited as Lewis acids, typically coordinating to CÀC double
and triple bonds, functionalities rarely present in enzymes.[34–37]
In this contribution, we report on the combination of Au-
catalyzed ketone formation with subsequent enzymatic reduc-
tion to secondary alcohols (Scheme 1), in which the metal-cata-
lyzed step is performed in a solvent that serves as an auxiliary
substrate for cofactor recycling in the subsequent biotransfor-
mation.
In addition to general feasibility, the preparation of chiral mole-
cules is also assessed by environmental and sustainable as-
pects within modern synthetic chemistry.[1–3] In this regard, the
combination of several reaction steps within one pot is an at-
tractive strategy, as the number of workup and purification
steps can be substantially reduced.[4–9] During the past de-
cades, biocatalysis was established as a highly potent method
for the introduction and manipulation of stereochemistry, in
particular on the basis of improved access to versatile enzymes
of natural origin or by enzyme engineering.[10–15] Linking
enzyme-mediated reactions with metal-assisted catalysis is
generally understood as a highly prospective approach, as
both areas offer complementary functional group interconver-
sions. Whereas the incorporation of metal-assisted catalysis in
a protein framework has been proven to be highly success-
ful,[16–22] this specific combination has proven particularly chal-
lenging in cascade processes on the basis of limited compati-
bility or the reaction conditions.
A similar transformation was reported recently by Rodrꢁ-
guez-ꢂlvarez et al.[38] In this contribution, KAuCl4 was used as
the gold source, and pentynoic acid was used as the substrate.
After converting the alkyne into a keto group, the latter was
reduced by a ketoreductase (KRED), and the obtained alcohol
cyclized spontaneously to the corresponding lactone. Alkynes
can be considered as surrogates for the ketone functionality,
as they can be readily converted into the latter by simple addi-
tion of water.[39] This can be exploited several ways, for exam-
ple, by access to specific structural motifs such as 1,4-dike-
Critical obstacles are encountered by differences in concen-
tration of the reactants, reaction temperature, solvent, pH
value, and, in particular, the envisaged coexistence of a metal
catalyst and biocatalyst in one pot. Consequently, most of
these processes need a form of compartmentalization to sepa-
rate the metal catalyst from the biocatalyst, thereby avoiding
poisoning effects.[23–25]
[a] Dr. P. Schaaf, V. Gojic, Dr. T. Bayer, Dr. F. Rudroff, Prof. Dr. M. Schnꢀrch,
Prof. Dr. M. D. Mihovilovic
Institute of Applied Synthetic Chemistry
TU Wien
Getreidemarkt 9/163-OC, 1060 Vienna (Austria)
E-mail: marko.mihovilovic@tuwien.ac.at
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under:
Scheme 1. Chemoenzymatic reaction sequence in which the solvent of the
https://doi.org/10.1002/cctc.201701752.
metal-catalyzed step serves as the auxiliary substrate for the enzymatic step.
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tones, which can be more readily synthesized by alkyne hydra-
tion of 3-alkynoates than by any other method.[40]
Table 1. Ketone synthesis.[a]
Another application in this regard is taking advantage of the
different reactivities of alkynes and ketones, which allows reac-
tions of the latter to be performed in the presence of alkynes
and only later are the alkynes transformed into another ketone
functionality. In this regard, the alkyne may be considered as a
“masked” ketone. Interestingly, examples of this strategy in the
literature remain scarce.[41–43]
Entry
1
Substrate AuCl3 [mol%] Product
Yield[b] [%]
1a
1b
1c
1d
1e
5
5
2a
2b
2c
2d
2e
98
As mentioned previously, nucleophilic addition of water or
alcohols to alkynes delivers ketones or enols.[39] Historically,
such hydrations were conducted by oxymercuration or with
large amounts of mineral acids[39,44] and alcohol solvents (often
methanol), but both of these methods are incompatible with
modern concepts of green chemistry.[40] A newer, more envi-
ronmentally benign method takes advantage of gold salts as
catalysts, mainly in methanol,[45–47] but other alcohol solvents
have also been tested.[48]
2
3
4
5
98
99
71
86
5
10
10
A substantial number of KREDs are self-sustainable, as in ad-
dition to the synthetically interesting ketone they can accept
auxiliary substrates for regeneration of the redox cofactor.
Such a coupled substrate strategy[49] would allow the use of
iPrOH, as a prominent example of an economically attractive
co-substrate for a bioreduction step. Specifically, regarding the
combination with another catalytic system, it is highly desira-
ble to limit the number of enzymes involved, which contrasts
conventional cofactor recycling systems that employ several
biocatalysts. The large excess amount of the acidic reagent (in
most cases sulfuric acid) that is often required for the hydra-
tion of unactivated alkynes is clearly critical as regards poten-
tial combination with a biocatalyst.
6
1 f
1g
1h
1i
10
10
10
10
10
10
2 f
2g
2h
2i
72
76
70
79
49
57
7
8
In 2015, for the first time Das et al. demonstrated a ligand-
free and acid-free procedure for the synthesis of methyl ke-
tones through the hydration of terminal alkynes by employing
gold(I) chloride as a key catalyst.[48] The presented method
generated the respective Markovnikov ketones without any
acid promoters or additives. We slightly varied the published
protocol with regard to biocompatibility by replacing MeOH
with iPrOH (prospectively enabling subsequent cofactor recy-
cling) and additionally by switching to gold(III) chloride as a
slightly less-expensive catalyst. Thus, by performing the hydra-
tion of phenylacetylene in iPrOH by applying 5 mol% AuCl3 as
the catalyst at 658C, we were pleased to observe the forma-
tion of acetophenone in 98% yield, as determined by GC anal-
ysis, after 24 h within the first model reaction (Table 1, entry 1).
This result matches the outcome of Das et al., who obtained
the same yield in MeOH with the use of AuICl as the catalyst.
We used this result as a starting point for subsequent investi-
gation into a future sequential chemoenzymatic one-pot pro-
cess, for which the biocatalyst would be added after the for-
mation of the ketone. After selecting representative alkynes
1a–k with varying substitution patterns, the respective hydra-
tion reactions were conducted. The modified hydration proce-
dure gave moderate to excellent yields (49–99%, determined
by GC analysis) of corresponding acetophenones 2a–k
(Table 1). Notably, for all cases that could be directly compared
with the Das protocol (Table 1, entries 1, 2, 4, 6, and 8), the
9
10
11
1j
2j
1k
2k
[a] Reaction conditions: substrate (0.5 mmol), AuCl3, H2O (4 equiv.), iPrOH,
658C. [b] Measured by GC analysis after a reaction time of 24 h.
yields were the same within experimental error. Electron-with-
drawing substituents led to decreased yields, which was partic-
ularly evident for substrates in which the strongly electron-
withdrawing trifluoromethyl group was incorporated in the
alkyne scaffold (Table 1, entries 10 and 11).
On the basis of these promising results for the metal-cata-
lyzed step, we investigated the overall chemoenzymatic pro-
cess by using phenylacetylene (1a) as a model substrate for
alkyne hydration and the solvent-tolerant, NADH-dependent,
and (S)-selective ADH-A (alcohol dehydrogenase A) from Rho-
dococcus ruber for the subsequent enzymatic reduction.[50]
After conducting the Au-mediated hydration at 658C, the reac-
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tion mixture was cooled to room temperature. Next, we direct-
ly supplemented the mixture of the hydration step (Table 1,
entry 1) (30%, v/v) with 50 mg whole-cell lyophilisate of ADH-A
resuspended in Tris-HCl buffer (350 mm, pH 8, 70%, v/v) at
308C without any other manipulation. To our delight, within
this model reaction, the enzymatic step gave the product in
93% yield (determined by GC analysis), which resulted in an
overall yield of 91% (determined by GC analysis) to (S)-phenyl-
ethanol (3a) with 99%ee over two steps. This finding indicated
that the gold catalyst does not deactivate the (S)-selective
ADH-A at the concentration used.
Table 2. Combination of alkyne hydration and subsequent enzymatic re-
duction by using the (S)-selective and NADH-dependent ADH-A from
Rhodococcus ruber and the (R)-selective and NADPH-dependent KRED
from Lactobacillus kefir.[a]
Entry
Product [(S)/
(R)-alcohol]
Conversion[b] [%]
ee[c] [%] [(S)/
(S)-Alcohol (R)-Alcohol (R)-alcohol]
A high buffer concentration of 350 mm was required to neu-
tralize HCl generated during the hydration to avoid any detri-
mental effect on the whole-cell biocatalyst.
1
2
3
3a
3b
3c
91
76
99
93
73
15
>99
>99
>99
To demonstrate the general applicability of the cascade
transformation, we chose an enantiocomplementary enzyme
with a largely overlapping substrate profile: the (R)-selective
and NADPH-dependent KRED from Lactobacillus kefir.[51] Upon
repeating the one-pot reaction by using 50 mg whole-cell lyo-
philisate of the KRED from Lactobacillus kefir, we observed a
comparable yield of (R)-phenylethanol (3a) of 93% (deter-
mined by GC analysis) over two steps with >99%ee (Table 2,
entry 1). Thus, neither the relatively high iPrOH content of 30%
(v/v) nor the metal catalyst displayed any detrimental effect on
the enzymatic reduction.
4
3d
3e
3 f
3g
3h
3i
71
86
71
76
67
53
49
57
65
74
69
29
67
17
49
0
>99
>99
>99
>99
>99
>99
>99
>99[d]
5
We aimed, in particular, to develop a simple and straightfor-
ward method that could be used in a facile fashion by re-
searchers without a pronounced biocatalytic background;
hence, we used both alcohol dehydrogenases as “easy-to-pre-
pare” whole-cell lyophilisates.
6
7
On the basis of the established conditions, we performed
the enzymatic reduction of a substrate library (Table 2, en-
tries 2–11) to generate both enantiodivergent alcohols 3b–k.
The yields of the cascade procedure, as determined by GC
analysis, ranged from 49 to 99% for the (S)-selective ADH-A.
Employing the (R)-selective KRED, yields up to 93% were ach-
ieved (Table 2). Both alcohol dehydrogenases delivered the re-
spective secondary alcohols with excellent ee values. The KRED
from Lactobacillus kefir was less efficient for meta-substituted
aromatic ketone substrates, presumably as a result of the steric
hindrance of the substituent, which impeded access to the
active site of the enzyme (Table 2, entries 3, 7, 9, and 11).
To demonstrate the synthetic utilization of the developed
process, two preparative-scale experiments were conducted by
using the (S)-selective ADH-A to generate alcohols (S)-3d and
(S)-3g, which were isolated in yields of 71 (50 mg) and 64%
(50 mg) respectively, both with an optical purity of >99%ee.
In summary, we presented a straightforward sequential che-
moenzymatic one-pot process for the production of enantio-
pure (S)- and (R)-aryl alkyl alcohols. The complete reaction mix-
ture from the metal-catalyzed step could be used in the subse-
quent enzymatic reduction without any spatial separation of
the metal species and biocatalyst. Furthermore, we successfully
designed a process that would be feasible for researchers from
fields other than biocatalysis.
8
9
10
11
3j
3k
[a] Reaction conditions: (R)- or (S)-selective KRED whole-cell lyophilisate
(50 mg, 170 mg KRED whole-cell lyophilisate for preparative-scale experi-
ments), 70% (v/v) Tris-HCl (350 mm, pH 8), 30% (v/v) hydration reaction
mixture, 308C. [b] Measured by GC after a reaction time of 24 h. [c] Mea-
sured by chiral-phase GC (for 3a–d, 3 f–h, and 3j) or HPLC (for 3e, 3i,
and 3k). Absolute configurations were determined by measuring [(S)-3d,
(S)-3j] or comparing with the values reported in the literature (see the
Supporting Information). [d] (S)-Alcohol product only.
factor regeneration in the subsequent enzymatic reduction.
After resuspension of the KRED-containing whole-cell lyophili-
sate, the catalyst could directly be added to the hydration re-
This was realized by applying iPrOH as a solvent for the AuIII-
catalyzed hydration; it served as an auxiliary substrate for co-
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action mixture. Thereby, we produced both enantiomeric alco-
hols in high optical purity with yields up to 99% over two
steps (as determined by GC analysis) in an economically attrac-
tive fashion that provided good functional group tolerance.
This operationally simple procedure is atom economical owing
to the application of iPrOH in the gold-catalyzed step, which is
fully reused in the subsequent enzymatic reduction as an auxil-
iary substrate.
Chemoenzymatic one-pot reaction for the production of
enantiopure alcohols 3a–k
AuCl3 (0.025–0.05 mmol, 5–10 mol%) and iPrOH (1 mL) were
charged into a screw-capped vial equipped with a magnetic stir-
ring bar. The mixture was stirred for 5 min, and then the starting
material (0.5 mmol, 1 equiv.) and H2O (4 equiv.) were added. The
mixture was heated at 658C for 24 h. The reaction was monitored
by GC–MS and was cooled to room temperature upon complete
conversion.
Experimental Section
Small-scale experiments
Hydration of terminal alkynes
Then, the (R)- or (S)-selective alcohol dehydrogenase whole-cell
lyophilisate (50 mg) was resuspended in 350 mm Tris-HCl buffer
pH 8 (700 mL) in a separate vial and was shaken for 1 h at 308C
and 200 rpm. Then, the hydration mixture (300 mL) was combined
with the resuspended enzyme, which resulted in an overall iPrOH
content of 30%. After 4 h, the chemoenzymatic one-pot reaction
was complete, as monitored by GC–MS, and was extracted with
EtOAc containing methyl benzoate as an internal standard, and the
conversion was determined by GC or GC–MS.
AuCl3 (0.025–0.05 mmol) and iPrOH (1 mL) were charged into a
screw-capped vial equipped with a magnetic stirring bar. The mix-
ture was stirred for 5 min. Then, the alkyne (0.5 mmol, 1 equiv.)
and H2O (4 equiv.) were added. The resulting mixture was heated
at 658C for 24 h. Upon completion of the reaction, a sample of the
mixture was diluted with ethyl acetate containing methyl benzoate
as an internal standard, and quantitative analysis was performed
by GC.
Preparative-scale experiments
Expression of alcohol dehydrogenases and whole-cell lyo-
philisate preparation
In the case of a preparative scale experiment, the (R)- or (S)-selec-
tive alcohol dehydrogenase whole-cell lyophilisate (170 mg) was
resuspended in 350 mm Tris-HCl buffer pH 8 (2.333 mL) in a sepa-
rate vial and was shaken for 1 h at 308C and 200 rpm. Then, the
complete hydration mixture (1 mL) was combined with the resus-
pended enzyme. After 4 h, the chemoenzymatic one-pot reaction
was complete, as monitored by GC–MS, and the overall mixture
was extracted with CH2Cl2 (3ꢄ10 mL), washed with H2O (2ꢄ
10 mL), and dried (Na2SO4). The solvent was evaporated, and the
product was purified by applying standard manual glass columns
by using silica gel from Merck (40–63 mm) and CH2Cl2 (raw prod-
uct/SiO2 =1:40). Within the preparative-scale experiments, (S)-3d
was isolated in 71% yield (50 mg) and (S)-3g was insolated in 64%
yield (50 mg).
Preparation of lyophilized cells of E. coliBL21(DE3)/pET22b(+) adh-
A
(from Rhodococcus ruber): E. coliBL21(DE3)/pET22b(+) adh-A
(RHRU231 470141, corresponding to Q8KLT9) was stored at À808C
in lysogeny broth containing ampicillin (LB-amp) containing 25%
(n/n) glycerol. Prior to use, cells were plated on LB-amp plates
(100 mgmLÀ1 final ampicillin concentration). A single colony was
used to inoculate TB-amp (200 mL, 100 mgmLÀ1 final ampicillin
concentration) in a 1 L baffled shake flask. ZnCl2 was added from a
100 mm stock to a final concentration of 1 mm, and cells were
grown at 308C with shaking (120 rpm) for approximately 20 h. On
the next day, the optical density at l=590 nm (OD590) was checked
(OD590 ꢀ6.0) and ampicillin (50 mgmLÀ1 stock, 200 mL) was added.
Protein production was induced upon the addition of isopropyl-
beta-d-thiogalactopyranoside (IPTG) from a 100 mm stock to a final
concentration of 2 mm, and cells were cultivated at 208C with
shaking (120 rpm) for 24 h. Cells were harvested by centrifugation
(6000ꢄg, 15 min, 48C). The medium was discarded, and cells were
resuspended in sterile water, snap frozen in liquid nitrogen, and
lyophilized.
Acknowledgements
Financial support for this research program by TU Wien under
the internal grant ABC (Applied Biosynthetic Cell factories) is
gratefully acknowledged. The authors thank Prof. Dr. Werner
Hummel, Bielefeld University, for the generous donation of the ex-
pression system for the KRED from Lactobacillus kefir.
Preparation of lyophilized cells of E. coliBL21(DE3)/pET21b(+) LK-
ADH (from Lactobacillus kefir): E. coliBL21(DE3)/pET21b(+) LK-ADH
(GenBank: AY267012.1) was stored at À808C in LB-amp containing
25% (n/n) glycerol. Prior to use, cells were plated on LB-amp plates
(100 mgmLÀ1 final ampicillin concentration). A single colony was
used to prepare 4 mL of an overnight culture in LB medium con-
taining 100 mgmLÀ1 ampicillin (added from a 50 mgmLÀ1 stock).
The main culture was prepared by inoculation of TB-amp (200 mL,
100 mgmLÀ1 final ampicillin concentration) in a 1 L baffled shake
flask with 2 mL of the overnight culture. Cells were grown at 378C
with shaking (120 rpm) to OD590 =0.5. Enzyme expression was in-
duced by the addition of IPTG (1 mm final concentration) from a
100 mm IPTG stock. Cells were cultivated at 308C with shaking
(120 rpm) and were harvested by centrifugation (6000ꢄg, 15 min,
48C) after 24 h. The medium was discarded, and cells were resus-
pended in sterile water, snap frozen in liquid nitrogen, and lyophi-
lized.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alcohols
·
alkynes
·
biocatalysis
·
enantioselectivity · enzymes
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Manuscript received: November 3, 2017
Revised manuscript received: November 30, 2017
Version of record online: && &&, 0000
ChemCatChem 2018, 10, 1 – 6
www.chemcatchem.org
5
ꢃ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

COMMUNICATIONS
P. Schaaf, V. Gojic, T. Bayer, F. Rudroff,
M. Schnꢀrch, M. D. Mihovilovic*
&& – &&
Easy Access to Enantiopure (S)- and
(R)-Aryl Alkyl Alcohols by a
Combination of Gold(III)-Catalyzed
Alkyne Hydration and Enzymatic
Reduction
What can gold not do? We present a
sequential chemoenzymatic one-pot
process for the production of chiral al-
cohols. The reaction mixture from the
AuIII-catalyzed hydration step is used in
the subsequent enzymatic reduction
without separation of the metal species
from the biocatalyst. iPrOH is used as
the solvent and serves to regenerate
the cofactor in the enzymatic reduction.
Alcohols are obtained in high optical
purity with yields up to 99% over two
steps.
&
ChemCatChem 2018, 10, 1 – 6
www.chemcatchem.org
6
ꢃ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!