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

Contents lists available at ScienceDirect

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 and related derivatives. Since these compounds would
Compounds containing five-membered heteroaromatic sub- be prepared asymmetrically, their use as chiral building blocks for
units are important synthetic intermediates for a variety of the synthesis of bioactive compounds in their single enantiomer
chemical and biochemical transformations, due to both their wide form is of great value. Examples are the total synthesis of biologi-
range of biological activity [1] and great versatility, as they are cally active macrolides such Citreofuran [3] and Pyrenophorin [4],
readily converted into other functional groups [2]. Thus efforts to prepared from the same chiral building block (S)-2i (Fig. 1).
develop alternative approaches for the introduction of this func- Despite under natural conditions, where lipases can catalyse
tionality into diverse organic substrates have been intensified. the hydrolysis of esters, their activity and specificity in organic
Although chiral methodologies to prepare secondary alcohols con- solvents should be highlighted. Moreover, with the exclusion of
taining aromatic moiety is well established, the most general and water molecules hydrolysis is suppressed what has extended the
commonly used asymmetric methods of their production include range of their application in non-aqueous systems. Thus, a variety of
the addition of a reactive organometallic to the aldehydes using chi- lipases has been successfully used demonstrating their extraordi-
ral auxiliaries [5] or hydrogenation of ketones catalysed by chiral nary capability as catalysts used in the transesterification of several
ligands using boranes [6] or phosphines [7]. Alternatively, they can unnatural substrates in chemo-enzymatic process. Therefore, the
be prepared using chiral heavy metal complexes [8]. While catalytic use of isolated lipases linked to the high demand for chiral inter-
chemical procedures can be found, commonly equimolar quantities mediates in their single enantiomer form is on the rise.
of chiral auxiliary or metallic salts wastes are generated. Despite biocatalysis being a well-known efficient strategy to
Therefore 2-substituted furans containing secondary alcohols prepare enantioenriched secondary alcohols, very few of the pub-
should be considered as masked bis-oxo building blocks being use- 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-
∗ Corresponding author. Fax: +55 81 21268440. ment of high times of resolutions and the obtainment of compounds
E-mail address: [email protected] (J.L. Princival). 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 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
Fig. 2. EKR of (R/S)-2i. The vertical axis is conversion and the horizontal axis
different temperatures in up to 15 min of reaction.
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 The results of this study show that if the temperature is
(10 mg)/[5 mg/mL], vinyl-acetate (0.1 mL), n-hexane (2.0 mL), 150 rpm. 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
Analyzing the results from Table 1, is possible to infer that
catalysed experiments at 35 ◦ C upon (R/S)-2i.
among all tested lipases three of them showed to be efficient hav-
As the reactions upon (R/S)-2i were carried out raging the tem-
ing both high conversion (c = 50%) and excellent selectivity (E >200)
peratures from 25 ◦ C to 50 ◦ C, the reaction activation energy could
(Table 1; entries 1, 3 and 4). Refining the data CAL-B and AE07
be calculated by plotting the logarithms of the initial reaction rate
lipases have presented better results upon (R/S)-2i if compared with
versus 1/T in a graph. Thus, a linear relationship was achieved
A2AE011, analysing the ee and the time of conversion.
(R2 = 0.9888) and the Arrhenius equation could be used to deter-
Despite the reactions using both CAL-B and AE07 have shown
mine the Ea for CAL-B against (R)-2i (Fig. 4).
very similar enantioselectivity upon 2i, when the assay was per-
The low Ea calculated (17.1 kJ/mol) can be attributed to the
formed using CAL-B as catalyst, the reaction showed to be four
immobilized CAL-B possessing lower activation energy for protein
times faster (compare entries 1 with 3 on Table 1). It shows a mighty
unfolding when reacted with (R)-2i when n-hexane is used as sol-
rate of transesterification, that has needed only 15 min to be fin-
vent, making easier the enantiomers discrimination in the active
ished at 25 ◦ C. Thus, CAL-B was used for the further studies toward
site of the enzyme.
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 2.2.3. Effect of the solvent
the unreacted (S)-2i [˛]D 20 = −23.9 (c 1.0 in CHCl3 ), ee 99%, achieved Recently we reported the co-solvent effect on the activity of
from the resolution, with the literature, where [˛]D 20 = −14.4 (c 1.2 CAL-B using n-hexane as solvent [14]. Based upon that, the enzy-
in CHCl3 ), ee 74% is reported for (S)-(−)-2i [12]. matic resolution study was performed in analytical scale evaluating
The enantiopreference for the enantiomer (R)-2i on the active the ability of CAL-B in catalyse the acylation reaction upon (R/S)-
site of the CAL-B in the transesterification reaction is in agreement 2i, using n-hexane and THF as solvents, at different proportions
with Kazlauskas rule [13] considering methyl as small and the five (Table 2).
membered rings containing two CH2 spacer as large size groups, Analysing the results from Table 2 was possible to observe that
respectively. increasing the amount of THF, the reaction becomes to be slower,
even though maintaining high ee.
2.2.2. Effect of temperature When the amount of the THF was increased in up to 50% the
Since temperature can affect the rate of catalysed reactions, we immobilized CAL-B takes 60 min to convert the substrate, whereas
decided to investigate the temperature influence in order to tuning if pure THF is used 120 min was required for the same conversion.
the EKR experiments. For this, the reactions using CAL-B upon (R/S)- Thus the rate of the acylated product formation was 4 and 8 times

Fig. 3. Monitoring EKR experiments for (R/S)-2i.

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 purchased from Sigma (St. Louis, MO) whereas Lipase A amano12
(A12L-A) were purchased from Amano Enzymes Co. (Japan). The
3.1. General Lipases P. stutzeri (AE07) and Alcaligenes spp. (A2AE011) were
kindly donated by Mann Associates—Cambridge. The TLC analyses
All the solvents used in the reactions were previously purified were performed using aluminum TLC Plates 20 × 20 cm on silica gel
by distillation prior to use. In the case of dry THF (used to gen- 60 of MACHEREY-NAGEL® .
erate the organometallic reagents), the solvent was dried under The 1 H at 300 MHz and 13 C at 75 MHz NMR analysis were
reflux in the presence of metallic sodium using benzophenone performed on a VARIAN® Unity Plus-300 (300 MHz) spectrom-
as indicator. The commercially available ethynyl magnesium bro- eter, using deuterated chloroform (CDCl3 ) as solvent and Me4 Si
mide, thiophene or furane carboxaldehydes and propylene oxide as internal standard. The chemical shifts were expressed in ppm
were obtained from Aldrich Chemical Co. (Milwaukee, WI, USA) and and coupling constants (J) are in Hz. Optical rotations were mea-
used without further purification while furan and thiophene were sured using a JASCO® P-2000 polarimeter. The chiral-GC analysis
freshly distilled prior to use. The Amano Lipase G from P. camen- were performed by using a SHIMADZU® 2010 Plus chromato-
berti (PCL-G) and Novozym 435 (lipase B from C. antarctica) were 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 (11 mmol from 22 mL of 0.5 mol/L solution in THF). After stirring
analysis a Supelco BetaDexTM 120 (␤-cyclodextrin packing) chi- the solution at the same temperature for 45 min the reaction was
ral capillary column (30 m × 0.25 mm × 0.25 ␮m) was used. The warmed to 0 ◦ C quenched with a saturated solution of NH4 Cl (5 mL)
resolutions were carried out on a TECNAL® orbital shaker stirrer and the phases were separated. The aqueous phase was extracted
TE-424 with temperature control. The GCMS analysis were done in with ethyl acetate (2 × 10 mL) washed with brine, dried with mag-
a SHIMADZU® GC-17A Gas Chromatography System, coupled to a nesium sulphate, filtered off and the solvents removed in a rotary
GCMS-QP5000 detector using Ar as the carrier gas and Agilent J&W evaporator under vacuum. The crude was purified by chromatog-
DB-5 capillary column (30 m × 0.25 mm × 0.25 ␮m) as non-polar raphy on silica gel using a mix of n-hexane/ethyl acetate (6:1) as
column. eluent.

3.2. Synthesis of racemic alcohols 2a–i and acetates 3a–i 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,
3.2.1. General procedure for the preparation of alcohols ppm): ␦ 2.62 (d, J 4 2.4 Hz, 1H); ␦ 2.80 (s, 1H); ␦ 5.45 (d, J 4 2.4 Hz,
(R/S)-2a–d 1H); ␦ 6.35 (dd, J 3 1.8 Hz, J 3 3.2 Hz, 1H); ␦ 6.46 (dd, J 3 3.2 Hz, 1H);
To a round bottomed flask containing a solution of furan or thio- ␦ 7.41 (d, J 4 0.9 Hz, dd, J 3 1.8 Hz, 1H). RMN 13 C (100 MHz, CDCl3,
◦
phen (33 mmol) in dry THF (150 mL) at −78 C using N2 atmosphere ppm) 57, 74, 81, 108, 110, 143, 152. IV (Neat, cm-1) 744, 1010, 2124,
under stirring, n-butyl lithium (33 mmol from 36 mL of 0.92 mol/L 2884, 3293. MS m/z (rel int.): 122 [M+] (96), 105 (82), 94 (51), 77
solution in hexane) was drop wise added. After stirring the solution (38), 66 (100), 51 (53).
at the same temperature for 30 min the appropriate electrophile
(acetaldehyde or propylene oxide) (30 mmol) was added in one 3.2.3. General procedure for the preparation of alcohols (R/S)-2f-g
◦
portion. The reaction was warmed to 0 C quenched with a satu- To a round bottomed flask equipped with a drying tube (CaCl2 )
rated solution of NH4 Cl (50 mL) and the aqueous phase extracted containing a solution of enone 5a or 5b (10 mmol) in ethyl alcohol
◦
with ethyl acetate (2 × 50 mL). The organic phase was washed with (15 mL) at 0 C was added NaBH4 (15 mmol, 0.6 g). After stirring
brine, dried over magnesium sulphate, filtered off and the solvents the solution at the same temperature for 10 min the reaction was
removed in a rotary evaporator under vacuum. The crude was puri- warmed to room temperature and stirred for 20 min before be
fied by chromatography on silica gel using a mix of n-hexane/ethyl quenched with a saturated solution of NH4 Cl (20 mL). The phases
acetate (4:1) as eluent. were separated and the aqueous phase extracted with ethyl acetate
(2 × 30 mL) washed with brine, dried with magnesium sulphate and
3.2.1.1. (R/S)-1-(2-furyl) ethanol, (R/S)-2a. Colorless oil yield 2.7 g filtered off. The organic solvent was removed in a rotary evaporator
(80%); CAS NR. 4208-64-4. 1 H NMR (300 MHz, CDCl3) ␦ 1.53 (d, J under vacuum and the crude purified by chromatography on silica
3 6.6 Hz, 3H), ␦ 2.16 (s, 1H), ␦ 4.87 (q, J 3 6.6 Hz, 1H), ␦ 6.22 (d, J 3 gel using a mix of n-hexane/ethyl acetate (4:1) as eluent.
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, 3.2.3.1. (R/S)-4-(2-furyl)-3-buten-2-ol, (R/S)-2f. Pale yellow oil
cm-1): 699; 1069; 2929; 2976; 3357. MS m/z (rel int.): 112 [M+] (2), yield 1.36 g (99%); CAS NR. 4229-85-0. 1 H NMR (300 MHz, CDCl3 ,
95 (100), 81 (30), 67 (20), 55 (6), 43 (8), 41 (14). 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);
3.2.1.2. (R/S)-1-(2-thienyl)-ethanol, (R/S)-2b. Colorless oil, yield ␦ 6.3 (m, 1H); ␦ 6.4 (d, J 3 15 Hz, 1H); ␦ 7.34 (B(s), 1H). RMN 13 C
2.94 g (77%); CAS NR. 2309-47-9. 1 H NMR (300 MHz, CDCl3, ppm): (75 MHz, CDCl3, ppm) 23, 68, 108, 111, 117, 132, 141, 152. IV (Neat,
␦ 1.58 (d, J 3 6.3 Hz, 3H); ␦ 2.33 (s, 1H); ␦ 5.1 (q, J 3 6.3 Hz, 1H); cm−1 ) 734, 1013, 2973, 3357. MS m/z (rel int.): 138 [M+] (73), 123
␦ 6.95 (d, J 3 2.1 Hz, 1H); ␦ 6.96 (d, J 3 4.2 Hz, 1H); ␦ 7.23 (dd, J 3 (18), 95 (100), 91 (32), 81 (76), 77 (29), 67 (40), 55 (31), 43 (48).
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 3.2.3.2. (R/S)-4-(2-thienyl)-3-buten-2-ol, (R/S)-2g. Colorless oil
m/z (rel int.): 128 [M+] (30), 113 (64), 85 (100), 45 (24). 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
3.2.1.3. (R/S)-1-(2-furyl)-2-methyl propanol, (R/S)-(2c). Colorless (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
oil, yield 1.95 g (53%); CAS NR. 66040-54-8. 1 H NMR (400 MHz, 3 15.6 Hz, 1H); ␦ 6.95 (d, J 3 3.6 Hz, 1H); ␦ 6.95 (d, J 3 1.8 Hz, 1H); ␦
CDCl3, ppm) ␦ 1.21 (d, J 3 6.2 Hz, 3H); ␦ 2.23 (s, 1H); ␦ 2,63–2,84 7.15 (dd, J 3 3.6 Hz; J 3 1.8 Hz, 1H). RMN 13 C (100 MHz, CDCl3, ppm)
(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 23, 68, 122, 124, 125, 127, 133, 141. IV (Neat, cm−1 ) 694, 1369,
0.8 Hz, 1H); ␦ 6.29 (dd, J 3 3 Hz; J 4 0.8 Hz, 1H); ␦ 7.32 (dd, J 3 2 Hz; 2972, 3333. MS m/z (rel int.): 154 [M+] (46), 135 (52), 111 (88), 97
J 4 0.8 Hz, 1H). RMN 13 C (100 MHz, CDCl3, ppm) 22; 37; 66; 106; (100), 91 (29), 77 (27), 55 (35), 43 (22).
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). 3.2.4. General procedure for the preparation of alcohols
(R/S)-2h-i
3.2.1.4. (R/S)-1-(2-thienyl)-2-methyl propanol, (R/S)-2d. Colorless To a round bottomed flask containing a suspension of LiAlH4
oil, yield 2.1 g (50%); CAS NR. 62119-81-7. 1 H NMR (300 MHz, (30 mmol, 1.14 g) in dry THF (30 mL) at 0 ◦ C was drop wise added
CDCl3, ppm) ␦ 1.26 (d, J 3 6.3 Hz, 3H); ␦ 1.8 (s, 1H); ␦ 2.94 (ddd, the enone 5a or 5b (15 mmol). After stirring for 2 h at room tem-
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 perature the mixture was cooled to 0 ◦ C and an aqueous solution
4 1.2 Hz, 1H); ␦ 6.96 (dd, J 3 5.1 Hz, J 3 3.6 Hz, 1H), ␦ 7.18 (dd, J 3 of NaOH (20% m/m) was slowly added. The white solid formed was
5.3 Hz, J 4 1.2 Hz, 1H). RMN 13 C (100 MHz, CDCl3, ppm) 22, 39, 68, filtered off and the resulting solution was dried with Na2 SO4 and
124, 125, 126, 140. IV (Neat, cm-1) 694, 1120, 1375, 1439, 2930, concentrated in a rotary evaporator under vacuum. The products
2970, 3365. MS m/z (rel int.): 142 [M+] (8), 97 (100), 53 (7), 45 (26). were purified by distillation in a Kugelrohr.

3.2.2. General procedure for the preparation of alcohol (R/S)-2e 3.2.4.1. (R/S)-4-(2-thienyl)-2-butanol, (R/S)-2h. Colorless oil, yield
To a round bottomed flask containing a solution of 2-furan car- 1.65 g (70%); CAS NR. 613684-31-4 1 H NMR (300 MHz, CDCl3, ppm)
boxaldehyde (10 mmol) in THF (20 mL) at −78 ◦ C under dry N2 ␦ 1.24 (d, J 3 6.3 Hz, 3H); 1.78–1.88 (m, 2H); ␦ 2.03 (s, 1H); ␦ 1.83 (q,
atmosphere was drop wise added ethynyl magnesium bromide 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 43

(sext., J 3 6.3 Hz, 1H); ␦ 6.81 (dd, J 3 3.3 Hz, J 4 0.9 Hz, 1H); ␦ 6.92 CDCl3, ppm) ␦ 2.13 (s, 3H); ␦ 2.64 (d, J 3 2.3 Hz, 1H); ␦ 6.4 (dd, J 3
(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 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,
(75 MHz, CDCl3, ppm) 23, 26, 40, 67, 123, 124, 126, 144. IV (Neat, 1H). ␦ 7.45 (dd, J 3 0.9 Hz, J 3 1.6 Hz, 1H) RMN 13C (100 MHz, CDCl3,
cm-1) 693, 1639, 2927, 2966, 3412. MS m/z (rel int.): 156 [M+] (22), ppm) 22; 37; 6 6; 106; 110; 141; 152. IV (Neat, cm-1) 1223; 1743;
138 (25), 123 (100), 97 (62), 84 (12), 77 (8), 53 (9), 45 (27). 2130; 2960; 3291. MS m/z (rel int.): 164 [M+] (14), 122 (43), 105
(100), 76 (60), 51 (37), 43 (29).
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) ␦ 3.2.5.6. (R/S)-4-(2-furyl)-3-buten-2-yl acetate, (R/S)-3f. Pale yellow
1.22 (d, J 3 6.3 Hz, 3H); ␦ 1.83–1.73 (m, 2H); ␦ 2.12 (s, 1H); ␦ 2.73 oil, yield 0.18 g (100%); CAS NR. 97602-78-3.1H NMR (400 MHz,
(dq, J 3 6.3 Hz, J 3 15.3 Hz, 2H); ␦ 3.83 (sext., J 3 6.3 Hz, 1H); ␦ 6.0 CDCl3, ppm) ␦ 1.38 (d, J 3 6.5 Hz, 3H); ␦ 2.06 (s, 3H); ␦ 5.48 (quint,
(dd, J 4 0.6 Hz, J 3 3 Hz, 1H); ␦ 6.27 (dd, J 3 1.2 Hz, J 3 3 Hz 1H); ␦ J 3 6.5 Hz, 2H); ␦ 6.11 (dd, J 3 15.9 Hz, J 3 6.6 Hz, 1H); ␦ 6,25 (d, J
7.29 (dd, J 4 0.6 Hz, J 3 1.2 Hz, 1H). RMN 13 C (75 MHz, CDCl3, ppm) 3 3.3 Hz, 1H); ␦ 6.36 (dd, J 3 3.3 Hz; J 3 1.5 Hz, 1H); ␦ 6.41 (d, J 3
23, 24, 37, 67, 104, 110, 140, 155. IV (Neat, cm-1) 730, 1007, 1638, 15,9 Hz, 1H), ␦ 7.34 (d, J 3 1.5 Hz, 1H). RMN 13C (100 MHz, CDCl3,
1598, 2928, 2967, 3404. MS m/z (rel int.): 140 [M+] (32), 122 (52), ppm) 20, 21, 70, 108, 111, 119; 127, 143, 151, 170. IV (Neat, cm-1)
109 (76), 81 (100), 77 (18), 68 (14), 53 (28), 45 (18). 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. General procedure for the preparation of acetates (R/S)-3a-i
To a round bottomed flask containing the respective alcohol 3.2.5.7. (R/S)-4-(2-thienyl)-3-buten-2-yl acetate, (R/S)-3g. Color-
(1 mmol) in DCM (2 mL) at room temperature and using dry N2 less oil, yield 0.19 g (100%); CAS NR. 709655-12-9. 1H NMR
atmosphere, under stirring, acetic anhydride (1.1 mmol) and DMAP (300 MHz, CDCl3, ppm) ␦ 1.39 (d, J 3 6.6 Hz, 3H); ␦ 2.07 (s, 3H);
(cat) were sequentially added. After stirring the solution at same ␦ 5.48 (dd, J 3 6.3 Hz, J 3 6.6 Hz, 1H); ␦ 6.01 (dd, J 3 15.6 Hz, J 3
temperature for 30 min the crude reaction was quenched with sat- 6.3 Hz, 1H); ␦ 6.73 (d, J 3 15.6 Hz, 1H); ␦ 6.92–6.99 (m, 2H); ␦ 7.17
urated solution of NaHCO3 (1 mL). The phases were separated and (dd, J 3 4.5 Hz, J 3 1.2 Hz 1H). RMN 13C (75 MHz, CDCl3, ppm) 20, 21,
the aqueous phase was extracted with DCM (2 × 2 mL) washed with 70, 124, 125, 126, 127, 128, 141, 170. IV (Neat, cm-1) 1646; 1731;
brine, dried over magnesium sulphate, filtered off and the solvent 2982. MS m/z (rel int.): 196 [M+] (0.2), 135 (100), 121 (13), 111 (23),
removed in a rotary evaporator under vacuum. The crude was puri- 97 (48), 91 (43), 77 (13), 65 (14), 45 (17), 43 (82).
fied by chromatography on silica gel using a mix of n-hexane/ethyl
acetate (10:1) as eluent. 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
3.2.5.1. (R/S)-1-(2-furyl)-ethyl acetate, (R/S)-3a. Colorless oil, yield (d, J 3 6,3 Hz, 3H); ␦ 1,92 (m, 2H); ␦ 2.04 (s, 1H); ␦ 2.87 (m, 2H);
0.15 g (100%); CAS NR. 22426-24-0 1 H NMR (300 MHz, CDCl3, ppm) ␦ 4.96 (m, 1H); ␦ 6.79 (dd., J 3 1,0 Hz, J 3 3.4 Hz, 1H); ␦ 6.91 (dd., J
␦ 1.57 (d, J 3 6.9 Hz, 3H), ␦ 2.04 (s, 3H), ␦ 5.95 (q, J 36.9 Hz, 2H), ␦ 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;.
6.31 (d, J 33.3 Hz, 1H), ␦ 6.32 (dd, J 3 2.1 Hz, J 3 3.3 Hz, 1H), ␦ 7.37 RMN 13C (75 MHz, CDCl3, ppm) 20, 21, 25,37, 70, 123, 124, 126,
(d, J 3 2.1 Hz, 1H). 13 C NMR (75 MHz, CDCl3, ppm) 18, 21, 65, 107, 144, 170. MS m/z (rel int.): 198 [M+] (1), 138 (55), 123 (100), 97
110, 142, 153, 170. IV (Neat, cm-1) 1232, 1738, 2939, 2990. MS m/z (45), 43 (28).
(rel int.): 154 [M+] (28), 112 (66), 95 (100), 66 (65), 55 (8), 43 (78).
3.2.5.9. (R/S)-4-(2-furyl)-butan-2-yl acetate, (R/S)-3i. Colorless oil,
3.2.5.2. (R/S)-1-(2-thienyl)-ethyl acetate, (R/S)-3b. Colorless oil, yield 0.18 g (100%); CAS NR. 105827-42-7. 1H NMR (300 MHz,
yield 0.17 g (100%); CAS NR. 22426-23-9. 1H NMR (300 MHz, CDCl3, CDCl3, ppm) ␦ 1.23 (d, J 3 6.3 Hz, 3H); ␦ 1.81–1.97 (m, 2H); ␦
ppm) ␦ 1.67 (d, J 3 6.6 Hz, 3H); ␦ 2.09 (s, 3H); ␦ 6.2 (q, J 3 6.6 Hz, 1.77–1.95 (m, 1H); ␦ 2,02 (s, 1H); ␦ 2.60–2.72 (m, 1H); ␦ 4.84–5.01
1H); ␦ 6.99 (dd, J 3 3.3 Hz; J 3 4.5 Hz, 1H); ␦ 7.09 (d, J 3 3.3 Hz, 1H); (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
␦ 7.29 (d, J 3 4.5 Hz, 1H). 13C NMR (75 MHz, CDCl3, ppm) 21, 22, 67, 3 Hz, 1H); ␦ 7.29 (dd, J 4 0.6 Hz, J 3 1,2 Hz, 1H). RMN 13C (75 MHz,
125.1, 125.2, 126, 144, 170. IV (Neat, cm-1) 1732, 2985, 3111. MS CDCl3, ppm) 19, 21, 24, 34, 70, 104, 110, 140, 155, 170. MS m/z (rel
m/z (rel int.): 170 [M+] (1), 128 (80), 110 (100), 84 (21), 77 (20), 66 int.): 198 [M+] (0.5), 122 (100), 107 (98), 93 (20), 81 (60), 66 (10),
(24), 45 (18), 43 (45). 53 (18), 43 (52).

3.2.5.3. (R/S)-1-(2-furyl)-propan-2-yl acetate, (R/S)-3c. Colorless 3.3. General procedure for the lipase-catalysed resolution
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 The enzymatic kinetic resolutions were carried out on a
6.4 Hz, 15 Hz, 2H); ␦ 5.14 (sext, J 3 6.4 Hz, 1H); ␦ 6.06 (dd, J 4 0.6 Hz, TECNAL® orbital shaker stirrer TE-424 with temperature control
J 3 2.4 Hz, 1H); ␦ 6.28 (dd, J 3 1.2 Hz, J 3 2.4 Hz, 1H); ␦ 7.31 (dd, J at 150 rpm, using a substrate solutions ranging from 50 mM to
4 0.6 Hz, J 3 1.2 Hz, 1H). 13C NMR (100 MHz, CDCl3, ppm) 19, 21, 200 mM and nearly equimolar quantities of vinyl acetate as acyl
34, 69, 106, 110, 141, 151, 170. IV (Neat, cm-1) 1243; 1373; 1740; donor in an appropriate Erlenmeyer flask capped with red rubber
2983. MS m/z (rel int.): 168 [M+] (1), 108 (100), 81 (38), 66 (2), 53 septa. A control reaction containing no enzymatic catalyst was held
(12), 43 (100) taking aliquots at different times concomitantly to the resolution.
To accomplish the progress of the reactions, at each time an aliquot
3.2.5.4. (R/S)-1-(2-thienyl)-propan-2-yl acetate, (R/S)-3d. Colorless (100 ␮L) was taken, filtered off on silica and injected, by using an
oil, yield 0.18 g (100%); 1H NMR (400 MHz, CDCl3, ppm) ␦ 1.25 (d, auto sampler, on a GC equipped with a chiral column (split 1/100)
J 3 6 Hz, 3H); ␦ 2.04 (s, 3H); ␦ 3.05 (ddd, J 3 15 Hz, J 3 6.2 Hz, 1H); for analysis. All the aforementioned were made in triplicate.
␦ 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, 3.3.1. Analytical scale enzymatic resolution
ppm) 19, 21, 35, 70, 124, 125, 126, 139, 170. IV (Neat, cm-1) 1738; To an Erlenmeyer flask with capacity for 10 mL containing
2981. MS m/z (rel int.): 184 [M+] (0.5), 124 (100), 97 (70), 43 (90). 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
3.2.5.5. (R/S)-1-(2-furyl)-2-propyn-1-yl acetate, (R/S)-3e. Pale yel- (10 mg). The crude reaction was stirred at 150 rpm on an orbital
low oil, yield 0.16 g (100%); CAS NR. 19275-25-3. 1H NMR (400 MHz, 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 3.3.8. (R)-4-(2-furyl)-3-buten-2-yl acetate, (R)-3f
enzyme. After 50% conversion the reaction medium was filtered off Oil, yield 41%; [˛]D 25 = + 139 (c 1, CHCl3 ); ee 96%.
on a Pasteur pipette containing silica and concentrated in a rotary
evaporator. The crude containing the unreacted enantiomer (S)-2i 3.3.9. (R)-4-(2-thienyl)-3-buten-2-yl acetate, (R)-3g
and the acetate (R)-3i were purified by chromatography on silica Oil, yield 51%; [˛]D 25 = + 140 (c 9.35, CHCl3 ); ee 93%.
gel using a mix of n-hexane/ethyl acetate (10:1) as eluent.
3.3.10. (R)-4-1-(2-thienyl)-butan-2-yl acetate, (R)-3h
3.3.2. General procedure for the enzymatic resolution on Oil, yield 49%; [˛]D 25 = + 7.5 (c 2.5, CHCl3 ); ee > 99%.
preparative scale
On a preheated orbital stirrer (35 ◦ C) was placed an Erlen-
3.3.11. (R)-4-(2-furyl)-butan-2-yl acetate, (R)-3i
meyer flask with capacity for 50 mL containing a n-hexane solution
Oil, yield 49%; [˛]D 25 = − 3.4 (c 1, CHCl3 ); ee > 99%.
(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 3.4. General procedure for the preparation of enones 5a–b
was stirred at 150 rpm until the conversion reached 50%. The sus-
pension was filtered off under vacuum on a büchner, concentrated To an Erlenmeyer flask containing a solution of 2-furan or 2-
in a rotary evaporator and the crude purified by chromatography thiophen carboxaldehyde (50 mmol) in acetone/water 2:1 (15 mL)
on silica gel using a mix of n-hexane/ethyl acetate (10:1) as elu- under ice bath was added aqueous solution of NaOH (2.5 mL of
ent. The optical rotation of (S)-2a–i and (R)-3a–i were confirmed 10% w/w aqueous solution) dropwise. The resulting solution was
by polarimetric analysis and the enantiomeric purity determined kept under stirring at room temperature until consume of starting
by gas chromatography equipped with chiral column comparing material. Then, aqueous HCl was added dropwise to the solution
the enantioenriched compounds with the racemic standards pre- until pH 4 followed by extraction with CH2 Cl2 (2 × 15 mL). Organic
viously injected. layers were washed with aqueous solution of NaHCO3 and brine
and then dried over Na2 SO4 . The media was concentrated in rotary
3.3.2.1. (S)-1-(2-furyl) etanol, (S)-2a. Oil, yield 45%; [˛]D 25 = −20 (c evaporator and the crude purified by distillation under vacuum in
1, CHCl3 ); ee > 99%. a kugelrohr device.

3.3.2.2. (S)-1-(2-thienyl) ethanol, (S)-2b. Oil, yield 48%; 3.4.1. 4-(2-furyl)-3-buten-2-one (5a)
[˛]D 25 = −21 (c 2.6, CHCl3 ); ee 97%. 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,
3.3.2.3. (S)-1-(2-furyl)-2-methyl propanol, (S)-(2c). Oil, yield 40%; J = 3.1 Hz; J = 1.8 Hz, 1H); ␦ 6.57 (d, J = 16 Hz, 1H); ␦ 6.63 (d, J = 3.1 Hz,
[˛]D 25 = +20.8 (c 4.0, CHCl3 ); ee 94%. 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,
3.3.2.4. (S)-1-(2-thienyl)-2-methyl propanol, (S)-2d. Oil, yield 48%; cm−1 ): 1255; 1663; 3105; 3501. MS m/z (rel int.): 136 [M+] (71),
[˛]D 25 = +20 (c 1, CH2 Cl2 ); ee >99%. 121 (100), 94 (66), 65 (88), 43 (38).

3.3.2.5. (S)-1-(2-furyl)-1-ethynyl propynol, (S)-2e. Oil, yield 50%; 3.4.2. 4-(2-thienyl)-3-buten-2-one (5b)
[˛]D 25 = + 19 (c 1.5, CHCl3 ); ee 95%. 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);
3.3.2.6. (S)-4-(2-furyl)-3-buten-2-ol, (S)-2f. Oil, yield 41%; ␦ 7.21 (dd, J = 3.5 Hz; J = 4.7, 1H); ␦ 7.44 (d, J = 3.5 Hz, 1H); ␦ 7.55 (d,
[˛]D 25 = −28 (c 5.8, CHCl3 ); ee >99%. 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 ):
3.3.2.7. (S)-4-(2-thienyl)-3-buten-2-ol, (S)-2g. Oil, yield 49%; 1620; 1254; 1017. MS m/z (rel int.): 152 [M+] (50), 137 (100), 109
[˛]D 25 = −29 (c 9.3, CHCl3 ); ee 92%. (63), 65 (21), 43 (10).

3.3.2.8. (S)-4-(2-thienyl)-2-butanol, (S)-2h. Oil, yield 47%; 4. Conclusions

[˛]D 25 = + 14.5 (c 3.5, CHCl3 ); ee > 99%.
In the present work, we have demonstrated an efficient and
3.3.2.9. (S)-4-(2-furyl)-2-butanol, (S)-2i. Oil, yield 49%; practical chemoenzymatic route for the synthesis of enantioen-
[˛]D 25 = −23.9 (c 1, CHCl3 ); ee > 99%. riched ␣-, ␤- and ␥- hydroxy furans and thiophenes. Thus alkylic
and allylic alcohols containing these moieties were obtained with
3.3.3. (R)-1-(2-furyl)-ethyl acetate, (R)-3a high ee. The adopted chemical routes prompted us to readily
Oil, yield 45%; [˛]D 25 = +154 (c 3.7, CHCl3 ); ee > 99%. prepare the substrates from commercially available starting mate-
rials. The optimized condition for the resolution experiments was
3.3.4. (R)-1-(2-thienyl)-ethyl acetate, (R)-3b achieved when CAL-B was used as catalyst and n-hexane as sol-
◦
Oil, yield 43%; [˛]D 25 = +114 (c 5.15, CHCl3 ); ee > 99%. vent at 35 C. Thus all compounds were obtained in an excellent E
and high degree of enantiomerical purity, including the compound
3.3.5. (R)-1-(2-furyl)-propan-2-yl acetate, (R)-3c (S)-2i considered as an advanced intermediate for the synthe-
Oil, yield 51%; [˛]D 25 = +6 (c 2.8, CHCl3 ); ee 91%. sis of Citreofuran and Pyrenophorine which was resolved in only
10 minutes by using this condition.
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%. Acknowledgements

3.3.7. (R)-1-(2-furyl)-2-propyn-1-yl acetate, (R)-3e The authors thank CNPq, FACEPE, CAPES and INCT-INAMI for
Oil, yield 42%; [˛]D 25 = + 34 (c 1.23, CHCl3 ); ee 98%. 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 45

Appendix A. Supplementary data [8] (a) Z. Han, H. Hanmin, ChemCatChem 5 (2013) 2253–2257;
(b) G. Kang, S. Lin, A. Shiwakoti, B. Ni, Catalysis Communications 57 (2014)
111–114;
Supplementary data associated with this article can be found, in (c) C. Li, L. Zhang, C. Zheng, X. Zheng, H. Fu, H. Chen, R. Li, Tetrahedron:
the online version, at http://dx.doi.org/10.1016/j.molcatb.2016.01. Asymmetry 25 (2014) 821–824.
014. [9] (a) E. Xun, Z. Wang, J. Zhao, J. Guo, J. Chem. Technol. Biotechnol. 90 (2015)
492–499;
(b) M.C. Hara, R. Turcu, M. Sundell, C. Tosa, F.D. Paizs, L.T. Irimie, Kanerva
References Tetrahedron: Asymmetry 24 (2013) 142–150;
(c) M. Szigeti, E.R. Töke, M.C. Turóczi, V. Nagy, G. Szakács, L. Poppe, ARKIVOC 3
[1] (a) Z.G. Yang, K. Matsuzaki, S. Takamatsu, S. Kitanaka, Molecules 16 (2011) (2008) 54–65;
6010–6022; (d) Y.K. Choi, J.H. Suh, D. Lee, I.T. Lim, J.Y. Jung, M.J. Kim, J. Org. Chem. 64
(b) L. De Lucia, D. Panzella, I. Melck, A. Giudicianni, A. Motta, M. Napolitano, (1999) 8423–8424.
Chem. Res. Toxicol. 22 (2009) 1922–1928; [10] H.J. Wu, K. Pan, J. Chem. Soc. Chem. Commun. (1987) 898–900.
(c) M.W. Khan, M.J. Alam, M.A. Rashid, R. Chowdhury, Bioorg. Med. Chem. 13 [11] M. Petrini, R. Ballini, G. Rosini, E. Marotta, Tetrahedron 42 (1986) 151–154.
(2005) 4796–4805. [12] G.J. Xin, L.Z. Yi, L.G. Qiang, Tetrahedron 49 (1993) 5805–5816.
[2] (a) B.H. Lipshutz, Chem. Rev. 86 (1986) 795–819; [13] R.J. Kazlauskas, A.N.E. Weissfloch, A.T. Rappaport, A. Cuccia, J. Org. Chem. 56
(b) X.L. Hou, H.Y. Cheung, T.Y. Hon, P.L. Kwan, T.H. Lo, S.Y. Tong, H.N.C. Wong, (1991) 2656–2665.
Tetrahedron 54 (1998) 1955–2020. [14] J.G. Ferreira, C.R. Princival, D.M. Oliveira, R.X. Nascimento, J.L. Princival, Org.
[3] F. Bracher, B. Schulten, Nat. Prod. Res. 17 (2003) 293–299. Biomol. Chem. 13 (2015) 6458–6462.
[4] T.K. Ngooi, A. Scilimati, Z. Guo, C.J. Sih, J. Org. Chem. 54 (1989) 911–914. [15] C.S. Chen, Y. Fujimoto, G. Girdaukas, C. Sih, J. Am. Chem. Soc. 104 (1982)
[5] (a) E.F. Mateos, B. Maciá, M. Yus, Eur. J. Org. Chem. (2012) 3732–3736; 1294–1299.
(b) E.F. Mateos, B. Maciá, M. Yus, Tetrahedron: Asymmetry 23 (2012) [16] (a) H.E. Hogberg, H. Edlund, P. Berglund, E. Hedenstrom, Tetrahedron:
789–794; Asymmetry 4 (1993) 2123–2126;
(c) P. Kotrusz J. Am. Chem. Soc. 128 (2006) 4940–4941; (b) B. Herradon, J. Org. Chem. 59 (1994) 2891–2893;
(d) Y.S. Sokeirik, H. Mori, M. Omote, K. Sato, A. Tarui, I. Kumadaki, A. Ando, (c) U. Bornscheuer, A. Herar, L. Kreye, V. Wendel, A. Capewell, H.M. Meyer, T.
Org. Lett. 9 (2007) 1927–1929. Scheper, F.N. Kolisis, Tetrahedron: Asymmetry 4 (1993) 1007–1016.
[6] (a) S. Itsuno, A. Hirao, S. Nakahama, N. Yamazaki, J. Chem. Soc. Chem. [17] C.M. König, K. Harms, U. Koert, Org. Lett. 9 (2007) 4777–4779.
Commun. (1981) 315–317; [18] T. Ohkuma, M. Koizumi, M. Yoshida, R. Noyori, Org. Lett. 2 (2000) 1749–1751.
(b) E.J. Corey, R.K. Bakshi, S. Shibata, J. Am. Chem. Soc 109 (1987) 5551–5553; [19] S. Akai, R. Hanada, N. Fujiwara, Y. Kita, M. Egi, Org. Lett. 12 (2010) 4900–4903.
(c) E.J. Corey, C.J. Helal, Angew. Chem. Int. Ed. Eng. 37 (1998) 1986–2012. [20] G. Palmieri, Tetrahedron: Asymmetry 11 (2000) 3361–3373.
[7] (a) P.O. Lagaditis, P.E. Sues, J.F. Sonnenberg, K.Y. Wan, A.J. Lough, R.H. Morris, J.
Am. Chem. Soc. 136 (2014) 1367–1380;
(b) T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K. Murata, E.
Katayama, T. Yokozawa, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 12 (1998)
13529–13530.