Journal of Molecular Catalysis B: Enzymatic 126 (2016) 37–45

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Journal of Molecular Catalysis B: Enzymatic

journal homepage: www.elsevier.com/locate/molcatb

Tuning lipase-catalysed kinetic resolution of 2-substituted thiophenes

and furans: A scalable chemoenzymatic route to masked
␥-bis-oxo-alcohols
Dartagnan S.P. Ferreira a , Jeiely G. Ferreira a , Everaldo F.S. Filho b , Jefferson L. Princival a,∗
a
Departamento de Química Fundamental, Universidade Federal de Pernambuco—UFPE, Av. Jornalista Aníbal Fernandes S/Cidade Universitária, CEP:
50740-560 Recife, PE, Brazil
b
Universidade Estadual de Campinas (UNICAMP), Instituto de Química, Campinas, CP6154 SP, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: The demand for greener and applicable approaches aiming at the synthesis of optically active com-
Received 12 August 2015 pounds as single enantiomers has seen a significant growth worldwide. Since most of the chemically
Received in revised form synthesized compounds are produced as racemates their kinetic resolution has been of great interest.
28 November 2015
For this purpose a number of chemo-enzymatic approaches were proposed. One of such approaches, the
Accepted 31 January 2016
use of isolated lipases, is a well-established alternative. Herein we report the kinetic resolutions of 2-
Available online 3 February 2016
Substituted five-membered heteroaromatic rings. By optimizing the reaction conditions it was possible
to produce (2-hydroxy)-2-substituted furans and thiophenes in high enantiomeric ratio (E > 200). Thus,
Keywords:
Biocatalysis
racemic mixtures of compounds with slight structural differences were resolved. The current chemo-
Lipase enzymatic strategy has been applied to a scalable approach leading to the formation of the enantiopure
Enantiopure (S)-2i a well-known building block used for the synthesis of bioactive natural compounds.
Organic synthesis © 2016 Elsevier B.V. All rights reserved.
Building blocks

1. Introduction ful intermediates which are readily converted into 1,4-dicarbonyl

Compounds containing five-membered heteroaromatic sub-
units are important synthetic intermediates for a variety of
chemical and biochemical transformations, due to both their wide
range of biological activity [1] and great versatility, as they are
readily converted into other functional groups [2]. Thus efforts to
develop alternative approaches for the introduction of this func-
tionality into diverse organic substrates have been intensified.
Although chiral methodologies to prepare secondary alcohols con-
taining aromatic moiety is well established, the most general and
commonly used asymmetric methods of their production include
the addition of a reactive organometallic to the aldehydes using chi-
ral auxiliaries [5] or hydrogenation of ketones catalysed by chiral
ligands using boranes [6] or phosphines [7]. Alternatively, they can
be prepared using chiral heavy metal complexes [8]. While catalytic
chemical procedures can be found, commonly equimolar quantities
of chiral auxiliary or metallic salts wastes are generated.
Therefore 2-substituted furans containing secondary alcohols
should be considered as masked bis-oxo building blocks being use-
∗ Corresponding author. Fax: +55 81 21268440.
E-mail address: princivalj@yahoo.com.br (J.L. Princival).
compounds and related derivatives. Since these compounds would
be prepared asymmetrically, their use as chiral building blocks for
the synthesis of bioactive compounds in their single enantiomer
form is of great value. Examples are the total synthesis of biologi-
cally active macrolides such Citreofuran [3] and Pyrenophorin [4],
prepared from the same chiral building block (S)-2i (Fig. 1).
Despite under natural conditions, where lipases can catalyse
the hydrolysis of esters, their activity and specificity in organic
solvents should be highlighted. Moreover, with the exclusion of
water molecules hydrolysis is suppressed what has extended the
range of their application in non-aqueous systems. Thus, a variety of
lipases has been successfully used demonstrating their extraordi-
nary capability as catalysts used in the transesterification of several
unnatural substrates in chemo-enzymatic process. Therefore, the
use of isolated lipases linked to the high demand for chiral inter-
mediates in their single enantiomer form is on the rise.
Despite biocatalysis being a well-known efficient strategy to
prepare enantioenriched secondary alcohols, very few of the pub-
lished methods uses isolated lipases as catalyst in the synthesis
of heteroaromatic compounds containing furans or thiophenes [9].
Besides, the major disadvantages of these methods are the require-
ment of high times of resolutions and the obtainment of compounds
with a low enantiomeric ratio (E-value) [9a,c]. Hence, the develop-

http://dx.doi.org/10.1016/j.molcatb.2016.01.014
1381-1177/© 2016 Elsevier B.V. All rights reserved.
38 D.S.P. Ferreira et al. / Journal of Molecular Catalysis B: Enzymatic 126 (2016) 37–45

Fig. 1. Bioactive macrolides from furan (S)-2i.

ment of an efficient and general method aiming at the preparation

of these compounds with high ee using shorter time is mandatory
in order to overcome the drawbacks reported in literature.
For the above-mentioned reasons and to develop alternative
methods for the asymmetric synthesis of considerable amounts of
optically active 2-substituted ␣, ␤ and ␥-furans and thiophenes, we
were interested in develop a general method with an aim to prepare
furans and thiophenes containing enantiopure secondary alcohols. Scheme 1. Preparation of alcohols 2a–e.
Thus a behavior study of five different lipases upon nine different
substrates in enzymatic kinetic resolutions was done. Using the
current method (S)-2i, a known key intermediate on the synthesis
of natural products, was prepared in scalable quantity highlighting
the potential of the process to be used.

2. Results and discussion

2.1. Preparation of racemic substrates 2a–i

In order to prepare the racemic substrates 2a–d, a one-pot oper-

ation reaction based on literature-modified method was employed
[10]. Thus, furan and thiophene were submitted to react with n- Scheme 2. Preparation of alcohols 2f–2i.
BuLi, through ␣-deprotonation reaction, followed by treatment of
the in situ generated lithium salt with acetaldehyde or propylene Table 1
oxide. For synthesizing the propargylic alcohol 2e, a commercially Screening based on conversion of (R/S)-2i.
available ethynyl Grignard reagent was reacted with 2-furaldehyde
Entry Lipase (S)-2i (ee) (R)-3i (ee) Time (min) C (%) E
(Scheme 1).
1 CAL-B >99% >99% 15 50 >200
To synthesize the 2-substituted chain-extended analogs 2f–i a
2 A12L-A 48% 73% 15 40 10
two-step sequence reaction based on literature modified method 3 AE07 >99% >99% 60 50 >200
[11] was employed. Thus the enones 5, prepared by Aldol reaction 4 A2AE011 96% 97% 120 50 >200
between dimethyl ketone and 2-furan or 2-thiophene carboxalde- 5 PCL-G 7% >99% 15 6,5 <5
hydes, were subjected to react with NaBH4 , which have furnished
the allylic alcohols 2f and 2g after reducing only the carbonyl moi-
ety. For preparing the tetrahydro analogs 2h and 2i, 5 were treated 2.2.1. Screening of lipases
with LiAlH4 , thus both the carbonyl and the C C double bonds were For the preliminary study, the screening of the lipases was con-
reduced (Scheme 2). ducted using 2i as model substrate, vinyl acetate as acyl donor
With these short routes of achieving (Schemes 1 and 2), signifi- and pure n-hexane as non-polar organic solvent. The progress of
cant amounts of racemic substrates 2a–i could be prepared, for the the resolution was accomplished by monitoring the consumption
further enzymatic studies. of the most reactive enantiomer on the racemate. For this, solid
supported Candida antarctica lipase B chemically immobilized on
2.2. Enzymatic kinetic resolution acrylic resin (CAL-B) and the powder free enzymes: Amano Lipase
G from Penicillium camenberti (PCL-G); Lipase A amano12 (A12L-A);
For the initial studies toward the enzymatic kinetic resolution, lipase from Pseudomonas stutzeri (AE07) and lipase from Alcali-
some experimental parameters such different solvents and tem- genes spp. (A2AE011) were used. The results from the enzymatic
peratures were tested. From these results was possible to observe screening upon (R/S)-2i are depicted in Table 1.
high influence on the enzyme activity upon substrate 2i against five Conditions (R/S)-2i (0.1 mmol), CAL-B (10 mg)[5 mg/mL], vinyl-
different lipases at different conditions. acetate (0.1 mL), n-hexane (2.0 mL), 150 rpm, 25 ◦ C.
 D.S.P. Ferreira et al. / Journal of Molecular Catalysis B: Enzymatic 126 (2016) 37–45
Fig. 2. EKR of (R/S)-2i. The vertical axis is conversion and the horizontal axis
shows the time of consumption. The column from left to right demonstrates the
increase of temperature during incubation. Conditions: (R/S)-2i (0.1 mmol), CAL-B
(10 mg)/[5 mg/mL], vinyl-acetate (0.1 mL), n-hexane (2.0 mL), 150 rpm.
Analyzing the results from Table 1, is possible to infer that
among all tested lipases three of them showed to be efficient hav-
ing both high conversion (c = 50%) and excellent selectivity (E >200)
(Table 1; entries 1, 3 and 4). Refining the data CAL-B and AE07
lipases have presented better results upon (R/S)-2i if compared with
A2AE011, analysing the ee and the time of conversion.
Despite the reactions using both CAL-B and AE07 have shown
very similar enantioselectivity upon 2i, when the assay was per-
formed using CAL-B as catalyst, the reaction showed to be four
times faster (compare entries 1 with 3 on Table 1). It shows a mighty
rate of transesterification, that has needed only 15 min to be fin-
ished at 25 ◦ C. Thus, CAL-B was used for the further studies toward
temperature effect and substrate promiscuity.
The enantiopreference of CAL-B for the (R)-2i in its active site
was confirmed comparing the optical rotation value obtained for
the unreacted (S)-2i [˛]D 20 = −23.9 (c 1.0 in CHCl3 ), ee 99%, achieved
from the resolution, with the literature, where [˛]D 20 = −14.4 (c 1.2
in CHCl3 ), ee 74% is reported for (S)-(−)-2i [12].
The enantiopreference for the enantiomer (R)-2i on the active
site of the CAL-B in the transesterification reaction is in agreement
with Kazlauskas rule [13] considering methyl as small and the five
membered rings containing two CH2 spacer as large size groups,
respectively.
2.2.2. Effect of temperature
Since temperature can affect the rate of catalysed reactions, we
decided to investigate the temperature influence in order to tuning
the EKR experiments. For this, the reactions using CAL-B upon (R/S)-
Fig. 3. Monitoring EKR experiments for (R/S)-2i.
39
Fig. 4. Effect of temperature on the initial reaction rates.
2i were accomplished raising the temperatures from 25 ◦ C to 50 ◦ C.
As can be seen in the graph (Fig. 2) the effect of the temperature in
the acylation reaction rate shows a very similar behavior at the six
different temperatures in up to 15 min of reaction.
The results of this study show that if the temperature is
increased from 25 ◦ C to 35 ◦ C the reaction became to be 33% faster,
leading to the formation of the (R)-(+)-3i with 99% ee in only 10 min
of resolution. The Fig. 3 depicts the chiral GC monitoring CAL-B
catalysed experiments at 35 ◦ C upon (R/S)-2i.
As the reactions upon (R/S)-2i were carried out raging the tem-
peratures from 25 ◦ C to 50 ◦ C, the reaction activation energy could
be calculated by plotting the logarithms of the initial reaction rate
versus 1/T in a graph. Thus, a linear relationship was achieved
(R2 = 0.9888) and the Arrhenius equation could be used to deter-
mine the Ea for CAL-B against (R)-2i (Fig. 4).
The low Ea calculated (17.1 kJ/mol) can be attributed to the
immobilized CAL-B possessing lower activation energy for protein
unfolding when reacted with (R)-2i when n-hexane is used as sol-
vent, making easier the enantiomers discrimination in the active
site of the enzyme.
2.2.3. Effect of the solvent
Recently we reported the co-solvent effect on the activity of
CAL-B using n-hexane as solvent [14]. Based upon that, the enzy-
matic resolution study was performed in analytical scale evaluating
the ability of CAL-B in catalyse the acylation reaction upon (R/S)-
2i, using n-hexane and THF as solvents, at different proportions
(Table 2).
Analysing the results from Table 2 was possible to observe that
increasing the amount of THF, the reaction becomes to be slower,
even though maintaining high ee.
When the amount of the THF was increased in up to 50% the
immobilized CAL-B takes 60 min to convert the substrate, whereas
if pure THF is used 120 min was required for the same conversion.
Thus the rate of the acylated product formation was 4 and 8 times
40 D.S.P. Ferreira et al. / Journal of Molecular Catalysis B: Enzymatic 126 (2016) 37–45

Table 2
Effect of solvent on conversion of (R/S)-2i.

Entry Solvent (S)-2i (ee) (R)-3i (ee) Time (min) C (%)

1 n-hexane 99% 99% 15 50

2 n-hexane/THF (1:1) 99% 99% 60 50
3 THF 98% 99% 120 49

Fig. 5. Recycling CAL-B experiments (R/S)-2i (0.1 mmol), CAL-B (10 mg), vinyl-
acetate (0.1 mL), n-hexane (2.0 mL).

slower, respectively, if compared when pure n-hexane was used as

solvent.
As the CAL-B has proved to be high efficient on the afore men-
tioned resolutions, we decided to investigate a turnover effect, Scheme 3. Synthesis of enantiopure standards.

since an immobilized lipase could be affected on reuse. Thus, both

the enzymatic conversion and the enentioselectivity upon 2i were
analyzed (Fig. 5).
The results of this study show a significant decrease in enzyme
activity after 7 rounds of turnover.
Experimental optical rotation obtained for (S)-2b is [˛]D 25 = −21
After having tuned, the scope of compounds was expanded and
(c 2.6, CHCl3 ); ee 97% whereas [˛]D 24 = − 26 (c 1.02, CHCl3 ); ee 99%
the substrates 2a–h were subjected to EKR using n-hexane as sol-
◦ is reported for (S)-(−)-2b [18].
vent, CAL-B and 35 C as standard conditions (Table 3).
The absolute stereochemistry for the acetates (R)-3f and (R)-3g,
Results from Table 3 depict high lipase selectivity for the pro-
was determined as follows:
duction of (R)-3 when (R/S)-2 were subjected to the CALB-catalysed
Experimental optical rotation obtained for (R)-3f is [˛]D 25 = +139
experiments. Interestingly when the reactions were performed in
(c 1, CHCl3 ); ee 96% whereas [˛]D 25 = +166 (c 1.17, CHCl3 ); ee 99%
a preparative scale (3 mmol of substrate) some compounds after
is reported for (R)-(+)-3f [19].
have been acylated in moderate selectivity, started to hydrolyse
Experimental optical rotation obtained for (R)-3g [˛]D 20 = +140
back to the (S)-enantiomer. This behavior can be attributed to the
(c 9.35, CHCl3 ); ee 93% whereas [˛]D 24 = +179 (c 1.17, CHCl3 ); ee
presence of residual water on the system either in the enzyme or
97% is reported for (R)-(+)-3g [19].
solvent [16]. Nonetheless, the selective hydrolysis of undesired (S)-
To determine the absolute configuration for those compounds
3 enantiomers turning back into alcohols (S)-2 has helped and was
that have not been reported previously in the literature or in case
used to enhance the ee for either (S)-2 and (R)-3 on the end of the
of some known compounds that have no optical rotation analysis
resolution.
characterized in details, strategic chemical reactions were made
In summary CAL-B has proved to be a very efficient biocatalyst
preparing enantiopure standards and comparing their optical rota-
resolving (R/S)-2a–i, leading to the formation of enantioenriched
tion data with compounds from the EKR (Scheme 3). Therefore the
compounds containing different chain-extended sizes with excel-
absolute configuration for (S)-2c [˛]D = +20.8 (c 4.0, CHCl3 ); ee 94%
lent esterification rate (degree of conversion) and selectivity
and (S)-2d [˛]D 25 = +20 (c 1, CH2 Cl2 ); ee >99% from the EKR was
(E-value). With this, seven of the ten substrates have been acylated
confirmed comparing the data obtained with standards prepared
by 60 min of reaction, especially (R)-2h and (R)-2i requiring only
from commercial available enantiopure (S)-propylene oxide.
10 min to be 50% converted into their respective acetates. Despite
The stereochemical assignment for the resolved compound
2b and 2f have taken longer time to be resolved both free alcohols
(S)-2e was indirectly done submitting this compound to the hydro-
and their acetates were achieved in excellent ee.
genation reaction in the presence of catalytic Pd/C in MeOH,
comparing the experimental optical rotation obtained with the lit-
2.3. Determination of the absolute configuration erature for (S)-4 [20].
Finally the achievement of the absolute configuration for com-
To confirm the absolute stereochemistry for the resolved known pound (S)-3h was done comparing the resulted (S)-3h, prepared
compounds, the assignments were immediately done by compar- from (S)-2g as describe in Scheme 3 (Eq. 3), with the standard
ing the obtained experimental specific rotation with the literature. prepared from EKR (Table 2, entry 8).
Thus the proof of the stereochemistry for the free alcohols (S)-2a The absolute stereochemistry confirmation for all compounds
and (S)-2b, the less reactive enantiomers in the kinetic resolution provided from kinetic resolution have been proved to be (R)-3a–i
of (R/S)-2a and (R/S)-2b respectively, was determined as follows: while for unreacted enantiomer from substrates was assigned as
Experimental optical rotation obtained for (S)-2a is [˛]D 25 = −20 (S)-2a–i. Actually, the present chemoenzymatic approach is being
(c 1, CHCl3 ); ee >99% whereas [˛]D 25 = − 20.1 (c 1, CHCl3 ); ee 98% is expanded for synthesize some poly-functionalized five members
reported for (S)-(−)-2a [17]. heterocycles possessing biochemical relevance.
 D.S.P. Ferreira et al. / Journal of Molecular Catalysis B: Enzymatic 126 (2016) 37–45 41

Table 3
Enzymatic kinetic resolution of (R/S)-2 catalysed by CAL-B.

Entry Substrate (S)-2a–i Time (min) C* (%) O.R.** (3a–j) O.R.** E***

1 (R/S)-2a 60 50 [˛]D = −20◦ (ee > 99%) [˛]D = +154◦ (ee >99%) > 200

2 (R/S)-2b 300 50 [˛]D = −21◦ (ee 97%) [˛]D = + 114◦ (ee >99%) > 200

3 (R/S)-2c 45 50 [˛]D = +20.8◦ (ee 94%) [˛]D = + 6◦ (ee 91%) > 200

4 (R/S)-2d 30 50 [˛]D = +20◦ (ee >99%) [˛]D = + 7◦ (ee >99%) > 200

5 (R/S)-2e 60 50 [˛]D = +19◦ (ee 95%) [˛]D = + 34◦ (ee 98%) > 200

6 (R/S)-2f 120 51 [˛]D = −28◦ (ee >99%) [˛]D = +139 (ee 96%) > 200

7 (R/S)-2g 30 50 [˛]D = −29◦ (ee 92%) [˛]D = +140 (ee 93%) > 200

8 (R/S)-2h 10 50 [˛]D = +14.5◦ (ee 99%) [˛]D = +7.5◦ (ee >99%) > 200

9 (R/S)-2i 10 50 [˛]D = −23.9◦ (ee 99%) [˛]D = −3.4◦ (ee >99%) > 200

Conditions: (R/S)-2 (3 mmol), CAL-B [5 mg/mL], vinyl-acetate (0.3 mL), n-hexane (15 mL), 150 rpm at 35 ◦ C.
*
Chiral GC analysis gave ees - and eep -values from which the degree of conversion was determined according to c = ees /(ees + eep ).
**
Optical Rotation measured from isolated compounds after purification on column.
ln[1−c {1+ee(p)}]
***
The enantiomeric ratio (E) was calculated using the eq. E = [15].
ln[1−c {1−ee(p)}]

3. Experimental
3.1. General
All the solvents used in the reactions were previously purified
by distillation prior to use. In the case of dry THF (used to gen-
erate the organometallic reagents), the solvent was dried under
reflux in the presence of metallic sodium using benzophenone
as indicator. The commercially available ethynyl magnesium bro-
mide, thiophene or furane carboxaldehydes and propylene oxide
were obtained from Aldrich Chemical Co. (Milwaukee, WI, USA) and
used without further purification while furan and thiophene were
freshly distilled prior to use. The Amano Lipase G from P. camen-
berti (PCL-G) and Novozym 435 (lipase B from C. antarctica) were
purchased from Sigma (St. Louis, MO) whereas Lipase A amano12
(A12L-A) were purchased from Amano Enzymes Co. (Japan). The
Lipases P. stutzeri (AE07) and Alcaligenes spp. (A2AE011) were
kindly donated by Mann Associates—Cambridge. The TLC analyses
were performed using aluminum TLC Plates 20 × 20 cm on silica gel
60 of MACHEREY-NAGEL® .
The 1 H at 300 MHz and 13 C at 75 MHz NMR analysis were
performed on a VARIAN® Unity Plus-300 (300 MHz) spectrom-
eter, using deuterated chloroform (CDCl3 ) as solvent and Me4 Si
as internal standard. The chemical shifts were expressed in ppm
and coupling constants (J) are in Hz. Optical rotations were mea-
sured using a JASCO® P-2000 polarimeter. The chiral-GC analysis
were performed by using a SHIMADZU® 2010 Plus chromato-
graph coupled with an auto sampler using a flame ionization
42 D.S.P. Ferreira et al. / Journal of Molecular Catalysis B: Enzymatic 126 (2016) 37–45
detector (FID) using N2 as the carrier gas. For the enantiomers
analysis a Supelco BetaDexTM 120 (␤-cyclodextrin packing) chi-
ral capillary column (30 m × 0.25 mm × 0.25 ␮m) was used. The
resolutions were carried out on a TECNAL® orbital shaker stirrer
TE-424 with temperature control. The GCMS analysis were done in
a SHIMADZU® GC-17A Gas Chromatography System, coupled to a
GCMS-QP5000 detector using Ar as the carrier gas and Agilent J&W
DB-5 capillary column (30 m × 0.25 mm × 0.25 ␮m) as non-polar
column.
3.2. Synthesis of racemic alcohols 2a–i and acetates 3a–i
3.2.1. General procedure for the preparation of alcohols
(R/S)-2a–d
To a round bottomed flask containing a solution of furan or thio-
◦
phen (33 mmol) in dry THF (150 mL) at −78 C using N2 atmosphere
under stirring, n-butyl lithium (33 mmol from 36 mL of 0.92 mol/L
solution in hexane) was drop wise added. After stirring the solution
at the same temperature for 30 min the appropriate electrophile
(acetaldehyde or propylene oxide) (30 mmol) was added in one
◦
portion. The reaction was warmed to 0 C quenched with a satu-
rated solution of NH4 Cl (50 mL) and the aqueous phase extracted
with ethyl acetate (2 × 50 mL). The organic phase was washed with
brine, dried over magnesium sulphate, filtered off and the solvents
removed in a rotary evaporator under vacuum. The crude was puri-
fied by chromatography on silica gel using a mix of n-hexane/ethyl
acetate (4:1) as eluent.
3.2.1.1. (R/S)-1-(2-furyl) ethanol, (R/S)-2a. Colorless oil yield 2.7 g
(80%); CAS NR. 4208-64-4. 1 H NMR (300 MHz, CDCl3) ␦ 1.53 (d, J
3 6.6 Hz, 3H), ␦ 2.16 (s, 1H), ␦ 4.87 (q, J 3 6.6 Hz, 1H), ␦ 6.22 (d, J 3
3.3 Hz, 1H), ␦ 6.32 (dd, J 3 1.8 Hz, J 3 3.3 Hz, 1H), ␦ 7.39 (d, J 3 1.8 Hz,
1H). 13 C NMR (75 MHz, CDCl3) ␦ 21, 63, 105, 110, 141, 157. IV (Neat,
cm-1): 699; 1069; 2929; 2976; 3357. MS m/z (rel int.): 112 [M+] (2),
95 (100), 81 (30), 67 (20), 55 (6), 43 (8), 41 (14).
3.2.1.2. (R/S)-1-(2-thienyl)-ethanol, (R/S)-2b. Colorless oil, yield
2.94 g (77%); CAS NR. 2309-47-9. 1 H NMR (300 MHz, CDCl3, ppm):
␦ 1.58 (d, J 3 6.3 Hz, 3H); ␦ 2.33 (s, 1H); ␦ 5.1 (q, J 3 6.3 Hz, 1H);
␦ 6.95 (d, J 3 2.1 Hz, 1H); ␦ 6.96 (d, J 3 4.2 Hz, 1H); ␦ 7.23 (dd, J 3
2.1 Hz, J 3 4.2 Hz, 1H). 13 C NMR (75 MHz, CDCl3, ppm) 25, 66, 123,
124, 126, 149. IV (Neat, cm-1): 699; 1069; 2929; 2976; 3357. MS
m/z (rel int.): 128 [M+] (30), 113 (64), 85 (100), 45 (24).
3.2.1.3. (R/S)-1-(2-furyl)-2-methyl propanol, (R/S)-(2c). Colorless
oil, yield 1.95 g (53%); CAS NR. 66040-54-8. 1 H NMR (400 MHz,
CDCl3, ppm) ␦ 1.21 (d, J 3 6.2 Hz, 3H); ␦ 2.23 (s, 1H); ␦ 2,63–2,84
(m, 2H); ␦ 4.1 (qt, J 3 6.2 Hz, J 3 5.7 Hz 1H); ␦ 6.09 (dd, J 3 3 Hz; J 4
0.8 Hz, 1H); ␦ 6.29 (dd, J 3 3 Hz; J 4 0.8 Hz, 1H); ␦ 7.32 (dd, J 3 2 Hz;
J 4 0.8 Hz, 1H). RMN 13 C (100 MHz, CDCl3, ppm) 22; 37; 66; 106;
110; 141; 152. IV (Neat, cm-1) 728; 1147; 2931; 2972; 3372. MS
m/z (rel int.): 126 [M+] (18), 82 (100), 53 (24), 45 (32).
3.2.1.4. (R/S)-1-(2-thienyl)-2-methyl propanol, (R/S)-2d. Colorless
oil, yield 2.1 g (50%); CAS NR. 62119-81-7. 1 H NMR (300 MHz,
CDCl3, ppm) ␦ 1.26 (d, J 3 6.3 Hz, 3H); ␦ 1.8 (s, 1H); ␦ 2.94 (ddd,
J 3 14 Hz; J 3 6.1 Hz, 2 H); ␦ 3.9–4 (m, 1H); ␦ 6.87 (dd, J 3 3.6 Hz, J
4 1.2 Hz, 1H); ␦ 6.96 (dd, J 3 5.1 Hz, J 3 3.6 Hz, 1H), ␦ 7.18 (dd, J 3
5.3 Hz, J 4 1.2 Hz, 1H). RMN 13 C (100 MHz, CDCl3, ppm) 22, 39, 68,
124, 125, 126, 140. IV (Neat, cm-1) 694, 1120, 1375, 1439, 2930,
2970, 3365. MS m/z (rel int.): 142 [M+] (8), 97 (100), 53 (7), 45 (26).
3.2.2. General procedure for the preparation of alcohol (R/S)-2e
To a round bottomed flask containing a solution of 2-furan car-
boxaldehyde (10 mmol) in THF (20 mL) at −78 ◦ C under dry N2
atmosphere was drop wise added ethynyl magnesium bromide
(11 mmol from 22 mL of 0.5 mol/L solution in THF). After stirring
the solution at the same temperature for 45 min the reaction was
warmed to 0 ◦ C quenched with a saturated solution of NH4 Cl (5 mL)
and the phases were separated. The aqueous phase was extracted
with ethyl acetate (2 × 10 mL) washed with brine, dried with mag-
nesium sulphate, filtered off and the solvents removed in a rotary
evaporator under vacuum. The crude was purified by chromatog-
raphy on silica gel using a mix of n-hexane/ethyl acetate (6:1) as
eluent.
3.2.2.1. (R/S)-1-(2-furyl)-1-ethynyl propynol, (R/S)-2e. Pale yellow
oil, yield 0.96 g (78%); CAS NR. 695-82-9. 1 H NMR (400 MHz, CDCl3,
ppm): ␦ 2.62 (d, J 4 2.4 Hz, 1H); ␦ 2.80 (s, 1H); ␦ 5.45 (d, J 4 2.4 Hz,
1H); ␦ 6.35 (dd, J 3 1.8 Hz, J 3 3.2 Hz, 1H); ␦ 6.46 (dd, J 3 3.2 Hz, 1H);
␦ 7.41 (d, J 4 0.9 Hz, dd, J 3 1.8 Hz, 1H). RMN 13 C (100 MHz, CDCl3,
ppm) 57, 74, 81, 108, 110, 143, 152. IV (Neat, cm-1) 744, 1010, 2124,
2884, 3293. MS m/z (rel int.): 122 [M+] (96), 105 (82), 94 (51), 77
(38), 66 (100), 51 (53).
3.2.3. General procedure for the preparation of alcohols (R/S)-2f-g
To a round bottomed flask equipped with a drying tube (CaCl2 )
containing a solution of enone 5a or 5b (10 mmol) in ethyl alcohol
◦
(15 mL) at 0 C was added NaBH4 (15 mmol, 0.6 g). After stirring
the solution at the same temperature for 10 min the reaction was
warmed to room temperature and stirred for 20 min before be
quenched with a saturated solution of NH4 Cl (20 mL). The phases
were separated and the aqueous phase extracted with ethyl acetate
(2 × 30 mL) washed with brine, dried with magnesium sulphate and
filtered off. The organic solvent was removed in a rotary evaporator
under vacuum and the crude purified by chromatography on silica
gel using a mix of n-hexane/ethyl acetate (4:1) as eluent.
3.2.3.1. (R/S)-4-(2-furyl)-3-buten-2-ol, (R/S)-2f. Pale yellow oil
yield 1.36 g (99%); CAS NR. 4229-85-0. 1 H NMR (300 MHz, CDCl3 ,
ppm) ␦ 1.35 (d, J 3 6.6 Hz, 3H); ␦ 1.85 (s, 1H); ␦ 4.38 (quint., J 3 6.6 Hz,
1H); ␦ 6.20 (dd, J 3 15 Hz; J 3 6.6 Hz, 1H); ␦ 6,23 (d, J 3 3.9 Hz, 1H);
␦ 6.3 (m, 1H); ␦ 6.4 (d, J 3 15 Hz, 1H); ␦ 7.34 (B(s), 1H). RMN 13 C
(75 MHz, CDCl3, ppm) 23, 68, 108, 111, 117, 132, 141, 152. IV (Neat,
cm−1 ) 734, 1013, 2973, 3357. MS m/z (rel int.): 138 [M+] (73), 123
(18), 95 (100), 91 (32), 81 (76), 77 (29), 67 (40), 55 (31), 43 (48).
3.2.3.2. (R/S)-4-(2-thienyl)-3-buten-2-ol, (R/S)-2g. Colorless oil
yield 1.54 g (100%); CAS NR. 613684-31-4. 1 H NMR (300 MHz,
CDCl3 , ppm) ␦ 1.38 (d, J 3 6.3 Hz, 3H); ␦ 1.74–2.10 (Bs, 1H); ␦ 4.44
(p, J 3 6.3 Hz, 1H); ␦ 6.10 (dd, J 3 15.6 Hz; J 3 6.3 Hz, 1H); ␦ 6.69 (d, J
3 15.6 Hz, 1H); ␦ 6.95 (d, J 3 3.6 Hz, 1H); ␦ 6.95 (d, J 3 1.8 Hz, 1H); ␦
7.15 (dd, J 3 3.6 Hz; J 3 1.8 Hz, 1H). RMN 13 C (100 MHz, CDCl3, ppm)
23, 68, 122, 124, 125, 127, 133, 141. IV (Neat, cm−1 ) 694, 1369,
2972, 3333. MS m/z (rel int.): 154 [M+] (46), 135 (52), 111 (88), 97
(100), 91 (29), 77 (27), 55 (35), 43 (22).
3.2.4. General procedure for the preparation of alcohols
(R/S)-2h-i
To a round bottomed flask containing a suspension of LiAlH4
(30 mmol, 1.14 g) in dry THF (30 mL) at 0 ◦ C was drop wise added
the enone 5a or 5b (15 mmol). After stirring for 2 h at room tem-
perature the mixture was cooled to 0 ◦ C and an aqueous solution
of NaOH (20% m/m) was slowly added. The white solid formed was
filtered off and the resulting solution was dried with Na2 SO4 and
concentrated in a rotary evaporator under vacuum. The products
were purified by distillation in a Kugelrohr.
3.2.4.1. (R/S)-4-(2-thienyl)-2-butanol, (R/S)-2h. Colorless oil, yield
1.65 g (70%); CAS NR. 613684-31-4 1 H NMR (300 MHz, CDCl3, ppm)
␦ 1.24 (d, J 3 6.3 Hz, 3H); 1.78–1.88 (m, 2H); ␦ 2.03 (s, 1H); ␦ 1.83 (q,
J 3 7.3, 2H); ␦ 2.94 (dtd, J 3 6.3 Hz, J 3 7.5 Hz, J 3 15 Hz, 2H); ␦ 3.86
 D.S.P. Ferreira et al. / Journal of Molecular Catalysis B: Enzymatic 126 (2016) 37–45
(sext., J 3 6.3 Hz, 1H); ␦ 6.81 (dd, J 3 3.3 Hz, J 4 0.9 Hz, 1H); ␦ 6.92
(dd, J 3 3.3; J 3 5.1 Hz, 1H); ␦ 7.1 (dd, J 3 5.1, J 4 0.9 Hz, 1H). RMN 13 C
(75 MHz, CDCl3, ppm) 23, 26, 40, 67, 123, 124, 126, 144. IV (Neat,
cm-1) 693, 1639, 2927, 2966, 3412. MS m/z (rel int.): 156 [M+] (22),
138 (25), 123 (100), 97 (62), 84 (12), 77 (8), 53 (9), 45 (27).
3.2.4.2. (R/S)-4-(2-furyl)-2-butanol, (R/S)-2i. Colorless oil, yield
1.26 g (60%); CAS NR. 6963-39-9 1 H NMR (300 MHz, CDCl3, ppm) ␦
1.22 (d, J 3 6.3 Hz, 3H); ␦ 1.83–1.73 (m, 2H); ␦ 2.12 (s, 1H); ␦ 2.73
(dq, J 3 6.3 Hz, J 3 15.3 Hz, 2H); ␦ 3.83 (sext., J 3 6.3 Hz, 1H); ␦ 6.0
(dd, J 4 0.6 Hz, J 3 3 Hz, 1H); ␦ 6.27 (dd, J 3 1.2 Hz, J 3 3 Hz 1H); ␦
7.29 (dd, J 4 0.6 Hz, J 3 1.2 Hz, 1H). RMN 13 C (75 MHz, CDCl3, ppm)
23, 24, 37, 67, 104, 110, 140, 155. IV (Neat, cm-1) 730, 1007, 1638,
1598, 2928, 2967, 3404. MS m/z (rel int.): 140 [M+] (32), 122 (52),
109 (76), 81 (100), 77 (18), 68 (14), 53 (28), 45 (18).
3.2.5. General procedure for the preparation of acetates (R/S)-3a-i
To a round bottomed flask containing the respective alcohol
(1 mmol) in DCM (2 mL) at room temperature and using dry N2
atmosphere, under stirring, acetic anhydride (1.1 mmol) and DMAP
(cat) were sequentially added. After stirring the solution at same
temperature for 30 min the crude reaction was quenched with sat-
urated solution of NaHCO3 (1 mL). The phases were separated and
the aqueous phase was extracted with DCM (2 × 2 mL) washed with
brine, dried over magnesium sulphate, filtered off and the solvent
removed in a rotary evaporator under vacuum. The crude was puri-
fied by chromatography on silica gel using a mix of n-hexane/ethyl
acetate (10:1) as eluent.
3.2.5.1. (R/S)-1-(2-furyl)-ethyl acetate, (R/S)-3a. Colorless oil, yield
0.15 g (100%); CAS NR. 22426-24-0 1 H NMR (300 MHz, CDCl3, ppm)
␦ 1.57 (d, J 3 6.9 Hz, 3H), ␦ 2.04 (s, 3H), ␦ 5.95 (q, J 36.9 Hz, 2H), ␦
6.31 (d, J 33.3 Hz, 1H), ␦ 6.32 (dd, J 3 2.1 Hz, J 3 3.3 Hz, 1H), ␦ 7.37
(d, J 3 2.1 Hz, 1H). 13 C NMR (75 MHz, CDCl3, ppm) 18, 21, 65, 107,
110, 142, 153, 170. IV (Neat, cm-1) 1232, 1738, 2939, 2990. MS m/z
(rel int.): 154 [M+] (28), 112 (66), 95 (100), 66 (65), 55 (8), 43 (78).
3.2.5.2. (R/S)-1-(2-thienyl)-ethyl acetate, (R/S)-3b. Colorless oil,
yield 0.17 g (100%); CAS NR. 22426-23-9. 1H NMR (300 MHz, CDCl3,
ppm) ␦ 1.67 (d, J 3 6.6 Hz, 3H); ␦ 2.09 (s, 3H); ␦ 6.2 (q, J 3 6.6 Hz,
1H); ␦ 6.99 (dd, J 3 3.3 Hz; J 3 4.5 Hz, 1H); ␦ 7.09 (d, J 3 3.3 Hz, 1H);
␦ 7.29 (d, J 3 4.5 Hz, 1H). 13C NMR (75 MHz, CDCl3, ppm) 21, 22, 67,
125.1, 125.2, 126, 144, 170. IV (Neat, cm-1) 1732, 2985, 3111. MS
m/z (rel int.): 170 [M+] (1), 128 (80), 110 (100), 84 (21), 77 (20), 66
(24), 45 (18), 43 (45).
3.2.5.3. (R/S)-1-(2-furyl)-propan-2-yl acetate, (R/S)-3c. Colorless
oil, yield 0.18 g (99%); CAS NR. 102422-76-4. 1H NMR (400 MHz,
CDCl3, ppm) ␦ 1.25 (d, J 3 6.4 Hz, 3H); ␦ 2.01 (s, 3H); ␦ 2. 87 (ddd, J 3
6.4 Hz, 15 Hz, 2H); ␦ 5.14 (sext, J 3 6.4 Hz, 1H); ␦ 6.06 (dd, J 4 0.6 Hz,
J 3 2.4 Hz, 1H); ␦ 6.28 (dd, J 3 1.2 Hz, J 3 2.4 Hz, 1H); ␦ 7.31 (dd, J
4 0.6 Hz, J 3 1.2 Hz, 1H). 13C NMR (100 MHz, CDCl3, ppm) 19, 21,
34, 69, 106, 110, 141, 151, 170. IV (Neat, cm-1) 1243; 1373; 1740;
2983. MS m/z (rel int.): 168 [M+] (1), 108 (100), 81 (38), 66 (2), 53
(12), 43 (100)
3.2.5.4. (R/S)-1-(2-thienyl)-propan-2-yl acetate, (R/S)-3d. Colorless
oil, yield 0.18 g (100%); 1H NMR (400 MHz, CDCl3, ppm) ␦ 1.25 (d,
J 3 6 Hz, 3H); ␦ 2.04 (s, 3H); ␦ 3.05 (ddd, J 3 15 Hz, J 3 6.2 Hz, 1H);
␦ 5.2–5.0 (m, 1H); ␦ 6.83 (d, J 3 3.6 Hz, 1H); ␦ 6,93 (dd, J 3 5.2 Hz; J
3 3.3 Hz, 1H); ␦ 7.15 (d, J 3 5.2 Hz, 1H). RMN 13C (100 MHz, CDCl3,
ppm) 19, 21, 35, 70, 124, 125, 126, 139, 170. IV (Neat, cm-1) 1738;
2981. MS m/z (rel int.): 184 [M+] (0.5), 124 (100), 97 (70), 43 (90).
3.2.5.5. (R/S)-1-(2-furyl)-2-propyn-1-yl acetate, (R/S)-3e. Pale yel-
low oil, yield 0.16 g (100%); CAS NR. 19275-25-3. 1H NMR (400 MHz,
43
CDCl3, ppm) ␦ 2.13 (s, 3H); ␦ 2.64 (d, J 3 2.3 Hz, 1H); ␦ 6.4 (dd, J 3
1.6 Hz, J 3 3.3 Hz, 1H); ␦ 6.51 (d, J 3 2.3 Hz, 1H); ␦ 6.58 (d, J 3 3.3 Hz,
1H). ␦ 7.45 (dd, J 3 0.9 Hz, J 3 1.6 Hz, 1H) RMN 13C (100 MHz, CDCl3,
ppm) 22; 37; 6 6; 106; 110; 141; 152. IV (Neat, cm-1) 1223; 1743;
2130; 2960; 3291. MS m/z (rel int.): 164 [M+] (14), 122 (43), 105
(100), 76 (60), 51 (37), 43 (29).
3.2.5.6. (R/S)-4-(2-furyl)-3-buten-2-yl acetate, (R/S)-3f. Pale yellow
oil, yield 0.18 g (100%); CAS NR. 97602-78-3.1H NMR (400 MHz,
CDCl3, ppm) ␦ 1.38 (d, J 3 6.5 Hz, 3H); ␦ 2.06 (s, 3H); ␦ 5.48 (quint,
J 3 6.5 Hz, 2H); ␦ 6.11 (dd, J 3 15.9 Hz, J 3 6.6 Hz, 1H); ␦ 6,25 (d, J
3 3.3 Hz, 1H); ␦ 6.36 (dd, J 3 3.3 Hz; J 3 1.5 Hz, 1H); ␦ 6.41 (d, J 3
15,9 Hz, 1H), ␦ 7.34 (d, J 3 1.5 Hz, 1H). RMN 13C (100 MHz, CDCl3,
ppm) 20, 21, 70, 108, 111, 119; 127, 143, 151, 170. IV (Neat, cm-1)
1738; 2983. MS m/z (rel int.): 180 [M+] (41), 137 (32), 121 (42), 95
(23), 91 (72), 77 (26), 65 (19), 55 (10), 43 (100).
3.2.5.7. (R/S)-4-(2-thienyl)-3-buten-2-yl acetate, (R/S)-3g. Color-
less oil, yield 0.19 g (100%); CAS NR. 709655-12-9. 1H NMR
(300 MHz, CDCl3, ppm) ␦ 1.39 (d, J 3 6.6 Hz, 3H); ␦ 2.07 (s, 3H);
␦ 5.48 (dd, J 3 6.3 Hz, J 3 6.6 Hz, 1H); ␦ 6.01 (dd, J 3 15.6 Hz, J 3
6.3 Hz, 1H); ␦ 6.73 (d, J 3 15.6 Hz, 1H); ␦ 6.92–6.99 (m, 2H); ␦ 7.17
(dd, J 3 4.5 Hz, J 3 1.2 Hz 1H). RMN 13C (75 MHz, CDCl3, ppm) 20, 21,
70, 124, 125, 126, 127, 128, 141, 170. IV (Neat, cm-1) 1646; 1731;
2982. MS m/z (rel int.): 196 [M+] (0.2), 135 (100), 121 (13), 111 (23),
97 (48), 91 (43), 77 (13), 65 (14), 45 (17), 43 (82).
3.2.5.8. (R/S)-4-1-(2-thienyl)-butan-2-yl acetate, (R/S)-3h. Color-
less oil, yield 0.19 (96%). 1H NMR (300 MHz, CDCl3, ppm) ␦ 1.25
(d, J 3 6,3 Hz, 3H); ␦ 1,92 (m, 2H); ␦ 2.04 (s, 1H); ␦ 2.87 (m, 2H);
␦ 4.96 (m, 1H); ␦ 6.79 (dd., J 3 1,0 Hz, J 3 3.4 Hz, 1H); ␦ 6.91 (dd., J
3 3.4 Hz, J 3 5.1 Hz, 1H); ␦ 7.41 (dd., J 3 1,0 Hz, J 3 5.1 Hz, 1H), 1H;.
RMN 13C (75 MHz, CDCl3, ppm) 20, 21, 25,37, 70, 123, 124, 126,
144, 170. MS m/z (rel int.): 198 [M+] (1), 138 (55), 123 (100), 97
(45), 43 (28).
3.2.5.9. (R/S)-4-(2-furyl)-butan-2-yl acetate, (R/S)-3i. Colorless oil,
yield 0.18 g (100%); CAS NR. 105827-42-7. 1H NMR (300 MHz,
CDCl3, ppm) ␦ 1.23 (d, J 3 6.3 Hz, 3H); ␦ 1.81–1.97 (m, 2H); ␦
1.77–1.95 (m, 1H); ␦ 2,02 (s, 1H); ␦ 2.60–2.72 (m, 1H); ␦ 4.84–5.01
(m,1H); ␦ 5.98 (dd, J 4 0.6 Hz, J 3 3 Hz 1H); ␦ 6.26 (dd, J 3 1.2 Hz, J 3
3 Hz, 1H); ␦ 7.29 (dd, J 4 0.6 Hz, J 3 1,2 Hz, 1H). RMN 13C (75 MHz,
CDCl3, ppm) 19, 21, 24, 34, 70, 104, 110, 140, 155, 170. MS m/z (rel
int.): 198 [M+] (0.5), 122 (100), 107 (98), 93 (20), 81 (60), 66 (10),
53 (18), 43 (52).
3.3. General procedure for the lipase-catalysed resolution
The enzymatic kinetic resolutions were carried out on a
TECNAL® orbital shaker stirrer TE-424 with temperature control
at 150 rpm, using a substrate solutions ranging from 50 mM to
200 mM and nearly equimolar quantities of vinyl acetate as acyl
donor in an appropriate Erlenmeyer flask capped with red rubber
septa. A control reaction containing no enzymatic catalyst was held
taking aliquots at different times concomitantly to the resolution.
To accomplish the progress of the reactions, at each time an aliquot
(100 ␮L) was taken, filtered off on silica and injected, by using an
auto sampler, on a GC equipped with a chiral column (split 1/100)
for analysis. All the aforementioned were made in triplicate.
3.3.1. Analytical scale enzymatic resolution
To an Erlenmeyer flask with capacity for 10 mL containing
n-hexane (2 mL), racemic substrate 2i (0.1 mmol)[50 mM] and
vinyl acetate (0.11 mmol)[5 mM] was added the respective enzyme
(10 mg). The crude reaction was stirred at 150 rpm on an orbital
stirrer (25 ◦ C) until half of substrate consumption. The times of the
44 D.S.P. Ferreira et al. / Journal of Molecular Catalysis B: Enzymatic 126 (2016) 37–45
resolution were from 15 to 120 min (see Table 1) depending of each
enzyme. After 50% conversion the reaction medium was filtered off
on a Pasteur pipette containing silica and concentrated in a rotary
evaporator. The crude containing the unreacted enantiomer (S)-2i
and the acetate (R)-3i were purified by chromatography on silica
gel using a mix of n-hexane/ethyl acetate (10:1) as eluent.
3.3.2. General procedure for the enzymatic resolution on
preparative scale
On a preheated orbital stirrer (35 ◦ C) was placed an Erlen-
meyer flask with capacity for 50 mL containing a n-hexane solution
(15 mL) of the substrates (R/S)-5a–i (3 mmol)[200 mM] and vinyl
acetate (3.3 mmol)[220 mM]. After 5 minutes equilibrating the
temperature, CAL-B (0.075 g)[5 mg/mL] was added and the reaction
was stirred at 150 rpm until the conversion reached 50%. The sus-
pension was filtered off under vacuum on a büchner, concentrated
in a rotary evaporator and the crude purified by chromatography
on silica gel using a mix of n-hexane/ethyl acetate (10:1) as elu-
ent. The optical rotation of (S)-2a–i and (R)-3a–i were confirmed
by polarimetric analysis and the enantiomeric purity determined
by gas chromatography equipped with chiral column comparing
the enantioenriched compounds with the racemic standards pre-
viously injected.
3.3.2.1. (S)-1-(2-furyl) etanol, (S)-2a. Oil, yield 45%; [˛]D 25 = −20 (c
1, CHCl3 ); ee > 99%.
3.3.2.2. (S)-1-(2-thienyl) ethanol, (S)-2b. Oil, yield
[˛]D 25 = −21 (c 2.6, CHCl3 ); ee 97%.
3.3.2.3. (S)-1-(2-furyl)-2-methyl propanol, (S)-(2c). Oil, yield 40%;
[˛]D 25 = +20.8 (c 4.0, CHCl3 ); ee 94%.
3.3.2.4. (S)-1-(2-thienyl)-2-methyl propanol, (S)-2d. Oil, yield 48%;
[˛]D 25 = +20 (c 1, CH2 Cl2 ); ee >99%.
3.3.2.5. (S)-1-(2-furyl)-1-ethynyl propynol, (S)-2e. Oil, yield 50%;
[˛]D 25 = + 19 (c 1.5, CHCl3 ); ee 95%.
3.3.2.6. (S)-4-(2-furyl)-3-buten-2-ol, (S)-2f. Oil, yield
[˛]D 25 = −28 (c 5.8, CHCl3 ); ee >99%.
3.3.2.7. (S)-4-(2-thienyl)-3-buten-2-ol, (S)-2g. Oil, yield
[˛]D 25 = −29 (c 9.3, CHCl3 ); ee 92%.
3.3.2.8. (S)-4-(2-thienyl)-2-butanol, (S)-2h. Oil, yield
[˛]D 25 = + 14.5 (c 3.5, CHCl3 ); ee > 99%.
3.3.2.9. (S)-4-(2-furyl)-2-butanol, (S)-2i. Oil, yield
[˛]D 25 = −23.9 (c 1, CHCl3 ); ee > 99%.
3.3.3. (R)-1-(2-furyl)-ethyl acetate, (R)-3a
Oil, yield 45%; [˛]D 25 = +154 (c 3.7, CHCl3 ); ee > 99%.
3.3.4. (R)-1-(2-thienyl)-ethyl acetate, (R)-3b
Oil, yield 43%; [˛]D 25 = +114 (c 5.15, CHCl3 ); ee > 99%.
3.3.5. (R)-1-(2-furyl)-propan-2-yl acetate, (R)-3c
Oil, yield 51%; [˛]D 25 = +6 (c 2.8, CHCl3 ); ee 91%.
3.3.6. (R)-1-(2-thienyl)-propan-2-yl acetate, (R)-3d
Oil, yield 42%; [˛]D 25 = +7 (c 1, CH2 Cl2 ); ee > 99%.
3.3.7. (R)-1-(2-furyl)-2-propyn-1-yl acetate, (R)-3e
Oil, yield 42%; [˛]D 25 = + 34 (c 1.23, CHCl3 ); ee 98%.
3.3.8. (R)-4-(2-furyl)-3-buten-2-yl acetate, (R)-3f
Oil, yield 41%; [˛]D 25 = + 139 (c 1, CHCl3 ); ee 96%.
3.3.9. (R)-4-(2-thienyl)-3-buten-2-yl acetate, (R)-3g
Oil, yield 51%; [˛]D 25 = + 140 (c 9.35, CHCl3 ); ee 93%.
3.3.10. (R)-4-1-(2-thienyl)-butan-2-yl acetate, (R)-3h
Oil, yield 49%; [˛]D 25 = + 7.5 (c 2.5, CHCl3 ); ee > 99%.
3.3.11. (R)-4-(2-furyl)-butan-2-yl acetate, (R)-3i
Oil, yield 49%; [˛]D 25 = − 3.4 (c 1, CHCl3 ); ee > 99%.
3.4. General procedure for the preparation of enones 5a–b
To an Erlenmeyer flask containing a solution of 2-furan or 2-
thiophen carboxaldehyde (50 mmol) in acetone/water 2:1 (15 mL)
under ice bath was added aqueous solution of NaOH (2.5 mL of
10% w/w aqueous solution) dropwise. The resulting solution was
kept under stirring at room temperature until consume of starting
material. Then, aqueous HCl was added dropwise to the solution
until pH 4 followed by extraction with CH2 Cl2 (2 × 15 mL). Organic
layers were washed with aqueous solution of NaHCO3 and brine
and then dried over Na2 SO4 . The media was concentrated in rotary
evaporator and the crude purified by distillation under vacuum in
a kugelrohr device.
48%; 3.4.1. 4-(2-furyl)-3-buten-2-one (5a)
Pale yellow crystalline solid, yield 4.8 g (74%). CAS NR. 41438-
24-8. RMN 1 H (400 MHz, CDCl3 , ppm): ␦ 2.28 (s, 3H); ␦ 6.44 (dd,
J = 3.1 Hz; J = 1.8 Hz, 1H); ␦ 6.57 (d, J = 16 Hz, 1H); ␦ 6.63 (d, J = 3.1 Hz,
1H); ␦ 7.23 (d, J = 16 Hz, 1H); ␦ 7.46 (s, 1H). RMN 13 C (100 MHz,
CDCl3, ppm): 27; 112; 115; 124; 129; 144; 150; 197. IR (Neat,
cm−1 ): 1255; 1663; 3105; 3501. MS m/z (rel int.): 136 [M+] (71),
121 (100), 94 (66), 65 (88), 43 (38).
3.4.2. 4-(2-thienyl)-3-buten-2-one (5b)
Colorless oil, yield 5.3 g (70%). CAS NR. 33603-63-3. RMN 1 H
(400 MHz, CDCl3, ppm): ␦ 2.48 (s, 3H); ␦ 6.67 (d, J = 16 Hz, 1H);
41%; ␦ 7.21 (dd, J = 3.5 Hz; J = 4.7, 1H); ␦ 7.44 (d, J = 3.5 Hz, 1H); ␦ 7.55 (d,
J = 4.7 Hz, 1H); ␦7.78 (d, J = 16 Hz, 1H). RMN 13 C (100 MHz, CDCl3,
ppm): 27; 125; 128.2; 128.9; 131; 135; 139; 197. IR (Neat, cm−1 ):
49%; 1620; 1254; 1017. MS m/z (rel int.): 152 [M+] (50), 137 (100), 109
(63), 65 (21), 43 (10).
47%; 4. Conclusions
In the present work, we have demonstrated an efficient and
49%; practical chemoenzymatic route for the synthesis of enantioen-
riched ␣-, ␤- and ␥- hydroxy furans and thiophenes. Thus alkylic
and allylic alcohols containing these moieties were obtained with
high ee. The adopted chemical routes prompted us to readily
prepare the substrates from commercially available starting mate-
rials. The optimized condition for the resolution experiments was
achieved when CAL-B was used as catalyst and n-hexane as sol-
◦
vent at 35 C. Thus all compounds were obtained in an excellent E
and high degree of enantiomerical purity, including the compound
(S)-2i considered as an advanced intermediate for the synthe-
sis of Citreofuran and Pyrenophorine which was resolved in only
10 minutes by using this condition.
Acknowledgements
The authors thank CNPq, FACEPE, CAPES and INCT-INAMI for
Financial support and UFPE as well as CETENE for the Infrastructure.
 D.S.P. Ferreira et al. / Journal of Molecular Catalysis B: Enzymatic 126 (2016) 37–45
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molcatb.2016.01.
014.
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