Extractive biocatalysis in the asymmetric reduction of α-alkyl, β-aryl enones by Baker's yeast

Article abstract of DOI:10.1016/j.tetasy.2017.05.009

We prepared various chiral α-alkyl, β-aryl ketones with good to excellent enantiomeric excess through the Baker's yeast asymmetric double-bond reduction of the corresponding α,β-unsaturated substrates adsorbed onto the resin Amberlite XAD-7. This methodology was compatible with substrates bearing both electron-donating and withdrawing groups attached to the aromatic ring. Elongation of the α-alkyl substituent of the starting material strongly affected the reactivity and enantioselectivity of the reaction.

Full text of DOI:10.1016/j.tetasy.2017.05.009

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Extractive biocatalysis in the asymmetric reduction of
enones by Baker’s yeast
a-alkyl, b-aryl
Rafaela M. Silva a, Laura T. Okano b, J. Augusto R. Rodrigues c, Giuliano C. Clososki a,b,
⇑
a Núcleo de Pesquisas em Produtos Naturais e Sintéticos, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Via do Café S/N, Ribeirão Preto-SP
14040-903, Brazil
b Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes 3900, Ribeirão Preto-SP 14040-901, Brazil
c Instituto de Química, Universidade Estadual de Campinas, Campinas-SP 13084-971, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
We prepared various chiral
the Baker’s yeast asymmetric double-bond reduction of the corresponding
a
-alkyl, b-aryl ketones with good to excellent enantiomeric excess through
,b-unsaturated substrates
adsorbed onto the resin Amberlite XAD-7. This methodology was compatible with substrates bearing
both electron-donating and withdrawing groups attached to the aromatic ring. Elongation of the -alkyl
Received 31 March 2017
Revised 11 May 2017
Accepted 16 May 2017
Available online xxxx
a
a
substituent of the starting material strongly affected the reactivity and enantioselectivity of the reaction.
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
resins are easy to handle and store and are only slightly harmful
to the environment.24–27
The development of techniques for the asymmetric synthesis of
enantiomerically enriched compounds remains a challenge for
researchers from both the academia and the industry.1–3 Knowing
that stereogenic centers are important for the biological activity of
many substances, pharmaceutical,1,4–6 agrochemical,7 food, and
fragrance8 companies have been increasingly engaged in achieving
stereochemical control during the preparation of enantiomerically
pure compounds.9–13
Biocatalysis stands out among the strategies used to produce
substances with high enantiomeric purity: various enzymes can
perform numerous synthetic procedures with high chemo-,
regio-, and enantioselectivity, which is not easy to achieve through
classic protocols of organic synthesis.6,14 Other advantages of bio-
catalysis include the possibility of conducting many reactions in
green solvents and in the absence of potentially hazardous heavy
metals, which culminates in environmentally friendly pro-
cesses.14–18
Given our interest in the development of biocatalytic protocols
for the enantioselective preparation of compounds of synthetic
interest, here we report the chemo- and enantioselective Baker’s
yeast-mediated double bond reduction of
a-alkyl-, b-aryl-unsatu-
rated ketones adsorbed onto the resin Amberlite XAD-7.20,22 The
a
-alkylketone moiety is present in a number of bioactive com-
pounds, including natural products28 and drugs29,30 and the
methodology describe herein should be an interesting strategy
for the asymmetric preparation of these compounds. More specif-
ically, optically active a-alkyl, b-aryl ketones could find application
as intermediates for the asymmetric synthesis of odorant mugue-
sia31,32 analogues.
2. Results and discussion
To investigate the bioreduction of activated double bonds bear-
ing carbonyls, we first prepared a series of a,b-unsaturated ketones
The ability of several organic substrates to inhibit enzymatic
activity is a drawback that has precluded the general use of bio-
catalysis in countless processes. To overcome this limitation, resins
emerged as a valuable tool to control the concentrations of the sub-
strate and the product in the reaction medium.19–23 In addition to
increasing the concentration of the substrate, resins can improve
the enantioselectivity and the yield of the reactions. Moreover,
for use as substrates. Thus, enones 3a-j were synthesized in yields
varying from 48% to 81% through the acid-catalyzed condensation
of aromatic aldehydes with aliphatic ketones (Scheme 1).33,34 NOE-
DIFF experiments confirmed the E-configuration of the double
bonds of the substrates.
In order to investigate how the amount of the resin Amberlite
XAD-7 influenced the conversion and enantiomeric excess of the
products, we used (E)-3-methyl-4-phenyl-3-buten-2-one 3a as
the model substrate. We conducted the screening in water
(50 mL) using 1 g of Baker’s yeast (Yeast from Saccharomyces
⇑
Corresponding author.
E-mail address: gclososki@yahoo.com.br (G.C. Clososki).
http://dx.doi.org/10.1016/j.tetasy.2017.05.009
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Silva, R. M.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.009

2
R. M. Silva et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
O
O
O
H2SO4
Ar
+
Ar
H
CH3CO2H
R1
3a-j
R1
4-24h
1a-j
25-50ºC
2
O
O
O
O
O
55%
61%
50%
3e
81%
65%
F
O
Cl
Br
3a
3d
3c
3b
3g
O
O
Br
O
O
Cl
O
N
Cl
62%
62%
66%
48%
48%
3f
3h
3j
3i
Scheme 1. Acid-catalyzed condensation of aromatic aldehydes with aliphatic ketones, to obtain enones 3a-j.
cerevisiae Type II from Sigma Aldrich) and 0.4 mmol of the sub-
strate. The reactions were incubated on an orbital shaker
(130 rpm) at 30 °C for 24 h (Scheme 2). We established the abso-
lute configuration of (S)-3-methyl-4-phenylbutan-2-one 4a by
the incubation period necessary for all the substrate to be consumed
was greater in the presence of the resin.19,22 Since we aimed to
improve stereoselectivity without significantly decreasing conver-
sion, we decided to use 0.5 g of the resin in the subsequent
experiments.
comparing the specific rotation ([
a
]TD) of this product with the data
available in the literature.33
Next, we evaluated the steric and electronic effects of sub-
stituents on the a,b-unsaturated ketones 3a-j, as shown in Table 1.
O
We monitored the reaction conversions by GC-MS and determined
the enantiomeric excess by chiral phase GC-FID. The optimized
conditions for substrate 3a (27 hours reaction) led to the desired
(S)-3-methyl-4-phenylbutan-2-one 4a in >99% conversion (42%
isolated yield) and with 81% ee (entry 1). The presence of an elec-
tron-donating group attached to the para-position of the aromatic
ring reduced both the reaction time and the selectivity. Thus, full
consumption of 3b took 48 hours and led to the expected deriva-
tive 4b with 76% ee (entry 2).
While the reactivity of substrates 3c-e could be related to the
different electron-withdrawing effect of the corresponding halo-
gens, in general, the presence of a halogen group attached to the
aromatic ring increased the enantioselectivity of the reaction. Thus,
the enantiomeric excess of 4c-e ranged from 83 to 89% ee (entries
3–5), and the chloride 3e was the best substrate in terms of enan-
tioselectivity. Moreover, chlorine at the meta- and ortho-positions
of the aromatic ring afforded higher enantiomeric excess (93 and
96% ee, entries 6 and 7, respectively). Although the presence of
bromo at the ortho-position of substrate 3h provided similar enan-
tioselectivity to the enantioselectivity observed for substrate 3g,
this substituent slowed down the reaction, and the maximum con-
version of 96% was achieved only after 168 h in the presence of an
extra amount of the enzyme (entry 8). These results indicate the
important role of the aromatic substituents in the stereo discrimi-
nation34,37–40 of the aliphatic double bond of the studied enones.
The substitution of the phenyl unit for a 2-pyridyl unit did not
change the enantioselectivity of the reaction, but it did affect the
reactivity of the substrate to a great extent—the starting hetero-
cyclic material 3i was fully converted four times faster than 3a
O
Baker´s yeast
XAD-7
H2O, 130 rpm,
30°C, 24 h
(S)-4a
3a
Scheme 2. Model reaction to study the influence of resin Amberlite XAD-7 on the
Baker’s yeast reduction of compound 3a.
In Fig. 1, comparison to the reaction performed in the absence of
the resin revealed that the enantiomeric excess of the product
increased when the substrate was adsorbed onto 0.25 g of the resin
(71 to 78% ee), while conversion of the substrate to the product
remained unaffected. Increasing the amounts of resin raised the
enantiomeric excess of the product, which reached 85% ee in the
presence of 2 g of the resin. Since the resin did not interfere in
other reaction parameters, the increased enantiomeric excess cor-
responded to a decrease in the amount of the starting material in
the aqueous phase.19–22,35,36
(entry 9). Finally, despite the longer reaction time, longer
a-alkyl
group (R1) significantly improved the enantioselectivity of the
reaction, allowing isolation of 3-benzylpentan-2-one 4j with 98%
ee. Thus, compared to the methyl group, the more pronounced
steric effect of
the molecular recognition of the active site of the enzyme.34,38 As a
result, the ,b-unsaturated carbonyl compound only underwent
a-ethyl may have elicited more interactions during
a
Fig. 1. Effect of the amount of XAD-7 on the reduction of 3a with Baker’s yeast.
reduction, with high selectivity, when it was properly seated in
the active site.
As in the case of 4a, we established the (S) configuration of 4b,
Increasing the mass of the resin from 0.5 to 2 g moderately aug-
mented the enantiomeric excess, but the conversion decreased
when the amount of resin was over 0.5 g. This was expected because
4e-g, 4i, and 4j by comparing their specific rotation data ([
a
]TD)
with the literature data.33,34 On the other hand, the absolute
Please cite this article in press as: Silva, R. M.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.009

R. M. Silva et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 1
Asymmetric reduction of 3a-j in aqueous medium by Baker’s yeast and 0.5 g of resin
O
O
Baker´s yeast
XAD-7
Ar
Ar
R1
R1
3a-j
4a-j
Entry
Product
Ar
R1
Time (h)
Conv.a
Yield (%)
([a
]TD)
Absolute configuration (ee%)b
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
27
48
48
24
72
>99
>99
>99
>99
>99
>99
>99
96
42
54
67
39
55
54
52
57
57
20
+33.7
+30.4
+16.7
+24.1
+25.1
+20.2
+46.0
+35.4
+12.9
+26.4
(S)c (81)
(S)c (76)
(S)d (83)
(S)d (85)
(S)c (89)
(S)c (93)
(S)c (96)
(S)d (92)
(S)c (81)
(S)c (98)
4-MeO-Ph
4-Br-Ph
4-F-Ph
4-Cl-Ph
3-Cl-Ph
2-Cl-Ph
2-Br-Ph
2-Py
30
48
168e
8
>99
98
4j
Ph
CH3-CH2–
168e
Conditions: 1 g of Baker’s yeast, 50 mL of water, 0.4 mmol of substrate adsorbed onto 0.5 g of the resin Amberlite XAD-7, stirring at 130 rpm, 30 °C.
a
Conversion determined by GC-MS.
b
Determined by chiral-GC-FID.
Determined by comparison of [
Inferred from the CD spectrum
c
d
e
T
a]
of products with the literature data.33,34
D
After 3 days of reaction, 1 g of S. cerevisiae yeast was added.
configuration of 4c, 4d, and 4g was determined by circular dichro-
ism using ketones (S)-4a and (S)-4c as reference compounds.
Compounds 4a-h were analyzed from 200 to 400 nm at 25 °C.
The carbonyl electronic transition n ? p⁄ was weak for all of these
compounds. However, 4a-h showed a positive circular dichroism
signal (or positive Cotton effect) because they all contained an
asymmetric carbon.41
acquire the IR spectra. The optical rotations ([
a
]TD) were measured
on a JASCO P-2000 spectropolarimeter. The melting point values
(m.p.) were obtained on a Fisatom apparatus, model 431. The
high-resolution mass spectra were obtained on a Bruker Daltonics
MicroTOF QII. Analyses of the mass spectra (GC-MS) were per-
formed on a Shimadzu QP-2010 instrument equipped with a DB-
5
MS fused silica capillary column from J&W Scientific
Since all the transformations undergone by 4c, 4d, and 4h did
not change their stereogenic centers, we were able to correlate
the known absolute configuration (S) of 4a and 4e with the com-
pounds synthesized herein.
It is worth mentioning that our results are in agreement with
those present in the literature,38 where the preference of OYE2
and OYE3 enzymes for the (S)-4 type isomers in the reduction of
(30 m  0.25 mm  25 mm). The chiral GC-FID analyses were con-
ducted on a Shimadzu GC-2014 instrument equipped with a BETA
DEXTM120 fused silica capillary chiral column from Supelco
(30 m  0.25 mm  0.25 mm). Baker’s yeast (Yeast from Saccha-
romyces cerevisiae Type II) and the resin Amberlite XAD-7 were
purchased from Sigma Aldrich. The circular dichroism (CD) spectra
were recorded on Jasco J-810 spectropolarimeter coupled to a Jasco
PTC-423S temperature control system; a quartz cell with optical
path of 1.0 cm was used at 25 °C. The baseline was acetonitrile,
the same solvent used for the solutions of compounds 4a-h at con-
centrations ranging from 2.2 to 3.0 Â 10À4 mol LÀ1. The CD spec-
trum recorded for each sample was an average of two CD spectra
with automatic baseline correction. The spectra were registered
from 400 to 200 nm at a rate of 200 nm minÀ1 in the continuous
mode.
a-alkyl, b-aryl ketones was well established.
In order to verify the occurrence of racemization during the bio-
transformation, enantiomerically enriched samples of compounds
(S)-4c, (S)-4e and (S)-4h were incubated free or adsorbed onto
the resin Amberlite XAD-7 under standard reaction conditions
but in the absence of yeast.39 After the corresponding reaction
times (48, 72 and 168 h, respectively), all samples preserved their
enantiomeric excesses.
4.2. General procedure 1 (GP-1): Synthesis of enones 3a-h
3. Conclusion
Glacial acetic acid (10 mL), 2-butanone (50 mmol), and the aro-
matic aldehyde (25 mmol) were added to a 50-mL round-bottom
flask equipped with a magnetic stirring bar, and the solution was
mixed at room temperature. Subsequently, concentrated H2SO4
(2.4 g) was added slowly, and the reaction was stirred for 4 h.
The reaction mixture was then poured onto water (50 mL), neutral-
ized with 25% aqueous NaOH, and extracted with ethyl acetate
(3 Â 50 mL). The organic layer was washed with aqueous NaHCO3
(20 mL) and brine (20 mL), and dried over MgSO4. After filtration,
the solvent was evaporated under vacuum, and the residue was
purified by column chromatography.
Adsorption of a,b-unsaturated ketones onto the resin Amberlite
XAD-7 has proven to be a noteworthy strategy to enantioselectively
reduce the double-bond of these compounds with Baker’s yeast.
This methodology is compatible with several b-aryl-substituted
substrates, and the low concentration of the substrates in aqueous
medium allowed us to isolate many chiral
a-alkylketones with
good to excellent enantiomeric excess. The scope of this methodol-
ogy as well as its application in the synthesis of naturally occurring
compounds is currently being investigated in our laboratories.
4. Experimental
4.1. General
4.2.1. (E)-3-Methyl-4-phenyl-3-buten-2-one 3a
Following GP-1, benzaldehyde 1a (2.7 g, 25 mmol) afforded 3a
(2.59 g, 65%) as a yellow solid after silica gel column chromatogra-
phy with gradient from pure hexane to hexane/ethyl acetate (9:1);
m.p. = 34–35 °C (lit.42 34.9–36.7 °C); 1H NMR (400 MHz, CDCl3) d
The 1H spectra were recorded at 400 and 500 MHz, and the 13C
NMR spectra were registered at 100 and 125 MHz on a Bruker
spectrometer.
A Shimadzu IR-Prestige-21 FT-IR was used to
Please cite this article in press as: Silva, R. M.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.009

4
R. M. Silva et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
(ppm): 7.53 (ap. q, J = 1.3 Hz, 1H), 7.44–7.33 (m, 5H), 2.48 (s, 3H),
2.07 (d, J = 1.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d (ppm):
200.3, 139.7, 137.7, 135.8, 129.7, 128.5, 128.4, 25.8, 12.9; EI-MS
m/z (% rel.): 160 (43, M+), 159 (72), 145 (26), 117 (84), 116 (24),
115 (100), 91 (43), 43 (67).
129.7, 129.4, 128.5, 127.7, 25.8, 12.9; EI-MS m/z (% rel.): 196 (6,
M++2), 194 (19, M+), 193 (18), 181 (7), 179 (21), 159 (60), 151
(26), 116 (67), 115 (100), 89 (17), 75 (12), 63 (16).
4.2.7. (E)-4-(2-Chlorophenyl)-3-methyl-3-buten-2-one 3g
Following GP-1, 2-chlorobenzaldehyde 1g (3.51 g, 25 mmol)
afforded 3g (2.33 g, 48%) as a yellow oil after silica gel column
chromatography with gradient from pure hexane to hexane/ethyl
acetate (8:2); 1H NMR (400 MHz, CDCl3) d (ppm): 7.63 (bs, 1H),
7.46–7.43 (m, 1H), 7.37–7.29 (m, 3H), 2.50 (s, 3H), 1.94 (d,
4.2.2. (E)-4-(4-Methoxyphenyl)-3-methyl-3-buten-2-one 3b
Following GP-1, 4-methoxybenzaldehyde 1b (3.4 g, 25 mmol)
afforded 3b (2.60 g, 55%) as a yellow oil after silica gel column
chromatography with gradient from pure hexane to hexane/ethyl
acetate (7:3); 1H NMR (500 MHz, CDCl3) d (ppm): 7.48 (bs,1H),
7.42 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 2.45
(s, 3H), 2.08 (d, J = 1.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) d
(ppm): 200.2, 159.9, 139.6, 135.8, 131.5, 128.4, 113.9, 55.3, 25.7,
12.9; EI-MS m/z (% rel.): 190 (44, M+), 189 (30), 176 (6), 175 (51),
159 (42), 147 (60), 146 (22), 132 (22), 131 (28), 121 (7), 117
(22), 116 (17), 115 (54), 107 (13), 104 (23), 103 (46), 102 (15),
91 (100), 89 (17), 78 (36), 77 (53), 63 (27), 51 (34).
J = 1.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d (ppm): 200.1,
139.1, 136.5, 134.2, 133.9, 130.4, 129.6, 129.5, 126.4, 25.8, 12.8;
EI-MS m/z (% rel.): 196 (0.4, M++2), 194 (1, M+), 193 (1), 179
(1), 160 (12), 159 (100), 151 (5), 116 (25), 115 (36), 89 (7), 75
(4), 63 (6).
4.2.8. (E)-4-(2-Bromophenyl)-3-methyl-3-buten-2-one 3h
Following GP-1, 2-bromobenzaldehyde 1h (4.63 g, 25 mmol)
afforded 3h (2.84 g, 48%) as an orange oil after silica gel column
chromatography with gradient from pure hexane to hexane/ethyl
4.2.3. (E)-4-(4-Bromophenyl)-3-methyl-3-buten-2-one 3c
Following GP-1, 4-bromobenzaldehyde 1c (4.63 g, 25 mmol)
afforded 3c (3.61 g, 61%) as a yellow solid after silica gel column
chromatography with gradient from pure hexane to hexane/ethyl
acetate (9:1); 1H NMR (500 MHz, CDCl3)
d (ppm): 7.64 (d,
J = 8.0 Hz, 1H), 7.57 (bs, 1H), 7.37–7.32 (m, 2H), 7.23–7.19 (m,
1H), 2.50 (s, 3H), 1.92 (d, J = 1.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d (ppm): 200.1, 138.9, 138.8, 136.0, 132.7, 130.5, 129.7, 127.1,
124.2, 25.9, 12.7; EI-MS m/z (% rel.): 240 (1, M++2), 238 (1, M+),
159 (100), 116 (43), 115 (33), 89 (9), 63 (8), 43 (36); IR (KBr)
cmÀ1: 2967, 2922, 1672, 1629, 1471, 1431,1360, 1243, 1022,
1004, 748; HRMS m/z calcd. for C11H11BrO [M+H]+: 239.0066;
found 239.0067.
acetate (8:2); m.p. = 51–53 °C; 1H NMR (400 MHz, CDCl3)
d
(ppm): 7.55 (d, J = 8.6 Hz, 2H), 7.44 (bs, 1H), 7.29 (d, J = 8.6 Hz,
13
2H), 2.46 (s, 3H), 2.03 (d, J = 1.3 Hz, 3H);
C NMR (100 MHz,
CDCl3) d (ppm): 200.0, 138.3, 138.2, 134.7, 131.7, 131.1, 122.7,
25.8, 12.9; EI-MS m/z (% rel.): 240 (14, M++2), 239 (14), 238 (14,
M+), 237 (13), 197 (8), 195 (8), 159 (66), 116 (100), 115 (67), 89
(12), 63 (11); IR (KBr) cmÀ1: 2971, 2924, 1658, 1622, 1586, 1489,
1359, 1075, 1004, 814; HRMS m/z calcd. for C11H11BrO [M+H]+:
239.0066; found 239.0068.
4.3. General procedure 2 (GP-2): Synthesis of 3i and 3j
Glacial acetic acid (36 mL), 2-alkyl ketone (50 mmol), and the
aromatic aldehyde (25 mmol) were added to a round-bottom flask
equipped with a reflux condenser, under magnetic stirring and an
N2 atmosphere. Subsequently, sulfuric acid (3.7 g) was slowly
added, and the reaction mixture was stirred at 50 °C for 24 h. After
the addition of 50 mL of water, the mixture was neutralized with
NaOH (25%) and extracted with ethyl acetate (3 Â 50 mL). The
organic phase was washed with aqueous NaHCO3 (20 mL) and sat-
urated NaCl solution (20 mL), and dried over anhydrous MgSO4.
After filtration, the solvent was evaporated under vacuum, and
the product was purified by flash column chromatography.
4.2.4. (E)-4-(4-Fluorophenyl)-3-methyl-3-buten-2-one 3d
Following GP-1, 4-fluorobenzaldehyde 1d (3.10 g, 25 mmol)
afforded 3d (3.61 g, 81%) as a brown oil after silica gel column
chromatography with gradient from pure hexane to hexane/ethyl
acetate (8:2); 1H NMR (400 MHz, CDCl3) d (ppm): 7.48 (bs, 1H),
7.44–7.39 (m, 2H), 7.14–7.08 (m, 2H), 2.46 (s, 3H), 2.04 (d,
J = 1.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d (ppm): 200.1, 162.5
1
4
(d, JC-F = 249.6 Hz), 138.4, 137.5, 131.9 (d, JC-F = 3.7 Hz), 131.6 (d,
2
3JC-F = 8.1 Hz), 115.5 (d, JC-F = 22 Hz), 25.8, 12.9; EI-MS m/z (%
rel.): 178 (43, M+), 177 (48), 163 (49), 135 (100), 133 (67), 115
(59), 109 (36), 83 (16); IR (KBr) cmÀ1: 2993, 2922, 1666, 1599,
1508, 1438, 1365, 1226, 1162, 832; HRMS m/z calcd. for
C
11H11FO [M+H]+: 179.0867; found 179.0870.
4.3.1. (E)-3-Methyl-4-(2-pyridyl)-3-buten-2-one 3i
Following GP-2, 2-pyridinecarboxaldehyde 1i (2.68 g, 25 mmol)
and 2-butanone (3.6 g, 50 mmol) afforded 3i (2.49 g, 62%) as a light
yellow solid after silica gel column chromatography with gradient
from hexane/ethyl acetate (9:1) to hexane/ethyl acetate (6:4); m.p.
= 40–42 °C; 1H NMR (400 MHz, CDCl3) d (ppm): 8.71–8.69 (m, 1H),
7.77 (dt, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.53 (ap. q, J = 1.3 Hz, 1H), 7.47
(bs, J = 7.8 Hz, 1H), 7.26 (ddd, J = 7.6 Hz, J = 4.8 Hz, J = 1.1 Hz, 1H),
2.49 (s, 3H), 2.20 (d, J = 1.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
(ppm): 200.6, 154.7, 149.2, 140.7, 137.4, 136.7, 125.6, 122.8, 26.0,
12.9; GC-MS m/z (% rel.): 161 (27, M+), 146 (3), 118 (100), 117
(55), 91 (24), 78 (11).
4.2.5. (E)-4-(4-Chlorophenyl)-3-methyl-3-buten-2-one 3e
Following GP-1, 4-chlorobenzaldehyde 1e (3.51 g, 25 mmol)
afforded 3e (2.41 g, 50%) as a light yellow solid after silica gel col-
umn chromatography with gradient from pure hexane to hexane/
ethyl acetate (9:1); m.p. = 49–50 °C (lit.42 49.4–50.0 °C); 1H NMR
(500 MHz, CDCl3) d (ppm): 7.46 (s, 1H), 7.39 (d, J = 8.6 Hz, 2H),
7.35 (d, J = 8.6 Hz, 2H), 2.46 (s, 3H), 2.03 (s, 3H); 13C NMR
(125 MHz, CDCl3) d (ppm): 199.9, 138.2, 138.1, 134.4, 134.3,
130.9, 128.7, 25.8, 12.9; EI-MS m/z (% rel.): 196 (9, M++2), 194
(24, M+), 193 (23), 181 (10), 179 (30), 159 (65), 151 (34), 116
(74), 115 (100), 89 (15), 75 (11), 63 (14).
4.3.2. (E)-3-Ethyl-4-phenyl-3-buten-2-one 3j
Following GP-2, benzaldehyde 1j (2.7 g, 25 mmol) and 2-pen-
tanone (4.3 g, 50 mmol) afforded 3j (2.69 g, 62%) as an orange oil
after silica gel column chromatography with gradient from pure
hexane to hexane/ethyl acetate (9:1); 1H NMR (400 MHz, CDCl3)
d (ppm): 7,48 (s, 1H), 7,43–7,34 (m, 5H), 2,54 (q, J = 7,3 Hz, 2H),
2,46 (s, 3H), 1,12 (t, J = 7,3 Hz, 3H). 13C NMR (100 MHz, CDCl3) d
(ppm): 200,1, 144,0, 139,4, 135,7, 129,2, 128,5, 26,1, 19,6, 13,8;
4.2.6. (E)-4-(3-Chlorophenyl)-3-methyl-3-buten-2-one 3f
Following GP-1, 3-chlorobenzaldehyde 1f (3.51 g, 25 mmol)
afforded 3f (3.19 g, 66%) as an orange oil after silica gel column
chromatography with gradient from pure hexane to hexane–ethyl
acetate (8:2); 1H NMR (400 MHz, CDCl3) d (ppm): 7.44 (bs, 1H),
7.40–7.28 (m, 4H), 2.46 (s, 3H), 2.04 (d, J = 1.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d (ppm): 199.9, 138.8, 137.8, 137.6, 134.4,
Please cite this article in press as: Silva, R. M.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.009

R. M. Silva et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
GC-MS m/z (% rel.): 174 (68, M+), 173 (80), 159 (53), 131 (93), 116
4.4.3. (S)-4-(4-Bromophenyl)-3-methyl-butan-2-one 4c
(36), 115 (49), 91 (100), 77 (23), 51 (21).
Following GP-3, enone 3c (95.2 mg, 0.4 mmol) was incubated
for 48 h to afford 4c (64.05 mg, 67%) as a yellow oil after silica
gel column chromatography with gradient from pure hexane to
hexane/ethyl acetate (9:1); 1H NMR (400 MHz, CDCl3) d (ppm):
7.40 (d, J = 8.3 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 2.95 (dd,
J = 13.6 Hz, J = 7.1 Hz, 1H), 2.84–2.75 (m, 1H), 2.52 (dd,
J = 13.6 Hz, J = 7.6 Hz, 1H), 2.09 (s, 3H), 1.09 (d, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d (ppm): 211.6, 138.7, 131.5, 130.7, 120.1,
48.6, 38.1, 28.9, 16.3; GC-MS m/z (% rel.): 242 (30, M++2), 240
(31, M+), 227 (29), 225 (29), 199 (14), 197 (15), 171 (97), 169
4.4. General procedure
reductions
3 (GP-3): S. cerevisiae mediated
The general biocatalytic conditions were water (50 mL),
Baker’s yeast (Yeast from Saccharomyces cerevisiae Type II) (1 g),
and the substrate (0.4 mmol) adsorbed onto Amberlite XAD-7
(0.5 g). The substrate was adsorbed onto the resin in a round-bot-
tom flask. Acetone (2 mL) was used as the solvent and removed
under reduced pressure. The fresh medium was preincubated
for activation on an orbital shaker at 130 rpm and 30 °C for
60 min, and then the resin-adsorbed substrate was added to the
biocatalytic medium. The reactions were incubated on an orbital
shaker (130 rpm) for 8–168 h, depending on the substrate, to
achieve maximum conversion. After the appropriate time, the
resin was filtered and washed with ethyl acetate. The filtrate
was also extracted with ethyl acetate (3 Â 50 mL). The organic
extracts were combined and dried over anhydrous MgSO4. The
solvent was evaporated in a rotary evaporator, and the products
were purified by flash chromatography on silica gel, classical sil-
ica, and preparative plate by using hexane/ethyl acetate as the
eluent.
The enantiomeric excesses were determined by GC-FID with
the aid of a chiral column BETA DEXTM120. The carrier gas was
nitrogen; the injector and the detector temperatures were kept
at 220 and 300 °C, respectively. Method 1: The oven temperature
was increased from 60 to 100 °C at 2 °C/min, kept at 100 °C for
2 min, increased to 150 °C at 0.5 °C/min, increased to 180 °C at
10 °C/min, and kept at 180 °C for 2 min. Method 2: The oven tem-
perature was increased from 60 to 100 °C at 2 °C/min, kept at
100 °C for 2 min, increased to 150 °C at 0.5 °C/min, increased to
190 °C at 10 °C/min, and kept at 190 °C for 10 min. Method 3:
The oven temperature was increased from 90 to 100 °C at 2 °C/
min, increased to 150 °C at 1 °C/min, and increased to 190 °C at
4 °C/min.
(100), 91 (25), 90 (50), 89 (42), 77 (20), 63 (25); IR (KBr) cmÀ1
:
2968, 2930, 1709, 1490, 1460, 1357, 1072, 1012, 798; HRMS m/z
calcd. for C11H13BrO [M+H]+: 241.0222; found 241.0221; Chiral
GC-FID- Method 2: [tR: 116 min (R)-4c and 116.6 min (S)-4c],
83% ee, [a]
23 = +16.7 (c 1, CHCl3) (S)-isomer.
D
4.4.4. (S)-4-(4-Fluorophenyl)-3-methyl-3-butan-2-one 4d
Following GP-3, enone 3d (71.3 mg, 0.4 mmol) was incubated
for 24 h to afford 4d (28 mg, 39%) as a yellow oil after silica gel col-
umn chromatography with gradient from pure hexane to hexane/
ethyl acetate (9:1); 1H NMR (400 MHz, CDCl3) d (ppm): 7.13–7.10
(m, 2H), 7.0–6.94 (m, 2H), 2.97 (dd, J = 13.6 Hz, J = 6.8 Hz, 1H),
2.85–2.76 (m, 1H), 2.55 (dd, J = 13.6 Hz, J = 7.6 Hz, 1H), 2.10 (s,
3H), 1.10 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d (ppm):
4
3
211.9, 135.3 (d, JC-F = 2.9 Hz), 130.3 (d, JC-F = 7.3 Hz), 115.2 (d,
2JC-F = 21.2 Hz), 48.9, 37.9, 28.9, 16.3; GC-MS m/z (% rel.): 180
(16, M+), 165 (19), 137 (11), 109 (100), 83 (12); IR (KBr) cmÀ1
:
2916, 2846, 1714, 1601, 1508, 1456, 1359, 1224, 1163, 823; HRMS
m/z calcd. for C11H13FO [M+H]+: 181.1023; found 181.1026; Chiral
GC-FID- Method 3: [tR: 32.6 min (R)-4d and 33 min (S)-4d], 85% ee,
[a]
23 = +24.1 (c 1, CHCl3) (S)-isomer.
D
4.4.5. (S)-4-(4-Chlorophenyl)-3-methyl-butan-2-one 4e
Following GP-3, enone 3e (78 mg, 0.4 mmol) was incubated for
72 h to afford 4e (43 mg, 55%) as a light yellow oil after silica gel
column chromatography with gradient from pure hexane to hex-
ane/ethyl acetate (9:1); 1H NMR (400 MHz, CDCl3) d (ppm): 7.24
(d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 2.97 (dd, J = 13.6 Hz,
J = 7.1 Hz, 1H), 2.84–2.75 (m, 1H), 2.53 (dd, J = 13.6 Hz, J = 7.3 Hz,
1H), 2.09 (s, 3H), 1.09 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d (ppm): 211.7, 138.1, 132.0, 130.3, 128.5, 48.7, 38.1, 28.9, 16.3;
GC-MS m/z (% rel.): 198 (4, M++2), 196 (12, M+), 181 (14), 153
(10), 127 (35), 125 (100), 117 (11), 115 (18), 91 (10), 89 (31), 63
(19); Chiral GC-FID- Method 1: [tR: 95 min (R)-4e and 95.6 min
4.4.1. (S)-3-Methyl-4-phenyl-butan-2-one 4a
Following GP-3, enone 3a (64 mg, 0.4 mmol) was incubated for
27 h to afford 4a (27.25 mg, 42%) as a light yellow oil after silica gel
column chromatography with gradient from pure hexane to hex-
ane/ethyl acetate (9:1); 1H NMR (400 MHz, CDCl3) d (ppm):
7.31–7.15 (m, 5H), 3.00 (dd, J = 13.5 Hz, J = 6.8 Hz, 1H), 2.89–2.80
(m, 1H), 2.58 (dd, J = 13.5 Hz, J = 7.6 Hz, 1H), 2.10 (s, 3H), 1.10 (d,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d (ppm): 212.2, 139.6,
128.9, 128.4, 126.2, 48.8, 38.9, 28.9, 16.2; GC-MS m/z (% rel.):
162 (18, M+), 147 (18), 119 (12), 91 (100), 43 (62); Chiral GC-
FID- Method 1: [tR: 56 min (R)-4a and 57.7 min (S)-4a], 81% ee;
(S)-4e], 89% ee, [
0.94, CHCl3) 99% ee, (S)-isomer.
a] [a]
23 = +25.1 (c 1, CHCl3); lit.33 23 = +27.7 (c
D D
4.4.6. (S)-4-(3-Chlorophenyl)-3-methyl-butan-2-one 4f
[
a]
D
23 = +33.7 (c 1, CHCl3); lit.33
[
a]
23 = +40.7 (c 0.9, CHCl3, 98% ee)
D
Following GP-3, enone 3f (77.9 mg, 0.4 mmol) was incubated
for 30 h to afford 4f (42.3 mg, 54%) as a colorless oil after silica
gel column chromatography with gradient from pure hexane to
hexane/ethyl acetate (9:1); 1H NMR (400 MHz, CDCl3) d (ppm):
7.23–7.15 (m, 3H), 7.05–7.02 (m, 1H), 2.99 (dd, J = 13.6 Hz,
J = 6.8 Hz, 1H), 2.86–2.77 (m, 1H), 2.52 (dd, J = 13.6 Hz, J = 7.6 Hz,
1H), 2.11 (s, 3H), 1.10 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d (ppm): 211.5, 141.8, 134.1, 129.6, 128.9, 127.2, 126.4, 48.5, 38.3,
28.8, 16.3; GC-MS m/z (% rel.): 198 (10, M++2), 196 (30, M+), 181
(22), 153 (19), 127 (34), 125 (100), 117 (14), 115 (21), 91 (12),
89 (29), 63 (15); Chiral GC-FID- Method 1: [tR: 90.3 min (R)-4f
(S)-isomer.
4.4.2. (S)-4-(4-Methoxyphenyl)-3-methyl-butan-2-one 4b
Following GP-3, enone 3b (76.1 mg, 0.4 mmol) was incubated
for 48 h to afford 4b (41.5 mg, 54%) as an orange oil after silica
gel column chromatography with gradient from pure hexane to
hexane/ethyl acetate (9:1); 1H NMR (400 MHz, CDCl3) d (ppm):
7.07 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H), 2.93
(dd, J = 13.6 Hz, J = 6.8 Hz, 1H), 2.83–2.75 (m, 1H), 2.52 (dd,
J = 13.6 Hz, J = 7.6 Hz, 1H), 2.08 (s, 3H), 1.08 (d, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d (ppm): 212.4, 157.9, 131.6, 129.8, 113.7,
55.2, 48.9, 38.0, 28.9, 16.1; GC-MS m/z (% rel.): 192 (10, M+), 121
(100), 91 (8), 77 (10). Chiral GC-FID-Method 2: [tR: 107.6 min
and 90.9 min (S)-4f], 93% ee, [
[a]
D
a]
23 = +20.2 (c 1, CHCl3); lit.33
D
21 = +22.6 (c 0.9, CHCl3) 98% ee, (S)-isomer.
(R)-4b and 108.3 min (S)-4b], 76% ee, [
a
]
23 = +30.4 (c 1, CHCl3);
4.4.7. (S)-4-(2-Chlorophenyl)-3-methyl-butan-2-one 4g
Following GP-3, enone 3g (77.9 mg, 0.4 mmol) was incubated
for 48 h to afford 4g (40.5 mg, 52%) as a yellow oil after silica gel
D
lit.33 23 = +42.1 (c 1.1, CHCl3, 98% ee) (S)-isomer.
[a]
D
Please cite this article in press as: Silva, R. M.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.009

6
R. M. Silva et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
column chromatography with gradient from pure hexane to hex-
ane/ethyl acetate (9:1); 1H NMR (400 MHz, CDCl3) d (ppm):
7.37–7.33 (m, 1H), 7.19–7.14 (m, 3H), 3.13 (dd, J = 13.6 Hz,
J = 6.4 Hz, 1H), 3.02–2.93 (m, 1H), 2.65 (dd, J = 13.6 Hz, J = 7.8 Hz,
1H), 2.13 (s, 3H), 1.10 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d (ppm): 211.9, 137.3, 134.0, 131.5, 129.6, 127.8, 126.7, 46.5, 36.5,
28.9, 16.0; GC-MS m/z (% rel.): 198 (0,4, M++2), 196 (1, M+), 181
(12), 161 (74), 153 (8), 127 (35), 125 (100), 117 (13), 115 (23),
91 (13), 89 (20), 63 (12); Chiral GC-FID- Method 1: [tR: 78.7 min
Acknowledgments
Authors thank the São Paulo Research Foundation – FAPESP
(Proc. 2015/12811-9), CNPq and CAPES for their financial support.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.05.
009.
(R)-4g and 79.6 min (S)-4g], 96% ee [
a]
23 = +46.0 (c 1, CHCl3);
D
lit.33 21 = +44.9 (c 1.1, CHCl3) 98% ee, (S)-isomer.
[a]
D
References
4.4.8. (S)-4-(2-Bromophenyl)-3-methyl-butan-2-one 4h
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Following GP-3, enone 3h (95.2 mg, 0.4 mmol) was incubated
for 168 h to afford 4h (54.8 mg, 57%) as a light yellow oil after silica
gel column chromatography with gradient from pure hexane to
hexane–ethyl acetate (9:1); 1H NMR (400 MHz, CDCl3) d (ppm):
7.54 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 7.24–7.17 (m, 2H), 7.10–7.06
(m, 1H), 3.14 (dd, J = 13.4 Hz, J = 6.6 Hz, 1H), 3.04–2.95 (m, 1H),
2.65 (dd, J = 13.4 Hz, J = 7.6 Hz, 1H), 2.13 (s, 3H), 1.10 (d,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d (ppm): 211.8, 138.9,
132.9, 131.6, 128.0, 127.3, 124.5, 46.5, 38.9, 28.9, 16.0; GC-MS m/
z (% rel.): 171 (26), 169 (27), 161 (60), 119 (20), 115 (19), 91(16),
90 (13), 89 (14), 43 (100); IR (KBr) cmÀ1: 2971, 2930, 1712,
1470, 1438, 1359, 1160, 1022, 750; HRMS m/z calcd. for C11H13BrO
[M+Na]+: 263.0041; found 263.0041; Chiral GC-FID- Method 2: [tR:
54.7 min (R)-4h and 55.2 min (S)-4h], 92% ee, [
CHCl3) (S)-isomer.
a]
27 = +35.4 (c 1,
D
4.4.9. (S)-3-Methyl-4-(2-pyridyl)-butan-2-one 4i
Following GP-3, enone 3i (64.5 mg, 0.4 mmol) was incubated
for 8 h to afford 4i (37 mg, 57%) as a brown oil after silica gel col-
umn chromatography with gradient from hexane/ethyl acetate
(6:5) to hexane/ethyl acetate (2:3); 1H NMR (400 MHz, CDCl3) d
(ppm): 8.52–8.51 (m, 1H), 7.58 (td, J = 7.8 Hz, 1.8 Hz, 1H), 7.10–
7.15 (m, 2H), 3.14–3.24 (m, 2H), 2.78–2.71 (m, 1H), 2.17 (s, 3H),
1.12 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d (ppm):
212.1, 159.5, 149.2, 136.3, 123.8, 121.3, 46.6, 40.7, 28.7, 16.4;
GC-MS m/z (% rel.): 163 (0,3, M+), 148 (30), 120 (100), 93 (45), 92
(28), 79 (13), 78 (15), 43 (34); Chiral GC-FID-Method 1: [tR:
21. Arrigo, P. D.; Fuganti, C.; Fantoni, G. P.; Servi, S. Tetrahedron 1998, 54, 15017–
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23. Nakamura, K.; Fujii, M.; Ida, Y. J. Chem. Soc., Perkin Trans. 2000, 1, 3205–3211.
24. Dafoe, J. T.; Daugulis, A. J. Biotechnol. Lett. 2014, 36, 443–460.
25. Monti, D.; Ottolina, G.; Carrea, G.; Riva, S. Chem. Rev. 2011, 111, 4111–4140.
26. Dafoe, J. T. S.; Daugulis, A. J. J. Chem. Technol. Biotechnol. 2011, 86, 1379–1385.
27. Morrish, J. L. E.; Daugulis, A. J. Biotechnol. Bioeng. 2008, 101, 946–956.
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381–389.
29. Shin, Y.; Fournier, J.-H.; Bruckner, A.; Madiraju, C.; Balachandran, R.; Raccor, B.
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63.4 min (R)-4i and 64.4 min (S)-4i] 81% ee, [
a]
26 = +12.9 (c 1,
D
CHCl3); lit.34 30 = +6.5 (c 1.77, EtOH) 49% ee, (S)-isomer.
[a]
D
32. Sprecker, M.A.; Weiss, R.A.; Hanna, M.R. US Patent 5,372,995.
33. Lu, S. M.; Bolm, C. Angew. Chem., Int. Ed 2008, 47, 8920–8923.
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4.4.10. (S)-3-Ethyl-4-phenyl-butan-2-one 4j
Following GP-3, enone 3j (69.7 mg, 0.4 mmol) was incubated
for 168 h to afford 4j (13.9 mg, 20%) as a light yellow oil after silica
gel column chromatography with gradient from pure hexane to
hexane/ethyl acetate (9:1); 1H NMR (400 MHz, CDCl3) d (ppm):
7.29–7.14 (m, 5H), 2.88 (dd, J = 12.9 Hz, J = 7.8 Hz, 1H), 2.79–2.72
(m, 1H), 2.68 (dd, J = 12.9 Hz, J = 6.3 Hz, 1H) 2.01 (s, 3H), 1.69–
1.62 (m, 1H), 1.58–1.47 (m, 1H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d (ppm): 221.5, 139.7, 128.8, 128.4, 126.2, 56.1,
37.4, 30.2, 24.5, 11.6; GC-MS m/z (% rel.): 176 (6, M+), 147 (71),
129 (9), 117 (8), 91 (100), 65 (17), 43 (54); Chiral GC-FID-Method
1: [tR: 65.2 min (R)-4j and 65.8 min (S)-4j], 98% ee, [
a]
26 = +26.4 (c
D
0.7 CHCl3); lit.33 23 = +35.8 (c 0.9, CHCl3) 98% ee, (S)-isomer.
[a]
D
42. Paula, B. R. S.; Zampieri, D. S.; Rodrigues, J. A. R.; Moran, P. J. S. Tetrahedron:
Asymmetry 2013, 24, 973–981.
Please cite this article in press as: Silva, R. M.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.009