Alcohol Dehydrogenases and N-Heterocyclic Carbene Gold(I) Catalysts: Design of a Chemoenzymatic Cascade towards Optically Active β,β-Disubstituted Allylic Alcohols

Article abstract of DOI:10.1002/anie.202015215

The combination of gold(I) and enzyme catalysis is used in a two-step approach, including Meyer–Schuster rearrangement of a series of readily available propargylic alcohols followed by stereoselective bioreduction of the corresponding allylic ketone intermediates, to provide optically pure β,β-disubstituted allylic alcohols. This cascade involves a gold N-heterocyclic carbene and an enzyme, demonstrating the compatibility of both catalyst types in aqueous medium under mild reaction conditions. The combination of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene][bis(trifluoromethanesulfonyl)-imide]gold(I) (IPrAuNTf₂) and a selective alcohol dehydrogenase (ADH-A from Rhodococcus ruber, KRED-P1-A12 or KRED-P3-G09) led to the synthesis of a series of optically active (E)-4-arylpent-3-en-2-ols in good yields (65–86 %). The approach was also extended to various 2-hetarylpent-3-yn-2-ol, hexynol, and butynol derivatives. The use of alcohol dehydrogenases of opposite selectivity led to the production of both allyl alcohol enantiomers (93->99 % ee) for a broad panel of substrates.

Full text of DOI:10.1002/anie.202015215

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How to cite:
International Edition: doi.org/10.1002/anie.202015215
German Edition: doi.org/10.1002/ange.202015215
Synthetic Methods
Hot Paper
Alcohol Dehydrogenases and N-Heterocyclic Carbene Gold(I)
Catalysts: Design of a Chemoenzymatic Cascade towards Optically
Active b,b-Disubstituted Allylic Alcohols
Sergio Gonzꢀlez-Granda, Ivꢀn Lavandera,* and Vicente Gotor-Fernꢀndez*
Abstract: The combination of gold(I) and enzyme catalysis is
used in a two-step approach, including Meyer–Schuster
rearrangement of a series of readily available propargylic
alcohols followed by stereoselective bioreduction of the
corresponding allylic ketone intermediates, to provide optically
pure b,b-disubstituted allylic alcohols. This cascade involves
a gold N-heterocyclic carbene and an enzyme, demonstrating
the compatibility of both catalyst types in aqueous medium
under mild reaction conditions. The combination of [1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-
Hence, the search for active metal complexes in aqueous
medium is a consolidated synthetic possibility, since water
soluble complexes made from gold, indium, iridium, nickel,
palladium, ruthenium, rhodium, osmium or zinc among many
others have been successfully applied in a plethora of organic
reactions.[22–26] Considering that gold catalysis has emerged in
the last decades as a powerful tool for chemical synthesis
through the activation of unsaturated systems and formation
of gold carbenes and vinylidenes,[27–36] herein it was envisaged
the possible combination of gold complexes and enzymes.
With that purpose and due to the large p-acidic character of
Au complexes, the selection of alkynes as benchmark
substrates flourish as a wise choice based on the diverse
chemical possibilities of this pair Au-alkyne.[37–41] Interest-
ingly, a broad number of organic transformations can be
successfully accomplished such as cyclization, hydration,
redox isomerization or rearrangements such as the Rupe or
Meyer–Schuster ones (Scheme 1),[42–46] gold N-heterocyclic
carbenes (NHCs) playing a relevant role in the catalysis of
these type of chemical processes.[47–49]
[bis(trifluoromethanesulfonyl)-imide]gold(I)
(IPrAuNTf2)
and a selective alcohol dehydrogenase (ADH-A from Rhodo-
coccus ruber, KRED-P1-A12 or KRED-P3-G09) led to the
synthesis of a series of optically active (E)-4-arylpent-3-en-2-
ols in good yields (65–86%). The approach was also extended
to various 2-hetarylpent-3-yn-2-ol, hexynol, and butynol
derivatives. The use of alcohol dehydrogenases of opposite
selectivity led to the production of both allyl alcohol enantio-
mers (93- > 99% ee) for a broad panel of substrates.
Introduction
The Meyer–Schuster rearrangement consists in the trans-
formation of propargylic (acetylated) alcohols into the
corresponding a,b-unsaturated carbonyl compounds, requir-
ing metal catalysis (Cu, Sc, Hg, Ag, Au, In…), and tradition-
ally performed under harsh reaction conditions (organic
solvent, acidic catalysis, high temperature.).[42,46,50] This is
a highly atom economy process occurring via formal 1,3-
hydroxy shift and tautomerization, that has attracted great
attention in the last decades questing for more sustainable
solutions. Therefore, a key point of this study is the replace-
ment of conventional organic solvents by aqueous media,
making the process compatible with a second enzymatic
reaction, foreseeing the use of NHC gold(I) complexes as
One-pot synthesis provides nowadays multiple advantag-
es over traditional stepwise approaches, avoiding the isolation
and purification of unstable intermediates, simplifying the
reaction set-up, reducing time and costs associated with the
chemical process, and generally leading to higher isolated
yields.[1–4] Focusing on the field of biocatalysis, apart from
multi-enzymatic transformations,[5–10] one-pot chemoenzy-
matic syntheses represent elegant alternatives to traditional
conventional organic multi-step strategies, combining bio-
transformations with other (un)catalyzed processes.[11–14]
Interestingly, the compatibility of organo-, photo-, or metal
catalysts with enzymes has been intensively investigated in
the last decade,[15–19] and many efforts have been put in the
setup of environmentally friendly media where the different
(bio)catalysts can be compatible, ranging from aqueous
systems to neoteric solvents.[20,21]
[*] S. Gonzꢀlez-Granda, Prof. I. Lavandera, Prof. V. Gotor-Fernꢀndez
Organic and Inorganic Chemistry Department
University of Oviedo
Avenida Juliꢀn Claverꢁa 8, 33006 Oviedo (Spain)
E-mail: lavanderaivan@uniovi.es
vicgotfer@uniovi.es
Scheme 1. Activation of alkynes with gold for the development of
diverse chemical transformations including Meyer–Schuster rearrange-
ments. General structure of N-heterocyclic carbenes appears in the
box.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202015215.
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a solution for the performance of this selective transformation Results and Discussion
under milder reaction conditions.
Particularly, the gold-enzyme pair has been successfully
applied in a concurrent cascade fashion combining gold(I) or
gold(III) species with hydrolases[51,52] and monoamine oxi-
dases.[53] Among them, the only stereoselective application
was demonstrated by Asikainen and Krause, who reported
the synthesis of optically active 2,5-dihydrofurans through
a tandem hydrolytic kinetic resolution/cycloisomerization
employing Pseudomonas cepacia lipase and HAuCl4.[51] On
the other hand, approaches involving gold catalysis and
alcohol dehydrogenases (ADHs) have also been described,
but through sequential transformations due to the incompat-
ibility of individual catalytic systems and reaction condi-
tions.[54–56] In this context, the one-pot two-step synthesis of
chiral sec-alcohol derivatives in high conversions and enan-
tiomeric excess was described via gold-catalyzed hydration of
terminal aryl- or alkyl acetylenes using either gold(III)
chloride at 658C in a water/2-propanol (2-PrOH) mixture,[55]
or HandaPhos-gold(I) chloride, a silver salt and a surfactant
in water that formed micelles under argon atmosphere,[56]
both followed by the ketone intermediate bioreduction with
external addition of the corresponding ADH and auxiliary
reagents (Scheme 2, top).
As a starting point, the (racemic) propargylic alcohols
3aÀx were synthesized in 59–92% yield from commercially
available carbonyl compounds 1 and the corresponding
Grignard or organolithium reagent (2, see Section III in the
Supporting Information). Then, 2-phenylpent-3-yn-2-ol (3a)
was selected as benchmark substrate for the study and
optimization of the Meyer–Schuster rearrangement to ex-
plore the influence of the gold catalyst type and the reaction
temperature in a medium composed of a mixture of water and
2-propanol.
Hence, two commercially available gold(I) catalysts were
initially tested (3 mol%, Table 1) containing the bis(trifluor-
omethanesulfo-nyl)imidate moiety (NTf2À) as a weakly coor-
dinating counteranion (entries 1 and 2). These are [1,3-
bis(2,6-diisopropylphenyl)imida-zol-2-ylidene]
Table 1: Meyer–Schuster rearrangement optimization (catalyst and
temperature).
Encouraged by the synthetic possibilities that a,b-unsa-
turated ketones offer, and considering the great applicability
of the Meyer–Schuster rearrangement,[42,46,50] herein we
propose the development of a concurrent cascade process to
get access to a series of enantioenriched b,b-disubstituted
allylic alcohols, by combining an active NHC gold(I) catalyst
in aqueous medium with ADHs of opposite selectivity
(Scheme 2, bottom), by considering 2-propanol as a key
element due to its compatibility with NHC gold complexes
and simultaneous key role in the enzyme cofactor recycling
action.
Entry
Catalyst
T [8C]
Yield [%][a]
(E)-4a
(Z)-4a
1
2
3
4
5
6
IPrAuNTf2
JohnPhosAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
30
30
20
25
40
45
85
75
80
80
87
94
15
25
20
20
13
6
IPrAuNTf2
[a] Percentage of products measured by GC analyses of the crude
reaction mixture. See the Supporting Information for detailed reaction
conditions and GC methods. Complete conversions were attained in all
cases.
Scheme 2. One-pot combinations of gold catalysis involving hydration or Meyer–Schuster rearrangement of alkynes and an alcohol dehydrogen-
ase-catalyzed bioreduction for the production of chiral alcohols.
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[bis(trifluoromethanesulfonyl)imide]gold(I)
(IPrAuNTf2)
achieved in all cases, resulting in a highly selective strategy
for most of the substrates under these conditions, 14 out of 22
(E)-allylic alcohols 4a-f,j,k,m,n,p-s being obtained with over
85% conversion (Table 2).
and (2-di-tert-butylphosphinobiphenyl)gold(I) [bis(trifluoro-
methanesulfonyl)imide] (JohnPhosAuNTf2).[49] The reactions
were carried out in a water:2-propanol (4:1 v/v) mixture,
which would increase the solubility of the substrate and the
gold catalyst in the reaction medium, and at the same would
facilitate the use of an ADH in a concurrent manner, since 2-
propanol is commonly used as hydrogen donor for ADH-
catalyzed bioreduction processes.[57] Satisfyingly, complete
conversions were attained in both cases after 3 h, finding
a higher selectivity for the IPrAuNTf2 catalyst (85:15, E vs. Z).
At this point, different temperatures were studied leading at
458C to the best selectivity towards (E)-allylic alcohol 4a
(94:6, entry 6). Higher temperatures were not tested due to
the potential enzyme deactivation using harsher conditions.
Bearing in mind this fact, 408C was selected as upper limiting
conditions, and the Meyer–Schuster rearrangement reaction
was next studied with the previously synthesized propargylic
alcohols 3aÀx.
In general, good results were found with 2-arylpent-3-yn-
2-ols 3a-o, only attaining poor selectivities for substrates
bearing electron-donating substitutions at the para position
(methyl and methoxy, entries 8 and 9), or electron-donating
and electron-withdrawing groups at the ortho-position (en-
tries 7 and 15), highlighting the preference change when the
nitro functionality at the ortho-position was subjected to
investigation (10:90 E vs. Z, entry 12). Trying to expand the
possibilities of our methodology, 2-hetarylpent-3-yn-2-ols
were considered, for instance containing a thienyl moiety at
C-2 or C-3 (3p and 3q), and good selectivities were found
(entries 16 and 17), being especially noticeable the exclusive
formation of (E)-4-(thiophen-2-yl)pent-3-en-2-one (4p).
Next, the reaction was performed with the propargylic alcohol
bearing a furyl group substituted at C-2 position, but
a complex mixture was found. This is in accordance with the
already described reactivity of furan derivatives in combina-
tion with gold catalysis, occurring e.g., furan-alkyne intra-
molecular cyclizations or other rearrangements.[58] At this
point, the use of pyridine derivatives was omitted since it is
well known that the basic nitrogen atom coordinates to the
gold catalyst leading to a dramatic loss of the metal activity,[59]
requiring therefore higher reaction temperatures[60] that on
the other hand would not be compatible with a second
enzymatic reaction.
For the substrate scope, three molecular engineering
vectors were selected (R1, R2 and R3, Scheme of Table 2)
including 2-(het)arylpent-3-yn-2-ols (3a-q), hexynols 3r,t,v
and butynols 3s,u,w,x bearing different pattern substitutions
for a total of 24 substrates. Complete conversions were
Table 2: Meyer–Schuster rearrangement of (racemic) propargylic alco-
hols 3aÀx.
This strategy was also applicable when developing the
rearrangement over the aliphatic derivative 3r (R1 = tBu)
with very high preference towards the recovery of (E)-4,5,5-
trimethylhex-3-en-2-one (96:4 E/Z, entry 18). Next, the
influence of the substitution at the carbon bearing the
hydroxyl functionality was studied, in comparison with our
model substrate (R2 = CH3, 3a, entry 1), and 3 different
substitutions (R2 = H, Et, or Ph, 3s-u) were also considered,
obtaining ketones 4s-u with complete conversion, although
a significant decrease of the E/Z selectivity was observed
when moving from the formation of the less bulky substrate
(E)-4s (R2 = H, > 97%, entry 19) to the ones bearing
aliphatic moieties 4a (R2 = Me, 87%) and 4t (R2 = Et,
54%) of the E-isomer (entries 1 and 20). Obviously, for 4,4-
diphenylbut-3-en-2-one (4u, entry 21), E/Z isomerism was
not applicable.
The replacement of the methyl substitution at the
terminal alkyne position by an ethyl or a phenyl group
(R3 = Et or Ph, entries 22 and 23) was also considered,
achieving also a complete transformation into ketones 4v and
4w, but observing a decrease or even an inversion of the E/Z
selectivity when enlarging the size of the terminal substitu-
tion, favoring the formation of the (Z)-ketones (43 and 71%,
entries 22 and 23), in contrast to the preferred formation of
(E)-4a (entry 1, only 13% of the Z isomer). Finally,
maintaining the terminal aromatic ring but replacing the
phenyl ring by a methyl group at the R1 substitution, 3-
methyl-1-phenylbut-2-en-1-one (4x, entry 24) was also ob-
tained in full conversion. Overall, a very general methodology
was developed for the straightforward synthesis of allylic
Entry 3a–x R1
R2
R3
Yield [%][a]
(E)À4a–x (Z)À4a–x
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
87
90
86
85
91
90
59
55
43
96
94
10
92
89
58
>97
86
96
13
10
14
15
9
10
41
45
57
4
6
90
8
11
42
<3
14
4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
3-F-C6H4
2-F-C6H4
2-Br-C6H4
4-CH3-C6H4
4-OCH3-C6H4 CH3
4-NO2-C6H4 CH3
3-NO2-C6H4 CH3
2-NO2-C6H4 CH3
4-CF3-C6H4
3-CF3-C6H4
2-OCH3-C6H4 CH3
2-thienyl
3-thienyl
tBu
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CH3
CH3
CH3
CH3
CH3
H
CH3CH2 CH3
Ph
CH3
CH3
CH3
s
t
u
v
w
x
Ph
Ph
Ph
Ph
Ph
CH3
>97
54
<3
46
CH3
CH3CH2
Ph
>97[b]
43
57
29
71
Ph
>97[b]
[a] Percentage of products measured by 1H NMR analyses of the crude
reaction mixture. See the Supporting Information for detailed reaction
conditions. Complete conversions to ketones 4a–x were attained in all
cases. [b] Not applicable the E–Z isomerism.
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ketones from propargylic alcohols in aqueous medium, and
loading of IPrAuNTf2 and enzyme, the use of additives,
next all the efforts were focused on the accomplishment of
a bioreduction process under similar reaction conditions.
Before exploring the possible compatibility of IPrAuNTf2
and ADHs under certain conditions, the bioreduction of (E)-
4-phenylpent-3-en-2-one (4a) was screened using a series of
ADHs. Among them, some ketoreductases were made in
house and overexpressed in E. coli, while others were
purchased from commercially available sources (Evoxx
Technologies GmbH and Codexis Inc). Thus, a wide biocat-
alyst screening is disclosed in Table S2 of the Supporting
Information, some of them providing enantioenriched allylic
alcohol (E)-5a with above 90% conversion and enantiomeric
excess (Scheme 3). Ten ADHs allowed the synthesis of the
different temperatures and reaction times. Among these data,
a few experiments are highlighted in Table 3. Reactions were
carried out in an orbital shaker at 220 rpm since the use of
higher speeding rates usually led to a conversion decrease as
the reactants spilled around the glass vial. Over 60%
conversion for the global process was reached when using
lyophilized cells of E. coli/LBADH (2:1 w/w enzyme:sub-
strate) at 30 and 408C during 24 and 72 h, respectively
(entries 1 and 2) without significant increasing the reaction
yield at prolonged reaction times. It must be highlighted that
in this case, the use of higher loadings of IPrAuNTf2 catalyst
(10 mol%) was required to obtain the mentioned conversion
levels. The reaction was also studied with the commercial
KRED-P1-A12 (entries 3–8), that provided higher conver-
sions and very high selectivities towards (R,E)-5a (> 96%ee).
Remarkably, the use of lower IPrAuNTf2 loadings resulted in
an efficient transformation at 7.5 mol% ratio, isolating the
desired enantiopure allylic alcohol in 78% yield after column
chromatography purification (entry 8).
At this point, the extension of the cascade approach to 18
propargylic alcohols 3 was undertaken to get access to both
(R)- and (S)-allylic alcohol enantiomers 5 (Table S9 and
Figure 1). Compounds bearing bromo, nitro or methoxy
substitutions at the ortho-position of the aromatic ring at
the R1 position (3g, 3l and 3o), an ethyl group at R2 (3t), or
the ones bearing an ethyl or phenyl rest at the terminal alkyne
position (3v and 3w), were omitted from the cascade reaction
scope due to the low selectivities achieved for the production
of the corresponding ketones (E)-4 (41–46% (Z)-4g,o,t,v), or
the preferred formation of the (Z)-isomers (10:90 and 29:71,
4l and 4w). It is important to remark that (Z)-allylic ketones 4
are not converted by the tested ADHs. In spite of the almost
negligible selectivity achieved in the Meyer–Schuster rear-
rangement for compounds substituted with electron donating
groups such as 4-methyl (h, 55:45) and 4-methoxy (i, 43:57),
Scheme 3. Screening of ADHs for the bioreduction of ketone (E)-4a
for the synthesis of (E)-5a alcohol enantiomers depending on the
ADH of choice.
alcohol (R)-5a (93–96% conversion and 98–99%ee), while
only two Prelog enzymes led to the (S)-5a antipode (94–96%
conversion and 98–99%ee). Satisfyingly, complementary
stereoselective overexpressed ADHs on E. coli such as the
one from Rhodococcus ruber (ADH-A)[61,62] and the one from
Lactobacillus brevis (LBADH)[63,64] were found, and also
various commercially available enzymes from the Codexis
Inc. kit. Absolute configurations were assigned based on the
known selectivity of the overexpressed ADHs on E. coli and
confirmed by comparing the measured specific optical
rotations with those previously described in the literature,
such as the allylic alcohol (S,E)-
5a.[65,66]
Table 3: Optimization of the Meyer–Schuster rearrangement and bioreduction concurrent cascade for
the production of allylic alcohol (R,E)-5a.
The coupling of gold species
and biocatalysts is still in its in-
fancy,[51–56] and as mentioned be-
fore only sequential attempts have
been reported when considering
ADHs,[54–56] mainly caused due to
the high temperatures required by
gold(I) and gold(III) catalysts in
aqueous media. For that reason,
the search for adequate reaction
conditions with model substrate 3a
(100 mM) was next chased, select-
ing the overexpressed LBADH on
E. coli and commercial KRED-P1-
A12 for the design of an efficient
concurrent cascade approach. An
exhaustive analysis can be found in
Table S8, displaying the influence
of experimental parameters that
affect to the gold and ADH cata-
lysts reactivity, including different
Entry
ADH[a]
IPrAuNTf2 [mol%]
T
[8C]
T
[h]
Yield [%][b]
ee [%][c]
(E)-5a
3a
4a
(E)-5a
1
2
3
4
5
6
7
8
E. coli/LBADH (46)
E. coli/LBADH (46)
KRED-P1-A12 (22)
KRED-P1-A12 (22)
KRED-P1-A12 (22)
KRED-P1-A12 (16)
KRED-P1-A12 (8)
KRED-P1-A12 (16)
10
10
10
5
7.5
10
10
7.5
40
30
30
30
30
30
30
40
72
24
72
24
24
24
24
24
35
38
<1
6
<1
<1
<1
<1
23
18
14
26
15
15
20
15
42
44
86
68
85
85
80
85 (78)
n.d.
94
98
97
98
98
97
99
[a] Amount of ADH in mg for 0.1 mmol of racemic substrate 3a. [b] Percentage of products was
measured by GC analyses. Yield of product isolated after liquid-liquid extraction and column
chromatography purification on silica gel appears within parentheses. See the Supporting Information
for additional analytical and experimental details. [c] Enantiomeric excess values of (R,E)-5a were
measured by GC analyses. n.d.: not determined
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Figure 1. Summary of the best results obtained in terms of yield of isolated product and optical purity for the production of a series of allylic
alcohols through a one-pot Meyer–Schuster rearrangement and bioreduction concurrent cascade using a commercial ADH or in a sequential
approach when employing E. coli/ADH-A or E. coli/LBADH.
these were considered in the study to broaden the scope of the
presented cascade methodology. Unfortunately, low conver-
sions into the allylic alcohols (< 25%, Table S9) were
observed.
bioreduction medium without enzyme, the isomerization
reaction occurred.
Finally, to demonstrate the practical applicability of both
concurrent and sequential approaches, the reaction with
racemic 2-(3-fluorophenyl)pent-3-yn-2-ol (3e) was scaled-up
to 100 mg using KRED-P1-A12 or E. coli/ADH-A, yielding
(R,E)- and (S,E)-5e enantiomers, respectively, with excellent
conversions (84–85%) and isolated yields (78–79%, Ta-
ble S10).
Overall, the AuI-ADH chemoenzymatic strategy resulted
feasible in a concurrent manner using commercial ketore-
ductases, especially KRED-P1-A12 and KRED-P3-G09 for
the synthesis of 2-arylpent-3-yn-2-ols, while better results in
terms of activity were found through a sequential approach
when employing enzymes overexpressed in E. coli. For
instance, ADH-A was found as a suitable biocatalyst for the
synthesis of alcohols (S,E)-5a-f,j,k,m,n,p-s and (S)-5u requir- Conclusion
ing the addition of the metal catalyst in two portions along the
process. Both sequential and cascade approaches provided
the desired alcohols in very high to excellent optical purities
(93- > 99%ee), compounds that were recovered in moderate
to high isolated yields (up to 86% for the (R)-alcohols and up
to 80% for the (S)-alcohols), obtaining lower yields for
alcohol 5r due to the high volatility of this aliphatic substrate.
The reaction resulted unsuccessful for the synthesis of alcohol
5x due to the spontaneous 1,3-rearrangement of the final
product in aqueous medium[67] forming the achiral (E)-2-
methyl-4-phenylbut-3-en-2-ol and therefore hampering the
development of a stereoselective process. In fact, when the
chemically synthesized racemic 5x was incubated in the
A novel chemoenzymatic cascade is described for the
stereoselective synthesis of a series of b,b-disubstituted allylic
alcohols, compounds which are not easily accessible by other
chemical means, and that have been used as precursors of, for
example, aroma compounds.[65] Initially, both (E)-4-(het)ar-
ylpent-3-en-2-ol enantiomers were synthesized by properly
combining the action of a gold(I) N-heterocyclic carbene
complex and a stereoselective alcohol dehydrogenase in
aqueous medium, using 2-propanol to improve the substrate
solubility and acting as hydrogen donor in the bioreduction
process. In general, high selectivities were achieved in the
Meyer–Schuster rearrangement to fully transform 2-(het)ar-
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ylpent-3-yn-2-ols into the corresponding (E)-4-(het)arylpent-
of Graz, Austria) for providing us with alcohol dehydrogen-
3-en-2-ones using IPrAuNTf2 at 408C, conditions that were
compatible with the use of made in house overexpressed and
commercial ketoreductases. Depending on the enzyme of
choice, the desired optically active allylic alcohols (96- >
99%ee) were obtained in good to high isolated yields (65–
86%). The cascade reaction was successfully achieved in
a concurrent mode with the commercial enzymes and worked
better through a sequential approach for the overexpressed
enzymes.
ases overexpressed in E. coli cells.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alcohols · enzymes · gold · rearrangements ·
stereoselectivity
Satisfyingly, the synthetic possibilities of the Meyer–
Schuster rearrangement and the metal-enzyme combination
were extended by considering various molecular engineering
vectors at both sides of the triple carbon-carbon bond as
depicted in Scheme 4, including hexynol and butynol deriv-
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Acknowledgements
Financial supports from the Spanish Ministry of Economy and
Competitiveness (MEC, Project CTQ2016-75752-R), the
Spanish Ministry of Science and Innovation (MCI,
PID2019-109253RB-I00), and the Asturian Regional Govern-
ment (FC-GRUPIN-IDI/2018/000181) are gratefully ac-
knowledged. We thank Prof. Wolfgang Kroutil (University
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
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Angewandte
Research Articles
Chemie
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Manuscript received: November 14, 2020
Revised manuscript received: February 22, 2021
Accepted manuscript online: March 15, 2021
Version of record online: && &&
,
&&&&
&&&&
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Research Articles
Synthetic Methods
A concurrent process involving a gold N-
heterocyclic carbene (IPrAuNTf2) and an
alcohol dehydrogenase is described for
the first time. This cascade approach
allows the development of a Meyer–
Schuster rearrangement for the trans-
formation of racemic propargylic alco-
hols, mostly with good selectivities
towards the corresponding E-allylic
ketone intermediates, in aqueous
S. Gonzꢁlez-Granda, I. Lavandera,*
V. Gotor-Fernꢁndez*
&&&& — &&&&
Alcohol Dehydrogenases and N-
Heterocyclic Carbene Gold(I) Catalysts:
Design of a Chemoenzymatic Cascade
towards Optically Active b,b-
Disubstituted Allylic Alcohols
medium, which are subsequently reduced
to obtain the desired alcohol enantiomers
with excellent optical purities.
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!