Stereoselective Bioreduction of Telluro-Acetophenones to Optically Active Hydroxy Tellurides

Article abstract of DOI:10.1002/ejoc.201901841

Organotellurium compounds exhibit a broad range of useful applications in organic synthesis, materials science and medicinal chemistry fields. Despite their increasing applicability, the synthesis of enantiomerically pure organotellurium compounds remains nowadays scarcely reported in the literature. Herein, the chemical synthesis and biocatalyzed reductions of a set of telluro-acetophenones using both (R) and (S)-selective alcohol dehydrogenases (ADHs) is described for the first time, obtaining enantiomerically enriched hydroxy tellurides with excellent selectivities under very mild reaction conditions. On the one hand, enantiopure para-substituted (S)-hydroxy tellurides were obtained using the Ras-ADH (77–95 % conversion) and ADH-A (52–75 %), the ADH-A leading to the enantiopure (S)-hydroxy tellurides substituted at the meta-position (69–75 %). On the other hand, the evo-1.1.200 displayed high selectivity towards the preparation of optically alcohols with substitutions at the para-position of the aromatic ring (60–68 % conversion and 92–97 % ee), while the Lb-ADH led to the best results when reducing bulky ketones at the meta-position (79–82% conversion and 88–99 % ee).

Full text of DOI:10.1002/ejoc.201901841

A Journal of
Accepted Article
Title: Stereoselective Bioreduction of Telluro-acetophenones to
Optically Active Hydroxy Tellurides
Authors: Pamela Taisline Bandeira, Vicente Gotor-Fernández, and
Leandro Piovan
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901841
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10.1002/ejoc.201901841
European Journal of Organic Chemistry
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Stereoselective Bioreduction of Telluro-acetophenones to
Optically Active Hydroxy Tellurides
Pamela Taisline Bandeira,[a],[b] Vicente Gotor-Fernández,*[b] and Leandro Piovan*[a]
Abstract: Organotellurium compounds exhibit a broad range of useful
applications in organic synthesis, materials science and medicinal
chemistry fields. Despite their increasing applicability, the synthesis of
enantiomerically pure organotellurium compounds remains nowadays
scarcely reported in the literature. Herein, the chemical synthesis and
biocatalyzed reductions of a set of telluro-acetophenones using both
(R) and (S)-selective alcohol dehydrogenases (ADHs) is described for
the first time, obtaining enantiomerically enriched hydroxy tellurides
with excellent selectivities under very mild reaction conditions. On the
one hand, enantiopure para-substiuted (S)-hydroxy tellurides were
obtained using the Ras-ADH (77-95% conversion) and ADH-A (52-
75%), the ADH-A leading to the enantiopure (S)-hydroxy tellurides
substituted at the meta-position (69-75%). On the other hand, the evo-
1.1.200 displayed high selectivity towards the preparation of optically
alcohols with substitutions at the para-position of the aromatic ring
(60-68% conversion and 92-97% ee), while the Lb-ADH led to the best
results when reducing bulky ketones at the meta-position (79-82%
conversion and 88-99% ee).
hydroxy10 organotellurides successfully applied as chiral building
blocks (Figure 1) and the development of non stereoselective
approaches when starting from optically active precursors of the
desired organotellurium compounds used as antioxidant agents,
and precursors of enzymatic inhibitors and antitumor agents
(Figure 1).11
Figure 1. Representative (chiral) Te-containing compounds with
synthetic applications and biological properties.
Nowadays, biocatalysis is a consolidated technology in
organic synthesis mainly due to the high level of stereoselectivity
displayed by enzymes under mild reaction conditions and the
wide number of existing enzymes able to catalyze multiple
transformations.12 Among asymmetric biotransformations, the
stereoselective reduction of carbonyl compounds catalyzed by
alcohol dehydrogenases (ADHs, E.C.1.1.1.1, also known as
ketoreductases or carbonyl reductases) provides an elegant
manner to produce optically active alcohols by using purified or
whole-cell enzyme forms.13 Interestingly, the versatility of ADHs
has been widely demonstrated for the stereoselective reduction
of a broad range of prochiral carbonyl compounds, including β-
nitroketones,14 β-keto amides15 or ketones containing halogens,16
sulfur,17 boron18 and others functionalities.19
Hence, we have focused in the chemical synthesis and later
development of ADH-catalyzed bioreductions of a set of telluro-
acetophenones using both (R)- and (S)-selective ADHs, which
could lead us to the development of a straightforward strategy
towards enantiomerically enriched hydroxy tellurides under very
mild reaction conditions in aqueous medium.
Introduction
The chemistry of tellurium (Te) has experienced great
progress in recent decades1 presenting Te-containing
compounds as versatile reagents and synthons for many
synthetic purposes, including carbon-carbon bond formation
reactions,2 and a variety of functional group interconversions.3
Organotellurium substances also have important and useful
applications in materials science,4 as well as displaying
remarkable pharmacological profiles5 with a broad range of
biological activities.6
Despite their synthetic and biological importance, especially
when considering their chiral versions, few efforts have been
focused on the synthesis of enantiomerically pure organotellurium
compounds. In contrast to the more deeply studied
organoselenium analogues,7 robust and straightforward routes
towards optically active organotellurium compounds remain
nowadays scarcely reported in the literature. To the best of our
knowledge, their asymmetric syntheses are limited to the
enzymatic kinetic resolutions (EKR) of aliphatic-,8 vinyl-,9 and β-
Results and Discussion
A series of prochiral telluro-acetophenones 3a-g bearing
[a]
[b]
Dr. Pamela Taisline Bandeira, Prof. Dr. Leandro Piovan
Federal University of Paraná, Department of Chemistry, Avenida
Coronel Francisco H. dos Santos 100, 81531991 Curitiba, Brazil.
E-mail: lpiovan@quimica.ufpr.br
Homepage: http://www.quimica.ufpr.br/paginas/leandro-piovan/
Prof. Dr. Vicente Gotor-Fernández
University of Oviedo, Department of Organic and Inorganic
Chemistry, Avenida Julián Clavería 8, 33006 Oviedo, Spain.
E-mail: vicgotfer@uniovi.es
n
n
variable alkyl aliphatic chains (R= Me, Et, Pr and Bu, Scheme
1) straight linked to the Te atom in meta and para positions was
chemically synthetized according to adapted protocols to the ones
described in the literature for structurally similar organotellurium
compounds.20 Firstly, commercially available 3’- and 4’-
bromoacetophenone were converted into the corresponding
acetals 1 using ethylene glycol with 98% (meta) and 82% (para)
isolated yields. Subsequently, the acetals were employed as
precursors for Grignard reagents to provide ditellurides 2 in 77%
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201901841
European Journal of Organic Chemistry
FULL PAPER
(meta) and 79% (para) isolated yields after the oxidative step.20
Finally, sodium borohydride was used for the Te-Te bond
cleavage, followed by alkylation and deprotection sequential
ones (3d and 3g). For analytical purposes, racemic hydroxy
tellurides 4a-g were prepared in 35-92% yields by chemical
reduction of ketones 3a-g with sodium borohydride in methanol.
steps led to telluroketones 3a-g in yields ranging from 35% to 55%. Thus, efficient analytical separations were developed using the
By using this strategy five novel telluro-acetophenones containing
methyl (3a), ethyl (3b and 3e) and n-propyl (3c and 3f) rests linked
to Te atom were synthesized besides of already known TenBu
gas chromatography (GC) technique, before carrying out the
stereoselective reductive biotransformations using a variety of
made in house and commercially available ADHs.
Scheme 1. Synthetic route for telluro-acetophenones 3a-g and the corresponding racemic hydroxy tellurides 4a-g. Reaction conditions: a) Ethylene glycol, p-TsOH,
toluene, reflux, 24 h (82-98% yield). b) i. Mg, THF, reflux, 3 h; ii. Te, r.t., overnight; iii. H2O, atmosphere, 1 h (77-79% yield). c) i. RX (R = Me, Et, nPr, nBu; X = Br or
I), NaBH4, MeOH, THF, 0 °C to r.t., 10 min; ii. p-TsOH, acetone, reflux, 1.5 h (35-55% yield). d) NaBH4, MeOH, 0 °C to r.t., 2 h (35-92% yield).
Next, the bioreductions of telluro-acetophenones 3a-g were
investigated (Table 1) under previously established
conditions.21As biocatalysts, lyophilized cells of Escherichia coli
(E. coli) overexpressing ADH from Ralstonia species (Ras-
ADH),22 Lactobacillus brevis (Lb-ADH),23 Sphingobium
yanoikuyae (Sy-ADH),24 Thermoanaerobacter ethanolicus (Tes-
ADH),25 Thermoanaerobacter species (ADH-T),26 Rhodococcus
ruber (ADH-A)27 and the commercially available evo 1.1.20028
were assayed.
Satisfyingly five out of the seven ADHs were able to catalyze
the enantioselective bioreduction of telluroketones 3a-g to the
desired optically active hydroxy tellurides 4a-g, attaining
depending on the enzyme choice moderate to excellent
selectivities towards the production of (R)-alcohols (58->99% ee),
while remarkably the synthesis of enantiopure (S)-alcohols 4a-g
was possible using the appropriate enzyme (Table 1).
Regarding bioreductive reactions of para-substituted
telluroketones 3a-d they were achieved in good to excellent
extension using the Ras-ADH (77-95% conversion, entry 1) and
the ADH-A (52-75% conversion, entry 6), obtaining in all cases
the (S)-hydroxy tellurides in enantiomerically pure form,
meanwhile the Sy-ADH (entry 3) led to modest activity and
selectivity values. Interestingly for the Ras-ADH, increasing the
alkyl length chain linked to Te atom from ethyl (3b, R = p-TeEt) to
butyl (3d, R = p-TenBu) a decrease in the conversion rates from
95 to 77% was observed (entry 1). An interesting trend was also
observed when changing the aromatic pattern substitution from
para to meta position, resulting in a significant decrease in activity
for the Ras-ADH in the bioreduction of 3e-g (40-54% conversion
and 72-86% ee, entry 1), while the ADH-A demonstrated its
versatility by producing the enantiopure (S)-alcohols in 69-75%
conversion (entry 6).
When anti-Prelog enzymes such as the Lb-ADH (entry 2) and
the commercially available evo-1.1.200 (entry 7) were employed,
the Lb-ADH acted with a moderate to excellent selectivity towards
para-substituted acetophenones (57->99% ee), reaching a
complete selectivity when the bulkier substrate 3d was
considered obtaining the corresponding butyl derivative 4d in
enantiopure form. A similar trend was observed with the evo-
1.1.200 (51-60% conversion and 58-84% ee), however a notable
difference between both enzymes was noticed when facing the
meta-substituted ketones 3e-g. In fact, a significant decrease in
activity was observed with the Lb-ADH, while high selectivities
and moderate conversions were reached with the evo-1.1-200
(60-68% conversion and 92-97% ee) for the production of (R)-4e-
g.
Finally, a semi-preparative scale ADH-catalysed reduction
was carried out employing 100 mg of telluro-acetophenone 3b (R
= p-TeEt) employing Ras-ADH as biocatalyst. After 24 h, the
conversion rate reached 84%, obtaining the optically active
hydroxy telluride (S)-(–)-4b with 42% of isolated yield and >99%
20
ee ([]D = –10.2 (c = 2.0, CHCl3)]) after silica gel column
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10.1002/ejoc.201901841
European Journal of Organic Chemistry
FULL PAPER
purification, demonstrating the robustness of the bioreduction
process.
Table 1. Bioreduction of telluro-acetophenones 3a-g catalyzed by alcohol dehydrogenases (ADHs)
4g
(R = m-
TenBu)
4a
4b
4c
4d
4e
4f
(R = p-TeMe)
(R = p-TeEt)
(R = p-TenPr)
(R = p-TenBu)
(R = m-TeEt)
(R = m-TenPr)
Alcohol
dehydrogenase
Entry
c
[%]a
ee
[%]b
c
[%]a
ee
[%]b
c
[%]a
ee
[%]b
c
[%]a
ee
[%]b
c
[%]a
ee
[%]b
c
[%]a
ee
[%]b
c
[%]a
ee
[%]b
86
(S)
1
2
3
E. coli/Ras-ADH
E. coli/Lb-ADH
E. coli/Sy-ADH
92
44
56
>99 (S)
57 (R)
46 (S)
95
>99 (S)
84 (R)
52 (S)
88
79
54
>99 (S)
88 (R)
63 (S)
77
82
67
>99 (S)
>99 (R)
95 (S)
54
32
68
77 (S)
97 (R)
58 (S)
48
13
58
72 (S)
n.d.
40
7
69
n.d.
71
(S)
62
80 (S)
56
4
5
E. coli/TeS-ADH
E. coli/ADH-T
<5
<5
n.d.
n.d.
17
19
n.d.
n.d.
13
22
n.d.
n.d.
<5
<5
n.d.
n.d.
9
8
n.d.
n.d.
<5
<5
n.d.
n.d.
<5
<5
n.d.
n.d.
>99
(S)
>99
(S)
6
7
E. coli/ADH-A
52
60
>99 (S)
58 (R)
69
53
>99 (S)
67 (R)
72
51
>99 (S)
73 (R)
75
52
>99 (S)
84 (R)
75
68
75
64
>99 (S)
96 (R)
69
60
92
(R)
evo-1.1.200
97 (R)
a Conversion values were determined by GC. b Enantiomeric excess values were determined by GC after removed the alkyl-tellurium moiety (“TeR”) with tBuLi.
Absolute configurations appear in brackets. n.d. not determined due to the low conversion rates.
active hydroxy tellurides, being possible the isolation of the (S)-
or (R)-enantiomers depending on the enzyme of choice.
Conclusions
In summary, a series of telluro-acetophenones, including five
novels ones, has been successfully reduced to the corresponding
Experimental Section
optically active hydroxy tellurides employing ADH-catalyzed
bioreduction processes. For the production of enantiopure para-
substituted (S)-hydroxy tellurides, the best results were obtained
using the Ras-ADH and ADH-A, the latest being also capable to
give access to the enantiopure (S)-hydroxy tellurides when the
substitution was present at the meta-position. In a complementary
approach, the Lb-ADH and the evo-1.1.200 allowed the
preparation of the (R)-alcohols displaying the best selectivities
with the Lb-ADH in the bioreduction of the most bulkier substrates,
while the evo-1.1.200 demonstrated its potential in the
preparation of optically alcohols with substitutions at the para-
position of the aromatic ring.
Chemical reagents for the synthesis of ketones 3a-g and alcohols 4a-
g were purchased from Sigma-Aldrich. For the bioreduction experiments,
D-glucose, NADH and NADPH were also acquired from Sigma-Aldrich,
while glucose dehydrogenase (GDH-105) was obtained from Codexis Inc.
and evo-1.1.200 from Evoxx Technologies GmbH. Made in house ADHs
were overexpressed in E. coli: Ralstonia species (Ras-ADH), Sphingobium
yanoikuyae
(Sy-ADH),
Thermoanaerobacter
species
(ADH-T),
Lactobacillus brevis (Lb-ADH), Thermoanaerobacter ethanolicus (TeS-
ADH) and Rhodococcus ruber (ADH-A).
Nuclear magnetic resonance (NMR) spectra (1H and 13C) were
recorded on a Bruker AV300 MHz spectrometer. 125Te NMR spectra were
recorded on a Bruker Avance III at 9.4 T (400.13 MHz for 1H NMR and
126.24 for 125Te NMR) and the chemical shifts for 125Te NMR were
registered relative to an external standard diphenyl ditelluride (Ph2Te) at
= 422 ppm. All chemical shifts (δ) are given in parts per million (ppm).
Gas chromatography (GC) analyses were performed on an Agilent
HP6890 GC chromatograph equipped with FID detector. Conversion rates
measurements were performed on non-chiral GC column DB-1701 (30 m
Overall, this is the first report of ADHs-catalyzed reduction of
Te-containing carbonyl substrates, demonstrating that the
biocatalytic reduction of prochiral telluroketones mediated by
ADHs is an efficient and powerful approach to produce optically
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10.1002/ejoc.201901841
European Journal of Organic Chemistry
FULL PAPER
x
0.25 mm, 0.25 μm), while for the enantiomeric excess values
300.13 MHz): = 1.64 (s, 3H), 3.72–3.82 (m, 2H), 4.00–4.10 (m, 2H), 7.18
(t, 1H, 3JH,H = 7.6), 7.34 (t, 1H, 3JH,H = 8.0 Hz), 7.76 (d, 1H, 3JH,H = 7.6 Hz),
7.97 (s, 1H) ppm; 13C NMR (CDCl3, 75.5 MHz): = 27.5, 64.4, 107.8, 108.3,
125.2, 129.1, 134.2, 137.0, 144.2 ppm; 125Te NMR (126.2 MHz): = 426
ppm.
determination chiral GC column Chirasil β-Dex (25 m x 0.25 mm, 0.25 μm)
were required. Melting points were measured in a Stuart apparatus SMP3
(Bibby Sterilin, Staffordshire, UK) introducing the samples in open capillary
tubes and the measurements are uncorrected. Optical rotation
measurement was performed at 590 nm on Autopol IV Automatic
polarimeter (Rudolph Research Analytical, Hackettstown, NJ, USA). Thin-
layer chromatography (TLC) analyses were conducted with Merck Silica
Gel 60 F254 precoated plates and visualized with UV, potassium
permanganate and vanillin stain. Column chromatographies were
performed using silica gel 60 (230-240 mesh).
Synthesis of telluroketones 3a-g
MeOH (2 mL) was added dropwise to a suspension of the corresponding
diacetal ditelluride 2 (0.58 mg, 1.0 mmol), the corresponding alkyl halide
(3.0 mmol) and NaBH4 (0.11 g, 3 mmol) in anhydrous THF (5 mL) under
nitrogen atmosphere at 0 °C. The mixture was left to warm until room
temperature and stirred for 1 h. After this period unreacted hydride excess
was destroyed adding an aqueous NH4Cl saturated solution (5 mL). The
mixture was extracted with CH2Cl2 (3 x 15 mL), combining the organic
layers that were next washed with brine (15 mL). The resulting organic
phase was dried over Na2SO4, filtered and concentrated under reduced
pressure. The crude product was dissolved in acetone (15 mL) and p-
TsOH (0.15 mmol) was added. The mixture was refluxed for 4 h, and after
this time, the solvent was removed under reduced pressure and the
reaction crude purified by column chromatography on silica gel (20%
EtOAc/hexane), affording the corresponding organotellurium ketones 3a-
g.
General procedures for the chemical synthesis of ketones 3a-g and
alcohols 4a-g
Acetalization of 3’- and 4’-bromoacetophenones20
A mixture of the corresponding bromoacetophenone (5.98 g, 25.0 mmol),
ethylene glycol (15 mL, 250.0 mmol), p-TsOH (0.25 mg, 1.50 mmol) and
anhydrous toluene (150 mL) was stirred and heated under reflux for 24 h.
Water formed during the reaction (about 0.5 mL) was removed using a
Dean-Stark trap. The reaction mixture was cooled and extracted with ethyl
acetate (3 x 50 mL), and the combined organic phase sequentially washed
with a NaHCO3 saturated aqueous solution (30 mL), water (30 mL) and
brine (30 mL). The resulting organic layer was dried over Na2SO4, filtered
and concentrated under reduced pressure, affording the corresponding
dioxolanes 1.
1-[4-(Methyltellanyl)phenyl]ethanone (3a). Yellow powder, 35%. Rf
(20% EtOAc/hexane): 0.43. IR (NaCl): = 1217, 1366, 1580, 1670, 1738,
2971 cm- 1. H NMR (CDCl3, 300.13 MHz): = 2.25 (s, 3H), 2.56 (s, 3H),
7.64 (dd, 2H, 3JH,H = 8.6 Hz, 4JH,H = 2.0 Hz), 7.75 (dd, 2H, 3JH,H = 8.6 Hz,
4JH,H = 2.0 Hz) ppm; 13C NMR (CDCl3, 75.5 MHz): =): –16.3, 26.6, 121.6,
128.6, 135.2, 135.8, 197.7 ppm; 125Te NMR (126.2 MHz): = 343 ppm.
2-(4-Bromophenyl)-2-methyl-1,3-dioxolane. White crystals, 82%. Rf
(20% EtOAc/hexane): 0.64; 1H NMR (CDCl3, 300.13 MHz): = 1.63 (s, 3H),
3.71–3.78 (m, 2H), 4.00–4.07 (m, 2H), 7.35 (dd, 2H, 3JH,H = 8.7 Hz, 4JH,H
1.9 Hz), 7.46 (dd, 2H, 3JH,H = 8.7 Hz and 4JH,H = 1.9 Hz) ppm.
=
1-[4-(Ethyltellanyl)phenyl]ethanone (3b). Pale yellow oil, 55%. Rf (20%
EtOAc/hexane): 0.68. IR (NaCl): = 1263, 1580, 1674, 2816, 2916, 2954
1
3
cm-1. H NMR (CDCl3, 300.13 MHz): = 1.69 (t, 3H, JH,H = 7.6 Hz), 2.57
(s, 3H), 2.96 (q, 2H, 3JH,H = 7.6 Hz), 7.74 (m, 4H) ppm; 13C NMR (CDCl3,
75.5 MHz): = 0.9, 17.3, 26.6, 120.7, 128.7, 136.0, 136.0, 197.8 ppm; 125Te
NMR (126.2 MHz): = 541 ppm.
2-(3-Bromophenyl)-2-methyl-1,3-dioxolane. Colorless oil, 98%. Rf (20%
EtOAc/hexane): 0.61. 1H NMR (CDCl3, 300.13 MHz): = 1.62 (s, 3H),
3.70–3.78 (m, 2H), 3.99–4.08 (m, 2H), 7.20 (t, 1H, JH,H = 7.8 Hz), 7.41–
7.46 (m, 2H), 7.63–7.65 (m, 1H) ppm.
Synthesis of diaryl ditellurides 220
3
1-[4-(Propyltellanyl)phenyl]ethanone (3c). Yellow oil, 53%. Rf (20%
EtOAc/hexane): 0.46. IR (NaCl): = 1262, 1589, 1675, 2867, 2925, 2956
3
cm-1. 1H NMR (CDCl3, 300.13 MHz): = 0.99 (t, 3H, JH,H = 7.2 Hz), 1.85
A suspension of magnesium (0.53 g, 22.0 mmol) in anhydrous THF (40
mL) was added to a solution of the corresponding 2-(bromophenyl)-2-
methyl-1,3-dioxolane (1, 4.86 g, 20.0 mmol) in anhydrous THF (10 mL)
under nitrogen atmosphere. The mixture was refluxed for 3 h and after this
time, the reaction was left to warm until room temperature. At this point,
elemental tellurium (20.0 mmol) was added in one-portion and kept under
stirring overnight. The solution was cooled to 0 °C and water (30 mL) was
added dropwise. The crude reaction was filtered through a celite pad and
washed exhaustively with CH2Cl2 (3 x 50 mL). The resulting organic phase
was finally washed with brine (50 mL), dried over Na2SO4, filtered and
concentrated under reduced pressure, isolating the corresponding diaryl
ditellurides 2 in satisfactory purity to be used in the next step without further
purification.
(sext, 2H, 3JH,H = 7.3 Hz), 2.55 (s, 3H), 2.94 (t, 3H, 3JH,H = 7.3 Hz), 7.71 (m,
4H) ppm; 13C NMR (CDCl3, 75.5 MHz): = 11.5, 16.7, 25.1, 26.5, 120.9,
128.5, 135.9, 136.8, 197.7 ppm; 125Te NMR (126.2 MHz): = 470 ppm.
1-[4-(Butyltellanyl)phenyl]ethanone (3d). Pale yellow oil, 45%. Rf (20%
EtOAc/hexane): 0.74. IR (NaCl): = 1261, 1580, 1676, 2869, 2925, 2954
cm-1. 1H NMR (CDCl3, 300.13 MHz): = 0.91 (t, 3H, 3JH,H = 7.4 Hz), 1.37–
1.42 (m, 2H), 1.76–1,86 (m, 2H), 2.57 (s, 3H), 2.97 (t, 3H, 3JH,H = 7.4 Hz),
7.72 (m, 4H) ppm; 13C NMR (CDCl3, 75.5 MHz): = 8.8, 13.5, 25.2, 26.6,
33.8, 121.0, 128.6, 135.9, 136.7, 197.8 ppm; 125Te NMR (126.2 MHz): =
477 ppm.
1-[3-(Ethyltellanyl)phenyl]ethanone (3e). Pale yellow oil, 46%. Rf (20%
EtOAc/hexane): 0.63. IR (NaCl): = 1249, 1562, 1679, 2860, 2917, 2953
cm-1. 1H NMR (CDCl3, 300.13 MHz): = 1.63 (t, 3H, 3JH,H = 7.6 Hz), 2.56
(s, 3H) 2.89 (q, 2H, 3JH,H = 7.6 Hz), 7.27–7.28 (m, 1H), 7.80–7.93 (m, 1H),
8.26 (s, 1H) ppm; 13C NMR (CDCl3, 75.5 MHz): = 1.0, 17.4, 26.7, 112.2,
127.5, 129,2, 137.6, 137.9, 142.6, 197.6 ppm; 125Te NMR (126.2 MHz): =
551 ppm.
1,2-bis[4-(2-Methyl-1,3-dioxolan-2-yl)phenyl]ditellane. Red powder,
77%. Mp: 139-141 °C. Rf (20% EtOAc/hexane): 0.33. 1H NMR (CDCl3,
300.13 MHz): = 1.63 (s, 3H), 3.76–3.77 (m, 2H), 4.02–4.03 (m, 2H), 7.30
4
3
4
(dd, 2H, 3JH,H = 8.4, JH,H = 1.8), 7.77 (dd, 2H, JH,H = 8.4 Hz, JH,H = 1.8
Hz); 13C NMR (CDCl3, 75.5 MHz): = 27.6, 64.5, 107.2, 108.5, 125.2, 126.3,
128.2, 137.3, 143.6 ppm; 125Te NMR (126.2 MHz): = 408 ppm.
1-[3-(Propyltellanyl)phenyl]ethanone (3f). Yellow oil, 43%. Rf (20%
EtOAc/hexane): 0.46. IR (NaCl): = 1249, 1561, 1680, 2867, 2925, 2956
1,2-bis[3-(2-Methyl-1,3-dioxolan-2-yl)phenyl]ditellane. Red powder,
79%. Mp: 140-143 °C. Rf (20% EtOAc/hexane): 0.41. 1H NMR (CDCl3,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901841
European Journal of Organic Chemistry
FULL PAPER
3
cm-1. 1H NMR (CDCl3, 300.13 MHz): = 0.98 (t, 3H, JH,H = 7.3 Hz), 1.82
1-[3-(Ethyltellanyl)phenyl]ethanol (4e). Pale yellow oil, 89%. Rf (20%
EtOAc/hexane): 0.38; IR (NaCl): = 697, 764, 1275, 2969, 3324 cm-1. 1H
NMR (CDCl3, 300.13 MHz): = 1.48 (d, 3H, JH,H = 6.5 Hz), 1.66 (t, 2H,
(sext, 2H, 3JH,H = 7.4 Hz), 2.58 (s, 3H), 2.93 (t, 3H, 3JH,H = 7.4 Hz), 7.27 (t,
3
4
3
1H, JH,H = 7.7 Hz), 7.81–7.89 (m, 2H), 8.27 (t, JH,H = 1.7 Hz, 1H) ppm;
13C NMR (CDCl3, 75.5 MHz): = 11.8, 16.7, 25.1, 26.7, 112.4, 127.5, 129.2,
137.7, 137.9, 142.6, 197.7 ppm; 125Te NMR (126.2 MHz): = 479 ppm.
3
3
3JH,H = 7.6 Hz), 2.89 (q, 2H, JH,H = 7.6 Hz), 4.84 (q, 1H, JH,H = 6.5 Hz),
7.16–7.21 (m, 1H), 7.26–7.29 (m, 1H), 7.59–7.62 (m, 1H), 7.72 (s, 1H)
ppm; 13C NMR (CDCl3, 75.5 MHz): = 1.2, 17.3, 25.3, 70.2, 112.0, 124.8,
129.3, 135.4, 137.4, 146.8 ppm; 125Te NMR (126.2 MHz): = 534 ppm.
1-[3-(Butyltellanyl)phenyl]ethanone (3g). Pale yellow oil, 49%. Rf (20%
EtOAc/hexane): 0.75. IR (NaCl): = 1249, 1562, 1681, 2869, 2925, 2955
cm-1. 1H NMR (CDCl3, 300.13 MHz): = 0.89 (t, 3H, 3JH,H = 7.3 Hz), 1.36–
1.43 (m, 2H), 1.73–1.81 (m, 2H), 2.58 (s, 3H), 2.94 (t, 2H, 3JH,H = 7.6 Hz),
7.26–7.31 (m, 1H), 7.84–7.86 (m, 2H), 8.27 (s, 1H) ppm; 13C NMR (CDCl3,
75.5 MHz): = 9.0, 13.5, 25.1, 26.7, 33.9, 112.5, 127.5, 129.3, 137.8, 142.6,
197.7 ppm; 125Te NMR (126.2 MHz): = 485 ppm.
1-[3-(Propyltellanyl)phenyl)ethanol (4f). Yellow oil, 79%. Rf (20%
EtOAc/hexane): 0.50. IR (NaCl): = 697, 764, 1267, 2959, 3323 cm-1. 1H
3
NMR (CDCl3, 300.13 MHz): = 0.99 (t, 3H, JH,H = 7.4 Hz), 1.48 (d, 3H,
3JH,H = 6.5), 1.82 (sext, 2H, 3JH,H = 7.4 Hz), 1.94 (brs, OH), 2.90 (t, 2H, 3JH,H
3
= 7.4 Hz), 4.84 (q, 1H, JH,H = 6.5 Hz), 7.15–7.20 (m, 1H), 7.28–7.29 (m,
1H), 7.58–7.61 (m, 1H), 7.72 (s, 1H) ppm; 13C NMR (CDCl3, 75.5 MHz): =
11.4, 16.8, 25.2, 25.3, 70.2, 112.0, 124.7, 129.3, 135.3, 137.2, 146.7 ppm;
125Te NMR (126.2 MHz): = 469 ppm.
Synthesis of racemic alkyltellurium-1-phenylethanols 4a-g
NaBH4 (0.57 mg, 1.5 mmol) was added in portions to a solution of the
corresponding telluroketone 3a-g (1 mmol) in dry MeOH (2 mL) under
nitrogen atmosphere and 0 °C. The mixture was left to warm until room
temperature and stirred for 1 h. Unreacted hydride excess was destroyed
adding an aqueous NH4Cl saturated solution (2 mL), and then MeOH was
evaporated in a rotary evaporator under reduced pressure. The mixture
was extracted with CH2Cl2 (3 x 10 mL), combing the organic layers that
were dried over Na2SO4, filtered and concentrated under reduced pressure.
The reaction crude was purified by column chromatography on silica gel
(20% EtOAc/hexane), affording the corresponding racemic hydroxy
tellurides 4a-g employed later for analytical purposes.
1-[3-(Butyltellanyl)phenyl]ethanol (4g). Pale yellow oil, 35%. Rf (20%
EtOAc/hexane): 0.56. IR (NaCl): = 698, 1064, 1267, 2956, 3334 cm-1. 1H
NMR (CDCl3, 300.13 MHz): = 0.90 (t, 3H, 3JH,H = 7.3 Hz), 1.38–1.41 (m,
2H), 1.47 (d, 3H, 3JH,H = 6.3 Hz), 1.76–1.79 (m, 2H), 2.04 (brs, 1H), 2.91
(t, 2H, 3JH,H = 7.7 Hz), 4.83 (q, 1H, 3JH,H = 6.3 Hz), 7.17 (t, 2H, 3JH,H = 7.4
Hz), 7.36–7.61 (m, 1H), 7.70 (s, 1H) ppm; 13C NMR (CDCl3, 75.5 MHz): =
8.6, 13.5, 25.2, 25.3, 34.0, 70.1, 124.7, 129.3, 135.2, 137.2, 146.7 ppm;
125Te NMR (126.2 MHz): = 462 ppm.
Bioreduction experiments
1-[4-(Methyltellanyl)phenyl]ethanol (4a). Pale yellow oil, 75%. Rf (20%
EtOAc/hexane): 0.36; IR (NaCl): =1086, 1111, 1396, 2925, 2970, 3370
cm- 1. 1H NMR (CDCl3, 300.13 MHz): = 1.47 (d, 3H, 3JH,H = 6.3 Hz), 2.00
ADH-catalyzed reduction experiments were performed in aqueous
medium (50 mmol L-1 Tris.HCl buffer pH 7.5) using a small quantity of
dimethylsulfoxide (DMSO, 2.5% v/v) as cosolvent aiming the solubilization
of telluroketones in aqueous media, all of them containing catalytic
amounts of NAD+ or NADP+ (10 mmol L-1) depending on the enzyme
cofactor dependency at 30 °C for 24 h. For cofactor regeneration purposes,
the usual substrate-coupled method was employed, in which 2-propanol
(iPrOH, 5% v/v) acted as co-substrate and co-solvent, except for Ras-ADH
that used the enzyme-coupled approach with glucose and glucose
dehydrogenase.
3
3
(brs, 1H), 2.19 (s, 3H), 4.85 (q, 1H, JH,H = 6.3 Hz), 7.22 (dd, 2H, JHH
=
7.9 Hz, 4JH,H = 1.8 Hz), 7.62 (dd, 2H, 3JH,H = 7.9 Hz, 4JH,H = 1.8 Hz) ppm;
13C NMR (CDCl3, 75.5 MHz): = –16.4, 25.3, 70.1, 111.1, 126.4, 137.0,
145.2 ppm; 125Te NMR (126.2 MHz): = 326 ppm.
1-[4-(Ethyltellanyl)phenyl]ethanol (4b). Pale yellow oil, 92%. Rf (20%
EtOAc/hexane): 0.36; IR (NaCl): = 750, 968, 1009, 2970, 3324 cm-1. 1H
3
NMR (CDCl3, 300.13 MHz): = 1.48 (d, 3H, JH,H = 6.5 Hz), 1.65 (t, 2H,
3
3JH,H = 6.5 Hz), 1.92 (brs, 1H), 2.87 (q, 2H, JH,H = 7.6 Hz), 4.87 (q, 1H,
3JH,H = 7.6 Hz), 7.23 (dd, 2H, 3JH,H = 8.0 Hz, 4JH,H = 1.9 Hz), 7.70 (dd, 2H,
3JH,H = 8.0 Hz, 4JH,H = 1.9 Hz) ppm; 13C NMR (CDCl3, 75.5 MHz): = 0.7,
17.5, 25.3, 70.2, 110.4, 126.4, 138.7, 145.4 ppm; 125Te NMR (126.2 MHz):
= 527 ppm.
Bioreduction mediated by E. coli/Ras-ADH
Lyophilized cells of E. coli//Ras-ADH (12 mg), DMSO (15 μL, 2.5% v/v), 1
mmol L-1 NADP+ (60 μL of a 10 mmol L-1 stock solution), 50 mmol L-1
glucose (60 μL of
a
500 mmol L-1 stock solution) and glucose
1-[4-(Propyltellanyl)phenyl]ethanol (4c). Yellow oil, 70%. Rf (20%
EtOAc/hexane): 0.45; IR (NaCl): = 750, 764, 1274, 2959, 3324 cm-1. 1H
dehydrogenase (10 U) were added into an Eppendorf tube containing
telluroketones 3a-g (25 mmol L-1) in a 50 mmol L-1 Tris.HCl buffer pH 7.5
(420 μL). The reaction was shaken at 30 °C and 250 rpm for 24 h, and
after this time, the mixture was extracted with ethyl acetate (3 x 500 μL).
The organic layers were separated by centrifugation (2 min, 5700 rpm),
combined and finally dried over Na2SO4. An aliquot was taken to inject in
the GC for the measurement of conversion and enantiomeric excess
values.
3
NMR (CDCl3, 300.13 MHz): = 0.99 (t, 3H, JH,H = 7.2 Hz), 1.47 (d, 3H,
3JH,H = 6.5 Hz), 1.80 (sext, 2H, 3JH,H = 7.2 Hz), 1.93 (brs, OH), 2.88 (t, 2H,
3
3JH,H = 7.2 Hz), 4.86 (q, 1H, JH,H = 6.5 Hz), 7.21 (dd, 2H, 3JH,H = 8.2 Hz,
4JH,H = 1.9 Hz), 7.68 (dd, 2H, 3JH,H = 8.2 Hz, 4JH,H = 1.9 Hz) ppm; 13C NMR
(CDCl3, 75.5 MHz): = 11.4, 16.7, 25.2, 25.3, 70.2, 110.5, 126.4, 138.6,
145.4 ppm; 125Te NMR (126.2 MHz): = 454 ppm.
1-[4-(Butyltellanyl)phenyl]ethanol (4d). Pale yellow oil, 89%. Rf (10%
EtOAc/hexane): 0.22; IR (NaCl): = 764, 1010, 1261, 2959, 3336 cm-1. 1H
NMR (CDCl3, 300.13 MHz): = 0.91 (t, 3H, 3JH,H = 7.2 Hz), 1.35–1.47 (m,
Bioreduction mediated by E. coli/Lb-ADH
Lyophilized cells of E. coli/Lb-ADH (12 mg), iPrOH (30 μL, 5% v/v), 1 mmol
L-1 NADP+ (60 μL of a 10 mmol L-1 stock solution) and 10 mmol L-1 MgCl2
(60 μL of a 100 mmol L-1 stock solution) were added into an Eppendorf
tube containing telluroketones 3a-g (25 mmol L-1) in a 50 mmol L-1 Tris.HCl
buffer pH 7.5 (480 μL). The reaction was shaken at 30 °C and 250 rpm for
24 h, and after this time, the mixture was extracted with ethyl acetate (3 x
500 μL). The organic layers were separated by centrifugation (2 min, 5700
3
2H), 1.73 (d, 3H, JH,H = 6.5), 1.78–1.80 (m, 2H), 2.01 (brs, OH), 2.89 (t,
3
3
2H, 3JH,H = 7.5 Hz), 4.85 (q, 1H, JH,H = 6.5 Hz), 7.19 (dd, 2H, JH,H = 8.3
Hz, 4JH,H = 1.8 Hz), 7.68 (dd, 2H, 3JH,H = 8.3 Hz, 4JH,H = 1.8 Hz) ppm; 13
C
NMR (CDCl3, 75.5 MHz): = 8.6, 13.5, 25.2, 25.3, 34.0, 70.2, 110.6, 126.3,
138.5, 145.3 ppm; 125Te NMR (126.2 MHz): = 461 ppm.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901841
European Journal of Organic Chemistry
FULL PAPER
rpm), combined and finally dried over Na2SO4. An aliquot was taken to
inject in the GC for the measurement of conversion and enantiomeric
excess values.
Lyophilized cells of E. coli//Ras-ADH (290 mg), DMSO (362 μL, 2.5% v/v),
1 mmol L-1 NADP+ (1.45 mL of a 10 mmol L-1 stock solution), 50 mmol L-1
glucose (1.45 mL of a 500 mmol L-1 stock solution) and glucose
dehydrogenase (10 U) were added into an Erlenmeyer flask containing
telluro-acetophenone 3b (100 mg, 0.36 mmol, 25 mmol L-1) in a 50 mmol
L-1 Tris.HCl buffer pH 7.5 (10 mL). The reaction was shaken at 30 °C and
250 rpm for 24 h, and after this time, the mixture was extracted with ethyl
acetate (3 x 500 μL). The organic layers were combined, dried over
Na2SO4 and filtered. The resulting reaction crude was purified by column
chromatography on silica gel (20% EtOAc/hexane), affording (S)-(–)-4b
[42% isolated yield and >99% ee, []D20 = –10.2 (c = 2.0, CHCl3)].
Bioreduction mediated by E. coli/Sy-ADH, E. coli/TeS-ADH and E.
coli/ADH-T
Lyophilized cells of E. coli/ADH (12 mg), iPrOH (30 μL, 5% v/v) and 1 mmol
L-1 NADP+ (60 μL of a 10 mmol L-1 stock solution) were added into an
Eppendorf tube containing telluroketones 3a-g (25 mmol L-1) in a 50 mmol
L-1 Tris.HCl buffer pH 7.5 (510 μL). The reaction was shaken at 30 °C and
250 rpm for 24 h, and after this time, the mixture was extracted with ethyl
acetate (3 x 500 μL). The organic layers were separated by centrifugation
(2 min, 5700 rpm), combined and finally dried over Na2SO4. An aliquot was
taken to inject in the GC for the measurement of conversion and
enantiomeric excess values.
Acknowledgments
The authors thank the national Council for Scientific and
Technological Development (CNPq, Brazil, Proc. 456834/2014),
the Coordination for the Improvement of Higher Level Personnel
(CAPES, Brazil), the Spanish Ministry of Economy and
Competitiveness (MINECO, CTQ-2013-44153-P project) and the
Government of the Principado de Asturias (FC-GRUPIN-
IDI/2018/000181) for financial supports. P. T. B thanks CAPES for
her PDSE felowship (Edital No 47/2017). Prof. Wolfgang Kroutil is
also acknowledged for the donation of overexpressed alcohol
dehydrogenases.
Bioreduction mediated by E. coli/ADH-A
i
Lyophilized cells of E. coli/ADH-A (12 mg), PrOH (30 μL, 5% v/v) and 1
mmol L-1 NAD+ (60 μL of a 10 mmol L-1 stock solution) were added into an
Eppendorf tube containing telluroketones 3a-g (25 mmol L-1) in a 50 mM
Tris.HCl buffer pH 7.5 (510 μL). The reaction was shaken at 30 °C and 250
rpm for 24 h, and after this time, the mixture was extracted with ethyl
acetate (3 x 500 μL). The organic layers were separated by centrifugation
(2 min, 5700 rpm), combined and finally dried over Na2SO4. An aliquot was
taken to inject in the GC for the measurement of conversion and
enantiomeric excess values.
Keywords: • Alcohol dehydrogenases • Asymmetric synthesis
Enzyme catalysis • Optically active organotellurides • Tellurium
Bioreduction mediated by evo-1.1.200
i
Commercially available evo-1.1.200 (10 mg), PrOH (25 μL, 5% v/v), 1
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European Journal of Organic Chemistry
FULL PAPER
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901841
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Tellurium chemistry
Pamela Taisline Bandeira, Vicente
Gotor-Fernández,* and Leandro Piovan*
Page No. – Page No.
Stereoselective Bioreduction of
Telluro-acetophenones to Optically
Active Hydroxy Tellurides
Text for Table of Contents (about 350 characters)
A series of telluro-acetophenones has been chemically synthesized and later reduced using alcohol dehydrogenases of complementary
selectivity. Therefore, (R) and (S)-hydroxy tellurides have been obtained in good to excellent optical purities under mild reaction
conditions in aqueous medium.
This article is protected by copyright. All rights reserved.