Deracemization of Secondary Alcohols by using a Single Alcohol Dehydrogenase

Article abstract of DOI:10.1002/cctc.201600160

We developed a single-enzyme-mediated two-step approach for deracemization of secondary alcohols. A single mutant of Thermoanaerobacter ethanolicus secondary alcohol dehydrogenase enables the nonstereoselective oxidation of racemic alcohols to ketones, followed by a stereoselective reduction process. Varying the amounts of acetone and 2-propanol cosubstrates controls the stereoselectivities of the consecutive oxidation and reduction reactions, respectively. We used one enzyme to accomplish the deracemization of secondary alcohols with up to >99 % ee and >99.5 % recovery in one pot and without the need to isolate the prochiral ketone intermediate.

Full text of DOI:10.1002/cctc.201600160

DOI: 10.1002/cctc.201600160
Communications
Deracemization of Secondary Alcohols by using a Single
Alcohol Dehydrogenase
Ibrahim Karume,[a] Masateru Takahashi,[b] Samir M. Hamdan,[b] and Musa M. Musa*[a]
We developed a single-enzyme-mediated two-step approach
for deracemization of secondary alcohols. A single mutant of
Thermoanaerobacter ethanolicus secondary alcohol dehydro-
genase enables the nonstereoselective oxidation of racemic al-
cohols to ketones, followed by a stereoselective reduction pro-
cess. Varying the amounts of acetone and 2-propanol cosub-
strates controls the stereoselectivities of the consecutive oxida-
tion and reduction reactions, respectively. We used one
enzyme to accomplish the deracemization of secondary alco-
hols with up to >99% ee and >99.5% recovery in one pot
and without the need to isolate the prochiral ketone inter-
mediate.
Deracemization of alcohol racemates provides an attractive ap-
Scheme 1. Deracemization of alcohols by a) stereoinversion and b) nonster-
eoselective oxidation followed by a stereoselective reduction catalyzed by
the same enzyme.
proach that could surpass the 50% yield limit of traditionally
used kinetic resolution methods. Deracemization strategies
that have been developed include dynamic kinetic resolution,
cyclic deracemization, enantioconvergence, and stereoinver-
sion.[1,2] Methods for chemical deracemization have been re-
ported using one[3] or two[4] catalysts. Although several ap-
proaches have been reported for the use of enzymes to medi-
ate the deracemization through stereoinversion of alcohols,
these require the use of multiple enzymes[5,6] in a process in-
volving tandem biocatalysis (Scheme 1a), and in some cases
whole cells are used.[7] These approaches suffer from problems
associated with incompatibility of the enzymes and difficulty in
elucidating their reaction mechanism. Herein, we report a strat-
egy and its implementation for the use of a single enzyme to
deracemize secondary alcohols with up to 99% ee and
>99.5% recovery. Specifically, the process operates using Ther-
moanaerobacter ethanolicus secondary alcohol dehydrogenase
(TeSADH, EC 1.1.1.2) catalyzed nonstereoselective oxidation of
racemic alcohols followed by an enantioselective reduction to
generate enantiomerically enriched alcohols using the same
enzyme (Scheme 1b).
TeSADH (Scheme 1b). TeSADH is a nicotinamide adenine dinu-
cleotide phosphate (NADP+) dependent ADH that exhibits
thermal stability[8] and tolerance to organic media.[9] TeSADH
has been further engineered by creating several mutants that
expanded its substrate specificity and manipulated its stereo-
selectivity.[10] In particular, mutations of the W110 residue that
is present in the large pocket of the active site of TeSADH sig-
nificantly affect its stereoselectivity.[11] W110A TeSADH is able
not only to reduce phenyl-ring-containing ketones with high
enantioselectivity,[12] but can also racemize the corresponding
enantiopure alcohols by inducing “selectivity mistakes”.[13] The
use of a site-saturation approach for the mutation of W110[11]
yielded a noticeable enhancement in racemization efficiency if
W110G TeSADH was compared to other W110 mutants.[14] The
reactions catalyzed by TeSADH and its W110 mutants obey
Prelog’s rule,[15] as the NADPH delivers its pro-R hydride from
the Re face of a prochiral ketone substrate.
We show how a one-pot deracemization method can be
performed in two steps by using a purified single mutant of
The first step of the reported deracemization approach uti-
lizes a mutant of TeSADH for the oxidation of racemic alcohols
to the corresponding ketones under nonstereoselective condi-
tions (i.e., taking advantage of “selectivity mistakes”). This step
is followed by a stereoselective reduction of the ketone, which
is catalyzed by the same TeSADH mutant, to the corresponding
S-configured alcohol in the same pot and without isolation of
the ketone intermediate (Scheme 1b).
[a] I. Karume, Prof. M. M. Musa
Chemistry Department
King Fahd University of Petroleum and Minerals
Dhahran, 31261 (Saudi Arabia)
E-mail: musam@kfupm.edu.sa
[b] Dr. M. Takahashi, Prof. S. M. Hamdan
Division of Biological and Environmental Sciences and Engineering
King Abdullah University of Science and Technology
Thuwal, 23955-6900 (Saudi Arabia)
We started by comparing the performance of three different
mutants of TeSADH (W110A, W110G, and I86A/W110A) in the
enantiospecific oxidation of (rac)-4-phenyl-2-butanol [(rac)-1a],
(rac)-4-(4’-methoxyphenyl)-2-butanol [(rac)-1b], (rac)-4-(4’-hy-
droxyphenyl)-2-butanol [(rac)-1c], (rac)-1-phenyl-2-propanol
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under http://dx.doi.org/10.1002/
cctc.201600160.
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Communications
[(rac)-1d], which are known to be accommodated by W110A
TeSADH[12]
and (rac)-1-(3’-trifluoromethylphenyl)-2-propanol
The W110G TeSADH-catalyzed oxidation of (rac)-1d showed
poor stereoselectivity, which was previously observed in the re-
duction of phenylacetone (2d) using this mutant.[11,12] The abil-
ity of W110G TeSADH to catalyze the nonstereoselective oxida-
tion of (rac)-1a–e (entries 2, 6, 9, 11, and 13) encouraged us to
choose the W110G mutant for our one-pot deracemization ap-
proach.
,
[(rac)-1e]. The reactions were performed in tris(hydroxymeth-
yl)aminomethane–HCl (Tris–HCl) buffer solutions containing
3 vol% acetone (Table 1), which is used as a cosubstrate and
cosolvent. The W110A TeSADH mutant showed lower activity
with higher stereoselectivity than W110G TeSADH in the oxida-
To determine the optimum conditions for the
W110G TeSADH-catalyzed oxidation reaction (i.e.,
Table 1. Activity and stereoselectivity of W110 A, W110G, and I86 A/W110 A TeSADH-
nonstereoselective conditions), we studied the ste-
reospecific oxidation of (rac)-1a at varying concentra-
tions of acetone (1–10 vol%). The stereoselectivity,
depicted by E value, of this reaction was found to in-
crease with increasing concentrations of acetone
(Figure 1); however, there was a drastic drop in enzy-
matic activity at concentrations above 3 vol%. This
result can be attributed to the inhibitory effects of
acetone on TeSADH at higher concentrations, as pre-
cipitation of enzyme was noticed. High conversion
and low stereospecificity were observed for reactions
containing 3 vol% of acetone and therefore this co-
substrate concentration was considered optimal for
the deracemization approach.
catalyzed enantiospecific oxidation of racemic phenyl-ring-containing alcohols.[a]
Entry Mutant
Substrate
R
Ketone ee
[%]
[%][c]
E (S/R)[d]
1
2
3
4
W110G
W110G
W110A
W110A
(rac)-1a
(rac)-1a
(rac)-1a
(rac)-1a
C6H5CH2CH2
C6H5CH2CH2
C6H5CH2CH2
C6H5CH2CH2
C6H5CH2CH2
72
46(R)
2.1
–
>99[b]
41
–
73(R) >100
>99(R)
26(R) >100
60[b]
11
24
5
I86A/W110A (rac)-1a
6
7
8
9
10
10
11
12
13
14
W110G
W110A
I86A/W110A
W110G
W110A
W110A
W110G
W110A
W110G
W110A
(rac)-1b
(rac)-1b
(rac)-1b
(rac)-1c
(rac)-1c
(rac)-1c
(rac)-1d
(rac)-1d
(rac)-1e
(rac)-1e
p-MeO-C6H4(CH2)2 >99
–
–
5.6
To determine the most stereoselective reduction
conditions, we performed the reduction of 4-phenyl-
2-butanone (2a) at various concentrations of 2-prop-
anol (1–30 vol%) using W110A and W110G mutants
of TeSADH (Figure 2). The results revealed that less
than 10 vol% of 2-propanol resulted in moderate
conversions of 2a to the corresponding (S)-1a and
low enantioselectivities, whereas concentrations
above 20 vol% resulted in high conversions and high
ee of (S)-1a. It was also apparent that the W110A
TeSADH-catalyzed reduction of 2a was more stereo-
selective than that catalyzed by the W110G mutant,
especially at concentrations of 2-propanol less than
20 vol%. These results are consistent with a previous
report that showed that the E values for the oxida-
tion reaction of 1d with W110A TeSADH and W110G
p-MeO-C6H4(CH2)2
p-MeO-C6H4(CH2)2
p-HO-C6H4(CH2)2
p-HO-C6H4(CH2)2
p-HO-C6H4(CH2)2
C6H5CH2
58
26
67(R)
59(R) >100
>99[b]
60[b]
60[b]
80[b]
25
–
99(R)
99(R)
42(R)
27(R)
1(R)
–
24
24
1.7
12
1.0
1.6
C6H5CH2
m-CF3-C6H4CH2
m-CF3-C6H4CH2
91[b]
73[b]
32(R)
[a] Unless stated, reactions were performed by using racemic alcohol [(rac)-1a–
e (0.03 mmol)], TeSADH mutant (0.1 mg), NADP+ (1.0 mg), and acetone (3 vol%).
[b] TeSADH mutant (0.2 mg). [c] The % ee of the corresponding acetate ester deriva-
tive of the unreacted alcohol was determined by GC using a chiral stationary phase.
[d] E: enantiomeric ratio, and can be calculated according to Equation (1) of support-
ing information.
tion of (rac)-1a (Table 1, entries 1–4) and (rac)-1b (entries 6
and 7). Similar results were obtained for the enantiospecific ox-
idation of (rac)-1c using the W110G and W110A mutants. The
enantiospecific oxidation of (rac)-1a and (rac)-1b using I86A/
W110A TeSADH, which was designed to enlarge the two pock-
ets of the active site, gave low conversions with high stereose-
lectivities (E value>100, E=enantiomeric ratio, entries 5 and
8). The poor stereoselectivity of W110G TeSADH (E valueꢀ2.1)
compared with >100 for W110A TeSADH and I86A/W110A
TeSADH in the enantiospecific oxidation of (rac)-1a greatly im-
proved the oxidation of the undesired R enantiomer (i.e., there
were more selectivity mistakes). As a less stereoselective
mutant, W110G TeSADH is superior to both W110A TeSADH
and I86A/W110A TeSADH for our purposes. I86A/W110A
TeSADH manifested the lowest activity in the oxidation of
(rac)-1b, with an unexpectedly high E value (>100) as com-
Figure 1. The effect of acetone concentration on the stereoselectivity and
activity of the W110G TeSADH-catalyzed oxidation of (rac)-1a. E values were
calculated according to Equation (1) in the Supporting Information.
pared to those of W110A TeSADH (E value=5.6) and W110G
TeSADH, which had negligible enantioselectivity (entries 6–8).
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Table 2. Deracemization of phenyl-ring-containing racemic alcohols cata-
lyzed by X TeSADH (X=W110A or W110G).[a]
Entry
Substrate
R
Mutant
Ketone
[%]
ee
[%][b]
1
2
3
4
5
6
7
8
(rac)-1a
(rac)-1b
(rac)-1b
(rac)-1c
(rac)-1c
(rac)-1d
(rac)-1d
(rac)-1e
C6H5CH2CH2
W110G
W110G
W110A
W110G
W110A
W110G
W110A
W110G
<0.5
<0.5
<0.5
<0.5
<0.5
2
94
72
87
>99
20
47
p-MeO-C6H4CH2CH2
p-MeO-C6H4CH2CH2
p-HO-C6H4CH2CH2
p-HO-C6H4CH2CH2
C6H5CH2
C6H5CH2
m-CF3-C6H4CH2
<0.5
<0.5
21(R)
76
Figure 2. The effect of 2-propanol concentration on the stereoselectivity and
activity of the W110A and W110G TeSADH-catalyzed reduction reaction of
[a] Unless stated, oxidation reactions were performed by using racemic al-
cohol [(rac)-1a–e (0.03 mmol)], W110X TeSADH (0.2 mg), NADP+
(1.0 mg), and acetone (3 vol%); reduction reactions were performed by
using 2-propanol (30 vol%). [b] The percentage of ee of the acetate ester
derivative of the product was determined by using GC with a chiral sta-
tionary phase.
2a.
TeSADH were 17.4 and 9.0, respectively.[11] The percentage of
conversion in the asymmetric reduction of 2a using W110G
TeSADH was higher than that using W110A TeSADH, which
could be attributed to the larger substrate-binding pocket of
the W110G mutant. The use of 30 vol% 2-propanol appeared
to be optimal for the enantioselective reduction using W110A
or W110G mutants of TeSADH. A drastic drop in the percent-
age of conversion was observed at concentrations above
30 vol% of 2-propanol. The significant effect of 2-propanol
concentration on the enantioselectivity of the W110G TeSADH-
catalyzed reduction of 2a compared with the W110A TeSADH-
catalyzed reduction indicated that this mutant could function
under both nonstereoselective and stereoselective modes by
varying the cosubstrate concentration.
W110G TeSADH, followed by the highly stereoselective reduc-
tion of the intermediate ketone (2c) using the same mutant.
However, deracemization of (rac)-1c was not effective using
W110A TeSADH, and (S)-1c was obtained in 20% ee. The low
efficacy of W110A TeSADH for the deracemization of (rac)-1c
was attributed to the inefficient oxidation of the alcohol sub-
strate by this mutant, which leaves the slow-reacting R enan-
tiomer behind in the oxidation reaction. Note that the percent-
age of ketone intermediate was less than 0.5% after the dera-
cemization reactions of (rac)-1a, (rac)-1b, and (rac)-1c. Moder-
ate deracemization was observed upon treatment of (rac)-1d
with W110G TeSADH, from which an ee of 47% for the S alco-
hol was measured (entry 6). This result was ascribed to the
ability of this substrate (owing to its small size) to fit in the
active site of W110A and W110G mutants of TeSADH in oppo-
site modes, which enhances selectivity mistakes and thus re-
sults in low stereoselectivity of the asymmetric reduction of
2d.[11] The R enantiomer was predominant, in contrast to that
which was expected from the W110A TeSADH-catalyzed dera-
cemization of (rac)-1d (entry 7), attributable to the low stereo-
selectivity in the reduction step for this substrate and the slow
oxidation of (rac)-1d to 2d, as previously reported.[12] Incom-
plete oxidation of (rac)-1d left much of the R enantiomer un-
reacted, and thus a poorly stereoselective reduction of the in-
termediate ketone predominantly generated (R)-1d in 21% ee
from (rac)-1d. A trifluoromethyl substituent at the meta posi-
tion significantly enhanced the oxidation of rac-(1e) to 2e,
which was reduced with relatively high stereoselectivity to
give (S)-1e with 76% ee (entry 8).
The ability to influence the stereoselectivity of W110G
TeSADH-catalyzed redox reactions by changing the concentra-
tion of the cosubstrate prompted us to conduct a single-
enzyme mediated deracemization reaction. We proceeded with
the deracemization of racemic alcohols by allowing the oxida-
tion reaction to occur in the presence of acetone (3 vol%) until
no alcohol was detected by gas chromatography. We then
added 2-propanol (30 vol%) to switch the reaction in favor of
the reduction pathway under highly stereoselective conditions
to obtain the S-configured alcohols (Scheme 1b).
W110G TeSADH-catalyzed deracemization of (rac)-1a result-
ed in (S)-1a with 94% ee (Table 2, entry 1), whereas (rac)-1b
was deracemized to 72% ee of (S)-1b under the same condi-
tions (entry 2). W110A TeSADH-catalyzed deracemization of
(rac)-1b resulted in the formation of (S)-1b with 87% ee. The
relatively high ee achieved using W110A TeSADH for the dera-
cemization of (rac)-1b was attributed to the ability of W110A
and W110G mutants to oxidize this substrate completely;
thus, the determining step in the deracemization of (rac)-1b is
the reduction, which is more enantioselective using the
W110A mutant. W110G TeSADH-catalyzed deracemization of
(rac)-1c gave (S)-1c in >99% ee (entry 4). This result was at-
tributed to the non-stereoselective oxidation of (rac)-1c that
enabled the conversion of both enantiomers to 2c using
Our single enzymatic deracemization approach gave compa-
rable results to other deracemization approaches that utilized
multiple enzymes.[5a] It also resulted in better percent recovery
than nonenzymatic deracemization.[4]
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by GC. The percentage of conversion and ee percentage of the
acetate ester derivatives were determined by chiral GC.
To enable this method to be used for organic synthesis on
a larger scale, we sought to perform W110G TeSADH-catalyzed
deracemization of (rac)-1c (known as rhododendrol), on
a larger scale than the reactions reported in Table 2. (S)-Rhodo-
dendrol is a naturally occurring alcohol that has been isolated
from Rhododendron maximum.[16] Indeed, our approach was
applicable using 0.2 mmol of (rac)-1c at a final concentration
of 20 mm, with the substrate deracemized to afford (S)-1c at
>99% ee and >99.5% recovery. This reaction was conducted
in Tris–HCl buffer solution containing acetone (2 vol%) as a co-
substrate for the oxidation reaction and 2- propanol (20 vol%)
as a cosubstrate for the reduction reaction. Under the same
conditions and using acetone (3 vol%), enzyme precipitation
was noticed and the oxidation of (rac)-1c gave low conversion.
To the best of our knowledge, this is the first report of
a single enzymatic one-pot deracemization reaction of secon-
dary alcohols. Designing more TeSADH mutants to tune the
stereoselectivity of its catalyzed reactions is crucial for the opti-
mization of this approach. The high thermal stability of this
enzyme together with its tolerance to organic solvents will
enable its use through the developed deracemization ap-
proach to produce valuable optically active alcohols with appli-
cations in pharmaceutical and agrochemical fields among
others.
General procedure for the deracemization of racemic
alcohols
The racemic alcohol [(rac)-1a–e (0.03 mmol)] was added to a mix-
ture of W110G TeSADH (0.2 mg) and NADP+ (1 mg) in Tris–HCl
buffer solution (970 mL, 50 mm, pH 8.0) containing acetone (30 mL)
in a 1.5 mL Eppendorf tube. The mixture was shaken at 180 rpm at
508C for 24 h. The progress of the reaction was monitored by GC;
if the oxidation was not complete, if applicable, fresh enzyme
(0.1 mg) and acetone (30 mL) were added. The reduction was ef-
fected by adding fresh enzyme (0.2 mg) and 2-propanol (300 mL)
to the same reaction vessel and the experiment was continued for
24 h.
Acknowledgements
The authors acknowledge the support provided by King Abdula-
ziz City for Science and Technology (KACST) through the Science
and Technology Unit at King Fahd University of Petroleum and
Minerals (KFUPM), for funding this work through project No. 11-
BIO1666–04, as part of the National Science, Technology and In-
novation Plan. The authors thank Prof. Claire Vieille, from the De-
partment of Microbiology and Molecular Genetics at Michigan
State University, for providing the plasmids of TeSADH and
W110A TeSADH. The authors also thank Prof. Omar M. Yaghi for
helpful suggestions.
In conclusion, the ability to control the stereoselectivity of
TeSADH-catalyzed reactions by varying the reaction media ena-
bled the development of a single enzymatic approach for the
deracemization of secondary alcohols. This approach relies on
selectivity mistakes in the oxidation pathway to allow for de-
pletion of both enantiomers to the corresponding ketone,
which is then reduced under stereoselective conditions to the
corresponding S-configured alcohol in the same pot and with-
out the need to isolate the ketone intermediate. The simple
control of the oxidation and reduction pathways by varying
the concentrations of acetone and 2-propanol cosubstrates, re-
spectively, was critical to the success of this method. The use
of a single enzyme is a significant improvement over previous
deracemization approaches that utilize at least two compatible
enzymes. Our concept should be readily extendable to other
ADH-catalyzed transformation reactions that involve selectivity
mistakes. Extensive mutation of TeSADH is currently conducted
in our laboratory to further improve this deracemization ap-
proach.
Keywords: alcohols · enantioselectivity · enzyme catalysis ·
oxidation · reduction
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General procedure for the oxidation
The racemic alcohol [(rac)-1a–e (0.03 mmol)] was added to a mix-
ture containing enzyme (0.1–0.2 mg, see Table 1), NADP+ (1.0 mg),
and Tris–HCl buffer solution (970 mL, 50 mm, pH 8.0) in a 1.5 mL Ep-
pendorf tube. The mixture was shaken at 180 rpm in a thermostat-
controlled shaker at 508C for 24 h. The reaction mixture was ex-
tracted with diethyl ether (2”500 mL). The combined organic layers
were dried with Na2SO4 and concentrated. For ee determination,
the alcohols were derivatized by treatment with acetic anhydride
(one drop) and pyridine (two drops) for 6 h prior to their analysis
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Received: February 9, 2016
Published online on March 1, 2016
ChemCatChem 2016, 8, 1459 – 1463
www.chemcatchem.org
1463
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim