Asymmetric synthesis of azolium-based 1,2,3,4-tetrahydronaphthalen-2-ols through lipase-catalyzed resolutions

Article abstract of DOI:10.1016/j.tetasy.2015.06.006

Abstract A series of racemic trans-1,2,3,4-tetrahydronaphthalen-2-ols bearing an azole nucleus at the C-1 or C-3 position has been synthesized by ring opening reactions of the corresponding epoxides using imidazole or 1,2,4-triazole. The kinetic resolutions of these racemates were undertaken through transesterification processes, finding good levels of activities and high to excellent enantiodiscrimination values for the Pseudomonas cepacia lipase immobilized on a ceramic carrier. Investigations into the optimum reaction conditions were carried out by consideration of different organic solvents, temperatures, enzyme loadings, and reaction times. With the best conditions in hand, the experiments were later carried out toward the resolution of the related racemic cis-alcohols, which were previously obtained through a Mitsunobu and deprotection chemical sequence from the trans-stereoisomers.

Full text of DOI:10.1016/j.tetasy.2015.06.006

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of azolium-based 1,2,3,4-
tetrahydronaphthalen-2-ols through lipase-catalyzed resolutions
⇑
Daniel Méndez-Sánchez, Nicolás Ríos-Lombardía, Vicente Gotor, Vicente Gotor-Fernández
Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, 33006 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of racemic trans-1,2,3,4-tetrahydronaphthalen-2-ols bearing an azole nucleus at the C-1 or C-3
position has been synthesized by ring opening reactions of the corresponding epoxides using imidazole
or 1,2,4-triazole. The kinetic resolutions of these racemates were undertaken through transesterification
processes, finding good levels of activities and high to excellent enantiodiscrimination values for the
Pseudomonas cepacia lipase immobilized on a ceramic carrier. Investigations into the optimum reaction
conditions were carried out by consideration of different organic solvents, temperatures, enzyme load-
ings, and reaction times. With the best conditions in hand, the experiments were later carried out toward
the resolution of the related racemic cis-alcohols, which were previously obtained through a Mitsunobu
and deprotection chemical sequence from the trans-stereoisomers.
Received 23 May 2015
Accepted 2 June 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
context, lipase-catalyzed resolutions of pyrazole-,10 imidazole-,11
and triazole-cycloalkanols12 have been studied in depth over the
The development of asymmetric synthetic routes toward chiral
1,2-amino alcohols, also known as b-amino alcohols, is an attractive
task because of the versatility of this motif that is present in
numerous biologically active compounds.1 In addition, enantiopure
1,2-amino alcohols are versatile organic compounds in coordination
chemistry and organocatalysis, playing an important role as chiral
auxiliaries and as ligands in multiple asymmetric transformations.2
Biocatalysis represents an elegant and sustainable strategy for
the preparation of optically active amino alcohol derivatives,3 as
lipases offering significant advantages in the resolution of racemic
N-substituted-2-amino-cycloalkanols by means of O-acetylation
protocols4 or complementary hydrolytic procedures.5
last two decades. The application of this class of hydrolytic enzymes
provides an efficient access to alcohol and ester derivatives with
high stereodiscrimination.
Herein, we have focused on the synthesis of a novel family of
racemic azole derivatives, studying their lipase-catalyzed kinetic
resolutions through transesterification reactions. The influence of
the azole subunit and the spatial disposition of the substituents
have been analyzed.
2. Results and discussion
2.1. Chemical synthesis and lipase-catalyzed resolution of
trans-3-(1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphthalen-2-ol
The presence of an azole subunit imparts remarkable properties,
offering a myriad of possibilities in both organocatalysis6 and
medicinal chemistry.7
A large list of azole drugs such as
The synthesis of racemic trans-3-(1H-imidazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-ol 2 was performed from commercially
available naphthalene. Following an already described pathway
involving the Birch reduction of naphthalene to 1,4-dihydronaph-
thalene using sodium in THF,13 and later transformation to the
corresponding epoxide 1 using meta-chloroperbenzoic acid in
dichloromethane for a global 36% isolated yield.14 Epoxide 1 was
reacted with a slight excess of imidazole (1.2 equiv) at 120 °C,
obtaining exclusively the alcohol ( )-trans-2 in good yield
(Scheme in Table 1). Then, a vast number of lipases were tested
using 3 equiv of vinyl acetate 3 as acyl donor in THF as solvent,
which was the one that provided the best solubility of the alcohol.
econazole, fluconazole, ketoconazole, miconazole, ravuconazole
and voriconazole are currently commercialized for the treatment
of human diseases. On the other hand, novel imidazole-based
dihydronaphthalenes and indenes have been used as building
blocks for the synthesis of potential inhibitors of aldosterone
synthases with applications in the treatment of congestive heart
failure and myocardial fibrosis.8 Recently racemic cycloalkyl azoles
have been described as potent antileishmanial agents.9 In this
⇑
Corresponding author. Tel.: +34 985 10 34 54; fax: +34 985 10 34 48.
E-mail address: vicgotfer@uniovi.es (V. Gotor-Fernández).
http://dx.doi.org/10.1016/j.tetasy.2015.06.006
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Méndez-Sánchez, D.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.006

2
D. Méndez-Sánchez et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 1
Synthesis and kinetic resolution of alcohol ( )-trans-2 (0.1 M) using different PSL preparations and 3 equiv of vinyl acetate 3 as the acyl donor and 250 rpm
O
3
OH
N
OAc
N
OH
N
imidazole
O
O
+
1,4-dioxane
24 h, 120 ºC
(73%)
lipase
N
N
N
organic solvent
T, 250 rpm
1
2
4
(2R,3R)-
(2S,3S)-2
(
)-trans-
b
b
Entry
1
Enzymea
Solvent
THF
T (°C)
t (h)
eeP (%)
eeS (%)
18
cc (%)
Ed
PSL IM (1:1)
30
38
97
16
79
2
3
PSL IM II (1:1)
PSL IM II (1:1)
THF
THF
30
45
48
48
99
95
11
25
10
20
>200
50
4
5
6
PSL-C I (1:1)
PSL-C I (2:1)
PSL-C I (1:1)
THF
THF
MTBE
30
30
30
48
48
48
95
95
94
83
82
8
46
46
8
102
99
35
a
b
c
Amount of enzyme in parentheses (ratio of enzyme:alcohol in weight).
Enantiomeric excess of product and substrate calculated by HPLC using a chiral column (see further details in Section 4).
Conversion: c = eeS/(eeS + eep).
d
Enantiomeric ratio: E = ln[(1 À c) Â (1 À eeP)]/ln[(1Àc) Â (1 + eeP)].15
1) PNBA, PPh3, DEAD
OH
N
OH
N
Unfortunately, no reaction was observed with Candida antarctica
lipase type B (CAL-B), Candida antarctica lipase type A (CAL-A), lipase
AK from Pseudomonas fluorescens, lipase from Rhizomucor miehei
(RML), porcine pancreatic lipase (PPL), Candida rugosa lipase (CRL),
and lipase from Thermomyces lanuginosus (TLL). Only Pseudomonas
cepacia lipase (PSL), currently known as Burkholderia cepacia lipase,
catalyzed the reaction to an appreciable degree and in general with
good selectivities. Various types of commercially available PSL were
tested such as PSL IM (entry 1) and PSL IM II (entries 2 and 3), both
supported on diatomite and only differing in the units per gram of
solid (see Section 4 for further details) and PSL-C I that is immobi-
lized onto a ceramic carrier (entries 4–6). Both PSL IM and PSL IM
II provided a high stereodiscrimination in the acetylation of the
(2R,3R)-alcohol although with low conversion values (entries 1
and 2), while an increase in the temperature resulted in an apprecia-
ble loss of the selectivity (entry 3).
Significantly, a 46% conversion and a high enantioselectivity
were achieved with PSL-C I at 30 °C (entry 4), without observing
appreciable improvements at higher enzyme loadings (entry 5).
Finally, other solvents were tested in the resolution of ( )-trans-
2, although the results did not improve upon the previous ones
obtained with THF. The more environmentally friendly 2-methyl-
tetrahydrofuran (2-Me-THF) did not solubilize the alcohol so the
reaction did not proceed in any extension, while methyl tert-butyl
ether (MTBE) led to lower conversion and selectivity values (entry
6). The absolute configurations were assigned as (2S,3S) for the
trans-alcohol 2 and (2R,3R) for the trans-acetate 4 by comparison
with previous investigations carried out in the lipase-catalyzed
resolution of N-substituted-2-aminocyclohexanols.4c,h,11a,12
THF, rt, 2 h
2) K2CO3, MeOH, H2O
16 h, rt (82%)
N
N
2
(
)-cis-
Scheme 1. Transformation of racemic alcohol trans-2 into cis-2 following
Mitsunobu and deprotection sequence.
a
significant activity. All the reactions were carried out in THF to
assure a proper solubilization of the alcohol and 3 equiv of 3 as acyl
donor. The results are summarized in Table 2.
Both PSL supported on diatomite displayed good selectivities in
the formation of the (2R,3S)-acetate 4 although with low conver-
sions (entries 1 and 2), decreasing the enantiopurity of the product
with longer reaction times. A better reactivity was observed with
PSL-C I in THF, achieving a 32% conversion for a 97% ee of the acetate
(entry 3). Trying to explore the possibilities of other reaction media,
MTBE was tested but although the stereodiscrimination was higher
the conversion became lower (entry 4). At this point, the loading of
the enzyme was doubled trying to obtain a conversion close to 50%
but a loss of selectivity was observed at shorter reaction times
(entry 5). Finally, higher temperatures led to an increase in the con-
version, although at 60 °C the conversion surpassed 50%, favouring
at this point the acetylation of the undesired enantiomer (entries 6
and 7). The absolute configurations were assigned (2S,3R) for the
cis-alcohol 2 and as (2R,3S) for the cis-acetate 4 by comparison with
previous investigations carried out in the lipase-catalyzed resolu-
tion of cis-N-substituted-2-aminocyclohexanols.4a,h,11b,12
2.2. Chemical synthesis and lipase-catalyzed resolution of cis-3-
(1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphthalen-2-ol
2.3. Chemical synthesis and lipase-catalyzed resolution of
trans- and cis-3-(1H-1,2,4-triazol-1-yl)-1,2,3,4-tetrahydronaph-
thalen-2-ols
In order to explore the reactivity of racemic cis-2, this alcohol
was prepared following a Mitsunobu and deprotection sequence
as depicted in Scheme 1. For this purpose, para-nitrobenzoic acid
(PNBA), triphenylphosphine (PPh3), and diethyl azodicarboxylate
(DEAD) were used in combination with THF as solvent, leading to
the total inversion of the C-2 position. Without isolation of the
ester intermediate, its deprotection in basic media was carried
out with potassium carbonate (K2CO3) in a mixture of water and
methanol, obtaining the alcohol ( )-cis-2 in an overall 82% isolated
yield. Then, the enzymatic resolution was attempted using differ-
ent PSL preparations and CAL-B, although only PSL displayed a
Once that the reactivity of cis- and trans-imidazolium-based
1,2,3,4-tetrahydronaphthalen-2-ols had been studied, we decided
to focus on derivatives with the triazole nucleus (Scheme 2).
Epoxide 1 was reacted with an equimolecular amount of 1,2,4-tri-
azole in the presence of 2 equiv of 1,8-diazabicycloundec-7-ene
(DBU) as the base using previously optimized reactions for the
opening of cyclopentene and cyclohexene oxides.12 Thus, the for-
mation of the undesired 1,3,4-triazole derivative was minimized,
and the racemic alcohol trans-5 was finally isolated in 63% yield
after column chromatography on silica gel. For the formation of
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D. Méndez-Sánchez et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
Table 2
PSL-catalyzed acetylation of ( )-cis-2 (0.1 M) using 3 equiv of vinyl acetate 3 as the acyl donor and 250 rpm
O
3
OH
N
OAc
N
OH
N
O
+
lipase
N
N
N
organic solvent
T, 250 rpm
2
4
(2R,3S)-
(2S,3R)-2
(
)-cis-
b
b
Entry
Enzymea
Solvent
THF
T (°C)
30
t (h)
48
eeP (%)
95
eeS (%)
cc (%)
14
Ed
1
2
PSL IM (1:1)
PSL IM II (1:1)
15
7
45
THF
30
48
99
7
>200
3
4
5
6
7
PSL-C I (1:1)
PSL-C I (1:1)
PSL-C I (2:1)
PSL-C I (2:1)
PSL-C I (2:1)
THF
MTBE
THF
THF
THF
30
30
30
45
60
48
48
24
24
24
97
99
86
95
86
45
9
54
71
94
32
8
39
43
53
102
>200
22
83
47
a
b
c
Amount of enzyme in parentheses (ratio of enzyme:alcohol in weight).
Enantiomeric excess of product and substrate calculated by HPLC using a chiral column (see further details in Section 4).
Conversion: c = eeS/(eeS + eep).
d
Enantiomeric ratio: E = ln[(1 À c) Â (1 À eeP)]/ln[(1 À c) Â (1 + eeP)].15
OH
The lipase-catalyzed resolutions of racemic trans- and cis-alco-
hols 5 were studied under similar conditions to those previously
described for 2, that is, 3 equiv of vinyl acetate, THF as solvent
for a 100 mM substrate concentration, 30 °C, and a ratio 1:1 of
lipase/alcohol in weight (Table 3).
1,2,4-triazole
DBU
O
N
N
1,4-dioxane
18 h, 100 ºC
(63%)
N
1
( )-trans-5
In all cases, excellent selectivities were observed, improving the
results obtained with the imidazole ring, that is, the presence of an
extra nitrogen atom provides a beneficial effect in the PSL action.
Remarkably, alcohol trans-5 was efficiently resolved with 48% con-
version when PSL-C I was used (entry 3), displaying a higher activity
incomparisonwithotherPSLpreparations(entries1 and2). Similarly,
but with a more modest conversion, the same enzyme exclusively
catalyzed the acetylation of the cis-(2R,3S)-5 isomer (entries 4 and 5).
1) PNBA, PPh3, DIAD
toluene, rt, 2 h
2) K2CO3, MeOH, H2O
16 h, rt (83%)
OH
N
N
N
5
2.4. Chemical synthesis and lipase-catalyzed resolution of
(
)-cis-
trans-1-(1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphthalen-2-ol
Scheme 2. Chemical synthesis of racemic triazoles trans- and cis-5.
Based on the exceptional antileishmanial properties reported
for tetrahydronaphthylazoles, the synthesis of racemic trans-1-
(1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphthalen-2-ol 8 was
performed opening epoxide 7 with imidazole in refluxing ethanol
(Scheme in Table 4).9 The synthesis of alcohol cis-8 was developed
following the Mitsunobu and deprotection inversion previously
described for triazole 5, that is, the use of PNBA, PPh3, DIAD in
the racemic alcohol cis-5, identical conditions to those previously
used with imidazole 2 were attempted, achieving a 78% yield. A
slight improvement in the synthetic methodology was attained
by employing toluene and diisopropyl azodicarboxylate (DIAD)
instead of THF and DEAD, respectively, isolating alcohol cis-5 in
83% after subsequent basic hydrolysis in the presence of K2CO3.
Table 3
PSL-catalyzed acetylation of ( )-trans- and ( )-cis-5 using 3 equiv of vinyl acetate 3 in THF (0.1 M) at 30 °C and 250 rpm
O
3
OH
OAc
OH
*
*
*
*
O
+
N
N
N
N
N
N
PSL
THF
30 ºC, 48 h
250 rpm
N
N
N
( )-trans-5
( )-cis-5
(2R,3R)-6
(2R,3S)-6
(2S,3S)-5
(2S,3R)-5
a
a
Entry
( )-5
Enzyme
eeP (%)
eeS (%)
cb (%)
Ec
140
>200
>200
1
2
3
trans
trans
trans
PSL IM
PSL IM II
PSL-C I
98
99
99
35
19
93
28
19
48
4
5
cis
cis
PSL IM II
PSL-C I
99
>99
7
29
7
23
>200
>200
a
b
c
Enantiomeric excess of product and substrate calculated by HPLC using a chiral column (see further details in Section 4).
Conversion: c = eeS/(eeS + eep).
Enantiomeric ratio: E = ln[(1 À c) Â (1 À eeP)]/ln[(1 À c) Â (1 + eeP)].15
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4
D. Méndez-Sánchez et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 4
Lipase-catalyzed acetylation of alcohol ( )-8 using 3 equiv of 3 as the acyl donor in THF (0.1 M) at 30 °C and 250 rpm
N
N
N
O
3
O
reference 9
N
O
N
*
N
*
+
OH
OAc
OH
lipase
THF
*
*
30 ºC,48 h
250 rpm
7
8
9
9
8
8
(
)-trans-
(1R,2R)-
(1S,2S)-
Mitsunobu and
deprotection sequence
(
)-cis-8
(1S,2R)-
(1R,2S)-
cb (%)
Ec
a
a
Entry
( )-8
Enzyme
eeP (%)
eeS (%)
1
2
3
trans
trans
trans
PSL IM
PSL-C I
CAL-B
>99
96
>99
<3
85
41
<3
43
30
>200
133
>200
4
5
6
cis
cis
cis
PSL IM
PSL-C I
CAL-B
—
98
—
—
98
—
—
50
—
—
>200
—
a
b
c
Enantiomeric excess of product and substrate calculated by HPLC using a chiral column (see further details in Section 4).
Conversion: c = eeS/(eeS + eep).
Enantiomeric ratio: E = ln[(1–c) Â (1–eeP)]/ln[(1–c) Â (1 + eeP)].15
toluene, and later deprotection of the resulting ester in a basic
medium (Scheme in Table 4). Using both stereoisomers, PSL and
CAL-B were tested as enzyme sources for the acetylation of the
C-2 position (Table 4), finding the best results for the PSL-C I
(entries 2 and 5), which acted with excellent stereodiscrimination
for both the trans-alcohol (43% conversion) and the cis-alcohol
(50% conversion) after 48 h at 30 °C. Remarkably, the CAL-B seems
to exclusively recognize the alcohol trans-(1R,2R)-8, while the cis-
stereoisomer was not acylated in any extension (entries 3 and 6).
The absolute configurations were assigned as (1S,2S) for the
trans-alcohol 8 and (1R,2R) for the trans-acetate 9 by comparison
with previous investigations carried out in the resolution of
N-substituted-1-aminoindan-2-ols by means of PSL-catalyzed
acetylation reactions.4b
Sigma–Aldrich, while the ones immobilized on diatomite PSL IM
(943 U/g) and PSL IM II (816 U/g) were provided by Amano
Europe Pharmaceutical Company. The pancreatic porcine lipase
(PPL, 46 U/mg) was purchased from Sigma. The Candida antarctica
lipase type A (CAL-A, 2.6 U/mg) was provided by Codexis.
Flash chromatography was performed using silica gel 60 (230–
240 mesh). Melting points were taken on samples in open capillary
tubes and are uncorrected. IR spectra were recorded using KBr pel-
lets. 1H, 13C NMR, and DEPT were obtained using Bruker AV-300
(1H, 300.13 MHz; 13C, 75.5 MHz) and Bruker DPX-300 spectrome-
ters (1H, 300.13 MHz, 13C, 75.5 MHz). Chemical shifts are given in
delta values (d, ppm) and the coupling constants (J) in Hertz
(Hz). APCI+ experiments were carried out using
a liquid
chromatograph mass detector to record mass spectra (MS). High
resolution mass experiments (HRMS) were measured by ESI+ and
carried out with a Bruker Micro TofQ.
3. Conclusions
High performance liquid chromatography (HPLC) analyses were
carried out in a Hewlett Packard 1100 chromatograph using the fol-
lowing chiral columns Chiralpak IC (25 Â 4.6 mm D.I.), Chiralcel OD-
H, (25 Â 4.6 mm D.I.), and Chiralcel OJ-H, (25 Â 4.6 mm D.I.) at
40 °C. Mixtures of hexane/2-propanol were employed as mobile
phases (see later further details for each individual compound). A
UV detector at 210 y 215 nm was used for the detection of the alco-
hols and acetates.
In conclusion, the high stereodiscrimination of Pseudomonas
cepacia lipase (PSL) has been demonstrated in the classical kinetic
resolution of trans- and cis-3-(1H-imidazol-1-yl)-1,2,3,4-tetrahy-
dronaphthalen-2-ol. Depending on the type of immobilization,
the best results were found with the PSL supported onto ceramics
rather than in diatomite, but in all cases PSL displayed better activ-
ities in comparison with other tested lipases. This methodology
was successfully extended to other families of substrates such
as 3-(1H-1,2,4-triazol-1-yl)-1,2,3,4-tetrahydronaphthalen-2-ol
and 1-(1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphthalen-2-ol both
with trans- or cis-relative disposition of the substituents.
4.2. Synthesis of ( )-trans-3-(1H-imidazol-1-yl)-1,2,3,4-tetra-
hydronaphthalen-2-ol ( )-trans-2
A solution of imidazole (227 mg, 3.23 mmol) and epoxide 1
(403 mg, 2.77 mmol) in 1,4-dioxane (1.4 mL) was placed in a sealed
tube and stirred at 120 °C until the complete disappearance of the
epoxide (24 h). The solvent was then evaporated and the resulting
crude purifies by column chromatography on silica gel (2–6%
MeOH/CH2Cl2), yielding the alcohol ( )-trans-2 as a white solid
(73% isolated yield). Mp: 169–171 °C. Rf (10% MeOH/CH2Cl2): 0.47;
4. Experimental section
4.1. General
Chemical reagents were purchased from different commercial
sources (Sigma–Aldrich, Acros and Fluka) and used without further
purification. Solvents were distilled over an adequate desiccant
IR (KBr):
m ;
3496, 3115, 2987, 1073, 745 cmÀ1 1H NMR (MeOD,
3
3
300.13 MHz): d 2.82 (1H, dd, JHH = 16.6 Hz; JHH = 9.4 Hz), 3.11
under nitrogen. Candida antarctica lipase type
B
(CAL-B,
(1H, dd, 3JHH = 16.6 Hz; 3JHH = 5.7 Hz), 3.16–3.23 (2H, m), 4.09 (1H,
7300 PLU/g) immobilized by adsorption in Lewatit E, Rhizomucor
miehei lipase (RML, 150 IUN/g) and Thermomyces lanuginosus lipase
(TLL, 250 IUN/g) were kindly donated by Novozymes. Pseudomonas
cepacia lipase immobilized over ceramic particles (PSL-C I,
1950 U/g), lipase AK from Pseudomonas fluorescens (22,100 U/g)
and Candida rugosa lipase (CRL, 965 U/mg) were purchased from
3
3
td, JHH = 9.4 Hz; JHH = 5.7 Hz), 4.20–4.31 (1H, m), 6.91 (1H, s),
7.01–7.07 (4H, m), 7.13 (1H, s), 7.65 (1H, s); 13C NMR (MeOD,
75.5 MHz): d 36.6 (CH2), 38.7 (CH2), 61.2 (CH), 70.6 (CH), 118.8
(CH), 127.4 (CH), 127.6 (CH), 128.9 (CH), 129.3 (CH), 129.8 (CH),
134.6 (C), 135.0 (C), 138.1 (CH); MS (APCI+, m/z): 215 [(M+H)+];
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D. Méndez-Sánchez et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
HRMS (ESI+, m/z) calcd for C13H15N2O (M+H)+: 215.1179 found:
215.1194.
(15 mL), after which brine (5 mL) was added, and then the resulting
mixture was extracted with EtOAc (3 Â 20 mL). The organic phases
were combined, dried over Na2SO4, and the solvent evaporated
under reduced pressure. Finally, the reaction crude was purified
by column chromatography on silica gel (2–6% MeOH/CH2Cl2),
yielding the alcohol ( )-cis-2 as a white solid (82% isolated yield).
4.3. Synthesis of racemic trans-3-(1H-imidazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-yl acetate ( )-trans-4
The synthesis of racemic trans-acetate 4 was performed just for
analytical purposes in order to calculate the enantiomeric excess of
the product in the lipase-catalyzed resolutions.
Mp: 166–168 °C. Rf (10% MeOH/CH2Cl2): 0.37; IR (KBr):
m 3415,
3023, 2971, 1015, 846 cmÀ1 1H NMR (MeOD, 300.13 MHz): d
;
2.69–2.76 (2H, m), 3.00–3.21 (2H, m), 3.30–3.42 (1H, m), 4.10–
4.25 (1H, m), 4.40–4.55 (1H, m), 6.85 (1H, s), 7.00–7.15 (5H, m),
7.66 (1H, s); 13C NMR (MeOD, 75.5 MHz): d 32.8 (CH2), 37.5 (CH2),
58.7 (CH), 69.1 (CH), 120.5 (CH), 127.6 (CH), 127.9 (CH), 128.5
(CH), 129.9 (CH), 130.8 (CH), 134.5 (C), 134.8 (C), 138.1 (CH); MS
(APCI+, m/z): 215 [(M+H)+]; HRMS (ESI+, m/z) calcd for C13H15N2O
(M+H)+: 215.1179, found: 215.1184.
To a solution of alcohol ( )-trans-2 (30 mg, 0.14 mmol) in dry
CH2Cl2 (1.4 mL), Et3N (59
lL, 0.42 mmol), DMAP (5 mg, 0.04 mmol),
and Ac2O (26 L, 0.28 mmol) were successively added under a
l
nitrogen atmosphere. The reaction was stirred at room temperature
for 2 h until the complete consumption of the starting material, and
then the solvent was evaporated under reduced pressure. The
reaction crude was purified by column chromatography on silica gel
(1–3% MeOH/CH2Cl2), to yield the acetate ( )-trans-4 as a pale
yellow solid (97% isolated yield). Mp: 91–93 °C. Rf (10%
4.6. Synthesis of racemic cis-3-(1H-imidazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-yl acetate ( )-cis-4
MeOH/CH2Cl2): 0.81; IR (KBr):
m 3112, 2984, 1733, 1265, 1071,
745 cmÀ1
;
1H NMR (CDCl3, 300.13 MHz): d 1.93 (3H, s), 2.98 (1H,
The synthesis of racemic cis-acetate 4 was performed just for
analytical purposes in order to calculate the enantiomeric excess
of the product in the lipase-catalyzed resolutions.
3
3
dd, JHH = 16.7 Hz; JHH = 8.8 Hz), 3.23–3.41 (3H, m), 4.47–4.55
(1H, m), 5.33–5.41 (1H, m), 6.97 (1H, s), 7.08–7.15 (3H, m), 7.18–
7.23 (2H, m), 7.57 (1H, s); 13C NMR (CDCl3, 75.5 MHz): d 21.1
(CH3), 34.4 (CH2), 35.2 (CH2), 56.6 (CH), 71.6 (CH), 127.2 (CH),
127.4 (CH), 128.8 (2CH), 129.4 (2CH), 130.0 (CH), 132.6 (C), 132.7
(C), 170.4 (C); MS (APCI+, m/z): 257 [(M+H)+]; HRMS (ESI+, m/z) calcd
for C15H17N2O2 (M+H)+: 257.1285, found: 257.1292.
To a solution of alcohol ( )-cis-2 (30 mg, 0.14 mmol) in dry
CH2Cl2 (1.4 mL), Et3N (59
lL, 0.42 mmol), DMAP (5 mg, 0.04 mmol),
and Ac2O (26 L, 0.28 mmol) were successively added under a
l
nitrogen atmosphere. The reaction was stirred at room temperature
for 2 h until the complete consumption of the starting material, and
then the solvent was evaporated under reduced pressure. The reac-
tion crude was purified by column chromatography on silica gel
(1–3% MeOH/CH2Cl2), yielding the acetate ( )-cis-4 as a pale yellow
solid (97% isolated yield). Mp: 136–138 °C. Rf (10% MeOH/CH2Cl2):
4.4. General procedure for the lipase-catalyzed resolution of the
alcohol ( )-trans-2
3022, 2971, 1735, 1266, 1020, 849 cmÀ1
;
1H NMR
To a suspension of alcohol ( )-trans-2 (30 mg, 0.14 mmol) and
PSL (30 mg) in dry THF (1.4 mL), vinyl acetate (39 lL, 0.42 mmol)
0.70; IR (KBr):
m
3
(CDCl3, 300.13 MHz): d 2.06 (3H, s), 2.97 (1H, dd, JHH = 17.5 Hz;
2JHH = 6.3 Hz), 3.19 (1H, dd, 3JHH = 17.5 Hz; 2JHH = 4.7 Hz), 3.36 (1H,
was added under a nitrogen atmosphere. The reaction was shaken
for the appropriate time at 30 °C and 250 rpm. Aliquots were
regularly analyzed by HPLC and stopped at 38 or 48 h. The enzyme
was filtered off using CH2Cl2 (3 Â 5 mL), the solvent evaporated
under reduce pressure and the reaction crude purified by flash
chromatography on silica gel (2–10% MeOH/CH2Cl2), affording the
corresponding optically enriched acetate (2R,3R)-4 and the alcohol
3
2
3
dd, JHH = 16.8 Hz; JHH = 5.7 Hz), 3.51 (1H, dd, JHH = 16.8 Hz;
2JHH = 8.0 Hz), 4.64–4.70 (1H, m), 5.35–5.39 (1H, m), 6.91 (1H, s),
6.96 (1H, s), 7.04 (1H, s), 7.01–7.13 (1H, m), 7.16–7.25 (3H, m)
7.54 (1H, s); 13C NMR (CDCl3, 75.5 MHz): d 21.0 (CH3), 32.0 (CH2),
32.1 (CH2), 54.4 (CH), 70.5 (CH), 118.1 (CH), 126.7 (CH), 126.8
(CH), 128.5 (CH), 129.0 (CH), 129.2 (CH), 131.7 (C), 132.0 (C),
136.4 (CH), 170.0 (C); MS (APCI+, m/z): 257 [(M+H)+], HRMS (ESI+,
m/z) calcd for C15H17N2O2 (M+H)+: 257.1285, found: 257.1299.
(2S,3S)-2 (see Table 1). Alcohol: [a]
20 = +26.0 (c 1.0, MeOH) for 83%
D
ee (Chiralcel OD-H; 50% Hexane/2-Propanol; 0.7 mL/min flow).
Acetate: [
a
]
20 = À4.5 (c 1.0, MeOH) for 99% ee (Chiralcel OD-H;
D
50% Hexane/2-Propanol; 0.7 mL/min flow).
4.7. General procedure for the lipase-catalyzed resolution of the
alcohol ( )-cis-2
4.5. Synthesis of racemic cis-3-(1H-imidazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-ol ( )-cis-2
To a suspension of alcohol ( )-cis-2 (30 mg, 0.14 mmol) and PSL
(30 mg) in dry THF (1.4 mL), vinyl acetate (39 lL, 0.42 mmol) was
The synthesis was based on a Mitsunobu inversion reaction fol-
lowed by the deprotection of the resulting ester group, and it is as
follows.
added under nitrogen atmosphere. The reaction was shaken for the
appropriate time at 30 °C and 250 rpm. Aliquots were regularly
analyzed by HPLC and stopped at 24 or 48 h. The enzyme was
filtered off using CH2Cl2 (3 Â 5 mL), the solvent evaporated under
reduce pressure and the reaction crude purified by flash chro-
matography on silica gel (2–10% MeOH/CH2Cl2), affording the
corresponding optically enriched acetate (2R,3S)-4 and the alcohol
4.5.1. Mitsunobu reaction
To a solution of alcohol ( )-trans-2 (359 mg, 1.68 mmol) in dry
THF (25.3 mL), p-nitrobenzoic acid (625 mg, 3.73 mmol), PPh3
(981 mg, 3.73 mmol), and DEAD (683 lL, 3.73 mmol) were succes-
(2S,3R)-2 (see Table 2). Alcohol: [a]
20 = +39.0 (c 1.0, MeOH) for 94%
D
sively added under nitrogen atmosphere. The mixture was stirred
for 2 h at room temperature, until complete consumption of the
starting alcohol by TLC analysis (5% MeOH/CH2Cl2). The organic
solvent was evaporated under reduced pressure to afford a reac-
tion crude that was immediately used for the deprotection step.
ee (Chiralpak IC; 60% Hexane/2-Propanol; 0.8 mL/min flow).
Acetate: [
a
]
20 = À14.4 (c 0.5, MeOH) for 99% ee (Chiralcel OJ-H;
D
80% Hexane/2-Propanol; 0.8 mL/min flow).
4.8. Synthesis of racemic trans-3-(1H-1,2,4-triazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-ol ( )-trans-5
4.5.2. Deprotection step
To a solution of the Mitsunobu reaction crude in MeOH (3.1 mL),
K2CO3 (514 mg, 3.73 mmol) and H2O (3.1 mL) were added. The mix-
ture was stirred for 16 h and then MeOH was evaporated under
reduced pressure. The resulting suspension was dissolved in H2O
A DBU solution (0.42 mL, 2.76 mmol) in 1,4-dioxane (0.42 mL)
was carefully added to
a solution containing 1,2,4-triazole
(96 mg, 1.38 mmol) and epoxide 1 (200 mg, 1.38 mmol) in
Please cite this article in press as: Méndez-Sánchez, D.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.006

6
D. Méndez-Sánchez et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
1,4-dioxane (1.8 mL). The reaction was stirred at 100 °C for 18 h
and then the mixture was cooled to room temperature. After this
time, the solvent was evaporated under reduced pressure and the
resulting crude purified by flash chromatography on silica gel
(2–10% MeOH/CH2Cl2), yielding the alcohol ( )-trans-5 as a white
solid (63% isolated yield). Mp: 149–151 °C. Rf (5% MeOH/CH2Cl2):
4.11.1. Mitsunobu reaction
To a suspension of the alcohol ( )-trans-5 (101 mg, 0.47 mmol)
in dry toluene (6.8 mL), p-nitrobenzoic acid (156 mg, 0.93 mmol)
and PPh3 (246 mg, 0.93 mmol) were successively added under a
nitrogen atmosphere, and warmed until the complete solubility
of the reagents. Next, DIAD (181 lL, 0.93 mmol) was added and
0.33; IR (KBr):
m
3494, 3107, 2984, 1078, 749 cmÀ1
;
1H NMR
the mixture stirred for 2 h, until the complete consumption of
the starting alcohol by TLC analysis (2% MeOH/CH2Cl2). The organic
solvent was evaporated under reduced pressure affording a reac-
tion crude that was immediately used for the deprotection step.
3
2
(CDCl3, 300.13 MHz): d 3.02 (1H, dd, JHH = 16.5 Hz; JHH = 8.4 Hz),
3
2
3.31 (2H, m), 3.59 (1H, dd, JHH = 16.3 Hz; JHH = 9.6 Hz), 4.14 (1H,
br s), 4.43–4.49 (2H, m), 7.13–7.23 (4H, m), 7.90 (1H, s), 8.17
(1H, s); 13C NMR (CDCl3, 75.5 MHz): d 34.5 (CH2), 37.2 (CH2),
62.6 (CH), 68.9 (CH), 126.6 (CH), 126.8 (CH), 128.4 (CH), 129.0
(CH), 132.6 (C), 133.4 (C), 143.6 (CH), 151.8 (C); MS (APCI+, m/z):
216 [(M+H)+]; HRMS (ESI+, m/z) calcd for C12H14N3O (M+H)+:
216.1131, found: 216.1150.
4.11.2. Deprotection step
To a solution of the Mitsunobu reaction crude in MeOH (800
K2CO3 (140 mg, 0.93 mmol) and H2O (800 L) were added. The mix-
lL),
l
ture was stirred for 16 h and then MeOH was evaporated under
reduced pressure. The resulting suspension was dissolved in H2O
(7 mL), after which brine (3 mL) was added, and then the resulting
mixture was extracted with EtOAc (4 Â 10 mL). The organic phases
were combined, dried over Na2SO4, and the solvent was evaporated
under reduced pressure. Finally, the reaction crude was purified by
column chromatography on silica gel (2–6% MeOH/CH2Cl2), yield-
ing alcohol ( )-cis-5 as a white solid (83% isolated yield). Mp:
4.9. Synthesis of racemic trans-3-(1H-1,2,4-triazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-yl acetate ( )-trans-6
The synthesis of racemic trans-acetate 6 was performed just for
analytical purposes in order to calculate the enantiomeric excess of
the product in the lipase-catalyzed resolutions.
104–106 °C. Rf (10% MeOH/CH2Cl2): 0.57; IR (KBr):
m 3411, 3055,
To a solution of alcohol ( )-trans-5 (30 mg, 0.14 mmol) in dry
2971, 1022, 844 cmÀ1 1H NMR (MeOD, 300.13 MHz): d 2.95 (1H,
;
CH2Cl2 (1.4 mL), Et3N (59
lL, 0.42 mmol), DMAP (5 mg, 0.04 mmol),
3
2
dd, JHH = 17.3 Hz; JHH = 4.2 Hz), 3.17–3.26 (2H, m), 3.58 (1H, dd,
and Ac2O (26 L, 0.28 mmol) were successively added under nitro-
l
3JHH = 15.9 Hz; JHH = 10.8 Hz), 4.45–4.48 (1H, m), 4.74–4.80 (1H,
2
gen atmosphere. The reaction was stirred at room temperature for
2 h until the complete consumption of the starting material, and
then the solvent was evaporated under reduced pressure. The reac-
tion crude was purified by column chromatography on silica gel
(1–3% MeOH/CH2Cl2), yielding the acetate ( )-trans-6 as a yellow solid
(97% isolated yield). Mp: 117–119 °C. Rf (5% MeOH/CH2Cl2): 0.66; IR
m), 7.10–7.17 (4H, m), 7.99 (1H, s), 8.59 (1H, s); 13C NMR (MeOD,
75.5 MHz): d 29.5 (CH2), 35.9 (CH2), 59.9 (CH), 66.5 (CH), 125.8
(CH), 126.2 (CH), 128.3 (CH), 129.0 (CH), 132.6 (C), 132.9 (C),
142.6 (CH), 150.1 (C); MS (APCI+, m/z): 216 [(M+H)+]; HRMS (ESI+,
m/z) calcd for C12H14N3O (M+H)+: 216.1131, found: 216.1155.
(KBr):
m ;
3115, 2983, 1728, 1259, 1070, 745 cmÀ1 1H NMR (CDCl3,
300.13 MHz): d 1.91 (3H, s), 2.97 (1H, dd, 3JHH = 16.5 Hz; 2JHH = 5.8.
4.12. Synthesis of racemic cis-3-(1H-1,2,4-triazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-yl acetate ( )-cis-6
Hz), 3.31 (1H, d, 3JHH = 5.8 Hz), 3.37 (1H, d, 3JHH = 5.8 Hz), 3.65 (1H,
3
2
3
dd, JHH = 16.7 Hz; JHH = 10.5 Hz), 4.71 (1H, td, JHH = 10.1 Hz;
2JHH = 5.8 Hz), 5.51 (1H, td, JHH = 9.3 Hz; JHH = 5.9 Hz), 7.10–7.21
(4H, m), 7.96 (1H, s), 8.13 (1H, s); 13C NMR (CDCl3, 75.5 MHz): d
20.7 (CH3), 33.8 (CH2), 34.1 (CH2), 58.8 (CH), 70.8 (CH), 126.8 (CH),
126.9 (CH), 128.4 (CH), 128.9 (CH), 132.2 (2C), 143.2 (CH), 152.0
(CH), 169.7 (C); MS (APCI+, m/z): 258 [(M+H)+]; HRMS (ESI+, m/z)
calcd for C14H16N3O2 (M+H)+: 258.1237, found: 258.1239.
3
2
The synthesis of racemic cis-acetate 6 was performed just for
analytical purposes in order to calculate the enantiomeric excess
of the product in the lipase-catalyzed resolutions.
To a solution of alcohol ( )-cis-5 (30 mg, 0.14 mmol) in dry
CH2Cl2 (1.4 mL), Et3N (59
lL, 0.42 mmol), DMAP (5 mg, 0.04 mmol),
and Ac2O (26 L, 0.28 mmol) were successively added under nitro-
l
gen atmosphere. The reaction was stirred at room temperature for
2 h until the complete consumption of the starting material, and
then the solvent was evaporated under reduced pressure. The reac-
tion crude was purified by column chromatography on silica gel
(1–3% MeOH/CH2Cl2), yielding the acetate ( )-cis-6 as a yellow solid
(96% isolated yield). Mp: 133–135 °C. Rf (10% MeOH/CH2Cl2): 0.65;
4.10. General procedure for the lipase-catalyzed resolution of
the alcohol ( )-trans-5
To a suspension of alcohol ( )-trans-5 (30 mg, 0.14 mmol) and
PSL (30 mg) in dry THF (1.4 mL), vinyl acetate (39 lL, 0.42 mmol)
IR (KBr):
m
3054, 2979, 1728 1264, 1074, 846 cmÀ1
;
1H NMR
was added under a nitrogen atmosphere. The reaction was shaken
for the appropriate time at 30 °C and 250 rpm. Aliquots were
regularly analyzed by HPLC and stopped at 48 h. The enzyme
was filtered off using CH2Cl2 (3 Â 5 mL), the solvent evaporated
under reduce pressure, and the reaction crude purified by flash
chromatography on silica gel (2–10% MeOH/CH2Cl2), affording
the corresponding optically enriched acetate (2R,3R)-6 and
3
(CDCl3, 300.13 MHz): d 2.00 (3H, s), 3.08 (1H, dd, JHH = 17.7 Hz;
2JHH = 4.8 Hz), 3.24 (1H, dd, 3JHH = 17.7 Hz; 2JHH = 4.3 Hz), 3.38 (1H,
3
2
3
dd, JHH = 16.3 Hz; JHH = 5.7 Hz), 3.64 (1H, dd, JHH = 16.3 Hz;
2JHH = 9.8 Hz) 4.90–4.95 (1H, m), 5.52–5.58 (1H, m), 7.12–7.25 (4H,
m), 7.94 (1H, s), 8.16 (1H, s); 13C NMR (CDCl3, 75.5 MHz): d 21.1
(CH3), 30.6 (CH2), 32.7 (CH2), 57.5 (CH), 69.5 (CH), 126.8 (CH),
127.0 (CH), 128.7 (CH), 129.3 (CH), 131.6 (C), 132.0 (C) 141.8 (CH),
151.5 (CH), 170.1 (C); MS (APCI+, m/z): 258 [(M+H)+]; HRMS (ESI+,
m/z) calcd for C14H16N3O2 (M+H)+: 258.1237, found: 258.1245.
the alcohol (2S,3S)-5 (see Table 3). Alcohol: [a]
20 = +35.0 (c 1.0,
D
MeOH) for 93% ee (Chiralcel OD-H; 60% Hexane/2-Propanol;
0.8 mL/min flow). Acetate: [
ee (Chiralcel OD-H; 60% Hexane/2-Propanol; 0.8 mL/min flow).
a
]
20 = À28.6 (c 1.0, MeOH) for >99%
D
4.13. General procedure for the lipase-catalyzed resolution of
the alcohol ( )-cis-5
4.11. Synthesis of racemic cis-3-(1H-1,2,4-triazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-ol ( )-cis-5
To a suspension of alcohol ( )-cis-5 (30 mg, 0.14 mmol) and PSL
(30 mg) in dry THF (1.4 mL), vinyl acetate (39 lL, 0.42 mmol) was
The synthesis was based on a Mitsunobu inversion reaction fol-
lowed by the deprotection of the resulting ester group, and it is as
follows.
added under a nitrogen atmosphere. The reaction was shaken for
the appropriate time at 30 °C and 250 rpm. Aliquots were regularly
analyzed by HPLC and stopped at 48 h. The enzyme was filtered off
Please cite this article in press as: Méndez-Sánchez, D.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.006

D. Méndez-Sánchez et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
using CH2Cl2 (3 Â 5 mL), the solvent was evaporated under reduce
4.17.1. Mitsunobu reaction
pressure and the reaction crude was purified by flash chromatogra-
phy on silica gel (2–10% MeOH/CH2Cl2), affording the correspond-
ing optically enriched acetate (R,S)-6 and alcohol (S,R)-5 (see
To a suspension of the alcohol ( )-trans-8 (100 mg, 0.47 mmol)
in dry toluene (6.8 mL), p-nitrobenzoic acid (156 mg, 0.93 mmol)
and PPh3 (246 mg, 0.93 mmol) were successively added under a
nitrogen atmosphere, and warmed until complete solubility of
Table 3). Alcohol: [a]
20 = +4.0 (c 1.0, MeOH) for 29% ee (Chiralcel
D
OD-H; 60% Hexane/2-Propanol; 0.8 mL/min flow). Acetate:
the reagents. Then, DIAD (181 lL, 0.93 mmol) was added and the
[
a]
D
20 = À29.0 (c 1.0, MeOH) for >99% ee (Chiralcel OD-H; 60%
mixture stirred for 2 h, until complete consumption of the starting
alcohol by TLC analysis (2% MeOH/CH2Cl2). The organic solvent
was evaporated under reduced pressure affording a reaction crude
that was immediately used for the deprotection step.
Hexane/2-Propanol; 0.8 mL/min flow).
4.14. Synthesis of racemic trans-1-(1H-imidazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-ol ( )-trans-8
4.17.2. Deprotection step
The synthesis of alcohol ( )-trans-8 was performed from
1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene 7 following the proto-
col as described by Marrapu et al.9
To a solution of the Mitsunobu reaction crude in MeOH
(800 lL), K2CO3 (140 mg, 0.93 mmol) and H2O (800 lL) were
added. The mixture was stirred for 16 h and then MeOH evapo-
rated under reduced pressure. The resulting suspension was
dissolved in H2O (7 mL), brine (3 mL) was added, and then the
resulting mixture was extracted with EtOAc (4 Â 10 mL). Organic
phases were combined, dried over Na2SO4, and the solvent evapo-
rated under reduced pressure. Finally, the reaction crude was puri-
fied by column chromatography on silica gel (2–6% MeOH/CH2Cl2),
yielding the alcohol ( )-cis-8 as a white solid (76% isolated yield).
4.15. Synthesis of racemic trans-1-(1H-imidazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-yl acetate ( )-trans-9
The synthesis of racemic trans-acetate 9 was performed just for
analytical purposes in order to calculate the enantiomeric excess of
the product in the lipase-catalyzed resolutions.
Mp: 202–204 °C; IR (KBr): 3411, 3023, 2971, 1018, 846 cmÀ1 1H
;
To a solution of alcohol ( )-trans-8 (30 mg, 0.14 mmol) in dry
NMR (300 MHz, MeOD): d 1.81–2.02 (2H, m), 2.86–2.97 (1H, m),
3.10–3.20 (1H, m), 4.18–4.22 (1H, m), 5.45–5.49 (1H, m), 6.89–
6.95 (3H, m), 7.14–7.18 (1H, m), 7.23–7.31 (2H, m), 7.57 (1H, s);
13C NMR (300 MHz, MeOD): d 26.1 (CH2), 26.2 (CH2), 60.0 (CH),
68.0 (CH), 120.4 (CH), 126.2 (CH), 126.4 (CH), 128.1 (CH), 128.6
(CH), 129.1 (CH), 132.7 (C), 136.8 (C), 138.0 (CH); MS (APCI+,
m/z): 215 [(M+H)+]; HRMS (ESI+, m/z) calcd for C13H15N2O
(M+H)+: 215.1179, found: 215.1178.
CH2Cl2 (1.4 mL), Et3N (59
lL, 0.42 mmol), DMAP (5 mg,
0.04 mmol), and Ac2O (26 L, 0.28 mmol) were successively added
l
under nitrogen atmosphere. The reaction was stirred at room tem-
perature for 2 h until the complete consumption of the starting
material, and then the solvent was evaporated under reduced pres-
sure. The reaction crude was purified by column chromatography
on silica gel (1–3% MeOH/CH2Cl2), yielding the acetate ( )-trans-9
as a yellow solid (89% isolated yield). Mp: 93–95 °C. Rf (10%
MeOH/CH2Cl2): 0.57; IR (KBr):
m 3117, 2986, 1732, 1262, 1072,
741 cmÀ1 1H NMR (CDCl3, 300.13 MHz): d 1.93–2.06 (1H, m),
;
4.18. Synthesis of racemic cis-1-(1H-imidazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-yl acetate ( )-cis-9
2.00 (3H, s), 2.17–2.26 (1H, m), 3.02–3.08 (2H, m), 5.20–5.27 (1H,
3
m) 5.33 (1H, d, JHH = 7.8 Hz), 6.82–6.88 (2H, m), 7.08 (1H, s),
7.14–7.29 (3H, m), 7.55 (1H, s); 13C NMR (CDCl3, 75.5 MHz): d
21.5 (CH3), 26.8 (CH2), 27.2 (CH2), 60.4 (CH), 73.9 (CH), 118.5
(CH), 127.3 (CH), 127.5 (CH), 128.9 (CH), 129.4 (CH), 130.5 (CH),
132.6 (C), 132.7 (C), 138.3 (CH), 170.6 (C); MS (APCI+, m/z): 257
[(M+H)+]; HRMS (ESI+, m/z) calcd for C15H17N2O2 (M+H)+:
257.1285, found: 257.1292.
The synthesis of racemic cis-acetate 9 was performed just for
analytical purposes in order to calculate the enantiomeric excess
of the product in the lipase-catalyzed resolutions.
To a solution of alcohol ( )-cis-8 (30 mg, 0.14 mmol) in dry
CH2Cl2 (1.4 mL), Et3N (59
lL, 0.42 mmol), DMAP (5 mg, 0.04 mmol),
and Ac2O (26 L, 0.28 mmol) were successively added under a nitro-
l
gen atmosphere. The reaction was stirred at room temperature for
2 h until the complete consumption of the starting material, and
then the solvent was evaporated under reduced pressure. The
reaction crude was purified by column chromatography on silica
gel (1–3% MeOH/CH2Cl2), yielding the acetate ( )-cis-9 as a yellow
solid (96% isolated yield). Mp: 83–85 °C. Rf (10% MeOH/CH2Cl2):
4.16. General procedure for the lipase-catalyzed resolution of
the alcohol ( )-trans-8
To a suspension of alcohol ( )-trans-8 (30 mg, 0.14 mmol) and
PSL (30 mg) in dry THF (1.4 mL), vinyl acetate (39 lL, 0.42 mmol)
0.58; IR (KBr):
m
3022, 2974, 1737, 1265, 1018, 896 cmÀ1; 1H NMR
was added under a nitrogen atmosphere. The reaction was shaken
for the appropriate time at 30 °C and 250 rpm. Aliquots were
regularly analyzed by HPLC and stopped at 48 h. The enzyme
was filtered off using CH2Cl2 (3 Â 5 mL), the solvent was evapo-
rated under reduce pressure ,and the reaction crude was purified
by flash chromatography on silica gel (2–10% MeOH/CH2Cl2),
affording the corresponding optically enriched acetate (1R,2R)-9
(CDCl3, 300.13 MHz): d 1.99–2.09 (2H, m), 2.06 (3H, s), 2.91–3.15
3
(2H, m), 5.25–5.31 (1H, m), 5.55 (1H, d, JHH = 4.3 Hz), 6.72–6.75
(1H, m), 6.96–7.03 (2H, m), 7.15–7.23 (2H, m), 7.27–7.30 (1H, m),
7.40 (1H, s); 13C NMR (CDCl3, 75.5 MHz): d 21.2 (CH3), 23.7 (CH2),
26.5 (CH2), 57.3 (CH), 71.0 (CH), 119.9 (CH), 127.0 (CH), 128.7
(CH), 128.9 (CH), 129.0 (CH), 129.7 (CH), 131.7 (C), 136.2 (C) 138.0
(CH), 170.4 (C); MS (APCI+, m/z): 257 [(M+H)+]; HRMS (ESI+, m/z)
calcd for C15H17N2O2 (M+H)+: 257.1285, found: 257.1282.
and the alcohol (1S,2S)-8 (see Table 4). Alcohol: [
a
]
20 = À2.1
D
(c 1.0, MeOH) for 85% ee (Chiralpak IC; 60% Hexane/2-Propanol;
0.8 mL/min flow). Acetate: [a]
20 = +7.0 (c 1.0, MeOH) for 99% ee
D
4.19. General procedure for the lipase-catalyzed resolution of
the alcohol ( )-cis-8
(Chiralpak IC; 60% Hexane/2-Propanol; 0.8 mL/min flow).
4.17. Synthesis of racemic cis-1-(1H-imidazol-1-yl)-1,2,3,4-
tetrahydronaphthalen-2-ol ( )-cis-8
To a suspension of alcohol ( )-cis-8 (30 mg, 0.14 mmol) and PSL
(30 mg) in dry THF (1.4 mL), vinyl acetate (39 lL, 0.42 mmol) was
added under a nitrogen atmosphere. The reaction was shaken for
the appropriate time at 30 °C and 250 rpm. Aliquots were regularly
analyzed by HPLC and stopped at 48 h. The enzyme was filtered off
using CH2Cl2 (3 Â 5 mL), the solvent evaporated under reduce
The synthesis was based on a Mitsunobu inversion reaction fol-
lowed by the deprotection of the resulting ester group, and it is as
follows.
Please cite this article in press as: Méndez-Sánchez, D.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.006

8
D. Méndez-Sánchez et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
J.; Rebolledo, F.; Gotor, V. Tetrahedron: Asymmetry 2008, 19, 2589–2593; (f)
González-Sabín, J.; Morís-Varas, F.; Peña, C.; Rebolledo, F.; Gotor, V. J. Mol. Catal.
B: Enzym. 2009, 59, 111–115; (g) Quijada, F. J.; Rebolledo, F.; Gotor, V.
Tetrahedron 2012, 68, 7670–7674; (h) González-Sabín, J.; Ríos-Lombardía, N.;
Gotor, V.; Morís, F. Tetrahedron: Asymmetry 2013, 24, 1421–1425.
5. Rouf, A.; Gupta, P.; Aga, M. A.; Kumar, B.; Parshad, R.; Taneja, S. Tetrahedron:
Asymmetry 2011, 22, 2134–2143.
6. Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606–5655.
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pressure, and the reaction crude purified by flash chromatography
on silica gel (2–10% MeOH/CH2Cl2), affording the corresponding
optically enriched acetate (1S,2R)-9 and the alcohol (1R,2S)-8
(see Table 4). Alcohol: [
a]
D
20 = À3.2 (c 1.0, MeOH) for 98% ee
(Chiralpak IC; 60% Hexane/2-Propanol; 0.8 mL/min flow).
Acetate: [a]
20 = +16.7 (c 1.0, MeOH) for 98% ee (Chiralpak IC; 60%
D
Hexane/2-Propanol; 0.8 mL/min flow).
Acknowledgments
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Financial supports from the Spanish Ministerio de Ciencia e
Innovación (CTQ-2013-44153-P), the Principado de Asturias
(SV-PA-13-ECOEMP-42) and the University of Oviedo (UNOV-13-
EMERG-01) are gratefully acknowledged.
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Please cite this article in press as: Méndez-Sánchez, D.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.06.006