Preparation of (R)-(-)- and (S)-(+)-3-hydroxymethyl-1-tetralone tosylates, key intermediates in the synthesis of new CNS drugs, via resolution of precursors

Article abstract of DOI:10.1016/S0957-4166(02)00822-4

The preparation of (R)-(-)- and (S)-(+)-3-hydroxymethyl-1-tetralone tosylates, key intermediates in the synthesis of new CNS drugs in the aminobutyrophenone family, has been developed via classical resolutions or lipase-catalyzed kinetic resolution of one of their precursors.

Full text of DOI:10.1016/S0957-4166(02)00822-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 381–387
Preparation of (R)-(−)- and (S)-(+)-3-hydroxymethyl-1-tetralone
tosylates, key intermediates in the synthesis of new CNS drugs,
via resolution of precursors
Yolanda Caro, Christian F. Masaguer and Enrique Ravin˜a*
Departamento de Qu´ımica Orga´nica, Laboratorio de Qu´ımica Farmace´utica, Facultad de Farmacia,
Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain
Received 7 November 2002; revised 14 November 2002; accepted 28 November 2002
Abstract—The preparation of (R)-(−)- and (S)-(+)-3-hydroxymethyl-1-tetralone tosylates, key intermediates in the synthesis of
new CNS drugs in the aminobutyrophenone family, has been developed via classical resolutions or lipase-catalyzed kinetic
resolution of one of their precursors. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
therefore lead to treatments with increased efficacy and
reduced side effects. Additionally, selective ligands may
form completely novel therapies.
Stereocontrolled recognition processes in chemistry,
biochemistry and pharmacology have received much
attention in modern drug discovery. Due to the asym-
metry of bioactive macromolecules including enzymes,
G-protein coupled receptors, ion-channels and nucleic
acids, the binding of chiral ligands and substrates pro-
ceeds stereoselectively. Thus, there is continuing interest
in the development of drugs as single enantiomers. The
dopamine D2 and the serotonin 5-HT2 receptors belong
to the G-protein coupled transmembrane receptor fam-
ily of biomolecules. The dopamine D2 receptors are
expressed in regions associated with motor, limbic and
neuroendocrine function, and D2 antagonists and ago-
nists are used in the treatment of schizophrenia and
Parkinson’s disease, respectively.1 The serotonin 5-HT2
The introduction of the butyrophenone haloperidol
(Haldol®, Fig. 1) into the clinic in 1959 was a signifi-
cant advancement in the treatment of schizophrenia,
due to its efficacy in countering the hallucinatory and
delusional (positive) symptoms to the disease.8 How-
ever, haloperidol is ineffective in the treatment of nega-
tive symptoms and neurocognitive deficits,9
a
therapeutic profile that could be rationalized by the
relatively low affinity for 5-HT2A receptors compared to
D2 receptors.10 In the last few years we have been
working on modulation of the butyrophenone system
with the aim of combining antagonism at 5-HT2 family
and D2 receptors in a single molecule.11 We have
reported the synthesis, pharmacology and molecular
modelling of the aminobutyrophenones QF0104B 1 and
QF0108B 2 (Fig. 1),12–14 which showed high affinity for
the 5-HT2A receptor subtype with Ki values of 1.6 and
2.7 nM, respectively, being compound 1 the most selec-
tive for the serotonin 5-HT2A receptor subtype, with a
5-HT2A/5-HT2C Ki ratio as high as 150.14 These com-
pounds are also potent D2 receptor antagonists,
although they display Ki values higher than those at
5-HT2A receptors.
receptors consist of three subtypes termed 5-HT2A
,
5-HT2B and 5-HT2C.2,3 They have been implicated in
the aetiology of many disease states, and may be partic-
ularly important in mental illness, such as depression,
anxiety, schizophrenia, migraine and panic disorder.4,5
The central dopaminergic and serotoninergic pathways
are connected anatomically and interact functionally in
brain regions implicated in schizophrenia.6,7 Many cur-
rently used treatments of this disorder act by modulat-
ing dopaminergic and serotoninergic tones, although
having non-selective effects on postsynaptic receptor
subtypes. The development of selective ligands may
The known chiral discriminatory properties of drug–
receptor interactions have prompted us to further inves-
tigate whether the receptor affinities of these
* Corresponding author. Tel.: +34-981-594-628; fax: +34-981-594-912;
e-mail: qofara@usc.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00822-4

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Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 381–387
Figure 1.
Scheme 1. Reagents and conditions: (i) (a) dimethyl succinate, t-BuOK/t-BuOH, reflux, 3 h, (b) NaOH, MeOH, reflux, 12 h, then
HCl; (ii) Pd/C, H2, AcOH, 75°C, 3 h; (iii) H2SO4, rt, 8 h; (iv) CH2N2, Et2O, rt, 2 h; (v) LiAlH4, THF, rt, 12 h; (vi) MnO2, CHCl3,
rt, 4 h; (vii) TsCl, Py, 0°C, 48 h.
compounds are associated with chirality. Since both
compounds have in common an optically active tetra-
lone framework and can be obtained from 3-hydroxy-
methyl-1-tetralone tosylate 3,14 the preparation of this
intermediate as a single enantiomer would allow us to
obtain enantiomerically pure aminobutyrophenones 1
and 2, in order to assess the effect of stereochemistry at
C-3 of tetralone on the in vitro affinities and selectivi-
ties of 1 and 2 at 5-HT2 and D2 receptors. Furthermore,
tosylate 3 is the precursor of a new series of butyrophe-
nones in developing state. Herein, we describe three
routes for the synthesis of the tosylates (+)-3 and (−)-3,
and the unambiguous determination of their absolute
configuration by X-ray crystallographic analysis.
Esterification with diazomethane and subsequent LAH-
reduction of the keto ester 7 afforded the cis-diol 8. The
relative configuration of the hydroxyl and the hydroxy-
methyl groups of 8 was unambiguously assigned by
means of the reduction of the g-lactone 1015 with the
cis-configuration at the carbons in question (Scheme 2).
Selective oxidation of the benzylic hydroxyl group in 8
was carried out with MnO2 to give hydroxymethyltetra-
lone 9, which upon reaction with tosyl chloride in
pyridine yielded the desired tosylate ( )-3.14 This syn-
thetic route afforded the desired tosylate in a seven-step
process from benzaldehyde with 20% overall yield.
2. Results and discussion
Scheme 2. Reagents and conditions: (i) Ac2O, Py, reflux, 3 h;
(ii) LiAlH4, Et2O, rt, 12 h.
The synthesis of tosylate ( )-3 was easily accomplished
in a seven-step procedure as shown in Scheme 1. Stobbe
condensation of benzaldehyde with dimethyl succinate
followed by hydrogenation of the double bond formed
in 4, and cyclization of the diacid 5 with conc. H2SO4
yielded the tetralonecarboxylic acid 6 (50% overall
yield).
Based on this synthetic route, we applied three different
methods for resolving one of the intermediates in the
general route towards the tosylate, which allowed us to
obtain (+)-3 and (−)-3 in high enantiomeric purity.

Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 381–387
383
The first route was based on the method for the resolu-
tion of benzylsuccinic acid 5 reported by Yamaguchi et
al.16 Thus, ( )-benzylsuccinic acid 5 was resolved by
crystallization of the diastereoisomeric salts formed
with (S)-(−)-a-methylbenzylamine in ethanol. After
three recrystallizations, (R)-(+)-benzylsuccinic acid was
obtained upon hydrolysis of the salt with HCl, in 10%
yield, 99% ee. In a similar fashion, (S)-(−)-benzylsuc-
cinic acid was prepared using (R)-(+)-a-methylbenzyl-
amine. The enantiomeric purity of the acids was
determined by HPLC using a chiral column after trans-
formation of the acids to the corresponding methyl
esters with methanol in the presence of catalytic p-
TsOH. The diacids (R)-(+)-5 and (S)-(−)-5 were
cyclized to give the corresponding (R)-(−)- and (S)-(+)-
3-carboxymethyltetralones,17 which were quantitatively
esterified to afford the methyl esters (R)-(−)-7 and
(S)-(+)-7, respectively. LAH-reduction of the enan-
tiomers yielded exclusively the cis-configured diols
(1R,3R)-(−)-8 and (1S,3S)-(+)-8, which were selectively
oxidized with MnO2 to the corresponding hydroxyke-
tones (R)-(−)-9 and (S)-(+)-9. Treatment of (R)-(−)-9 or
(S)-(+)-9 with p-toluenesulfonyl chloride in pyridine led
to the tosylates (R)-(−)-3 or (S)-(+)-3, respectively. The
advantages of this classical resolution approach include
the use of an inexpensive resolving agent, the simplicity
of the process, and the possibility of racemization of
the pharmacologically ‘undesired’ resolution precursor.
The main drawback of this methodology is the poor
chemical yield (about 10%) obtained in the resolution
step.
methodology can also be used on preparative scale in
the resolution of racemic ketones or aldehydes via
formation of diastereomeric hydrazones, chromato-
graphic separation and subsequent cleavage of the aux-
iliary.21 Thus, the mixture of the two diastereoisomeric
SAMP-hydrazones 12, easily prepared by treating the
carboxymethyltetralone ( )-6 with commercial (S)-1-
amino-2-(methoxymethyl)pyrrolidine (SAMP), could be
separated by column chromatography to give pure
(R,S)-(+)-12 (36% yield) and (S,S)-(+)-12 (37% yield)
SAMP-hydrazones.22 Enantiomerically pure (S)-(+)-
Scheme 3. Lipase-catalyzed kinetic resolution of hydroxy-
ketone ( )-9.
A different approach to the enantiopure tosylates is
outlined in Scheme 3. In this route racemic
hydroxymethyltetralone ( )-9 was submitted to lipase-
catalyzed kinetic resolution. The best results were
achieved with lipase from Pseudomonas fluorescens
adsorbed on Celite®,18 in benzene, which after 7 h at
room temperature yielded the hydroxy ketone (R)-(−)-9
(35% yield, 93% ee), and the acetate (S)-(+)-11 (40%
yield, 91% ee), with a enantioselectivity value E=72.19
The enantiomeric excess of the optically active alcohol
was determined by chiral HPLC (Chiracel® OD-H
column, Daicel), and that of the acetate was determined
after alkaline hydrolysis to the corresponding alcohol.
Ester hydrolysis with LiOH of (S)-(+)-11 afforded the
corresponding hydroxymethyltetralone (S)-(+)-9. The
lipase-catalyzed kinetic resolution methodology has
proven to be less hazardous, polluting, and energy
consuming than conventional chemical methodologies.
In addition, the enzyme is ease to use and recyclable.
Mild conditions and simple separation of the resolution
products are other benefits of this biocatalytic process.
However, this method provided both enantiomeric
alcohols with enantiomeric excesses lower than 95%.
We then examined a third method for preparation of
the tosylates (+)-3 and (−)-3. In this route we obtained
the esters (R)-(−)-7 and (S)-(+)-7 by diastereomeric
separation using the SAMP-hydrazone method
(Scheme 4). SAMP has been principally applied as a
chiral adjuvant in diastereoselective alkylations, aldol
condensations, and Michael additions.20 However, this
Scheme 4. Reagents and conditions: (i) SAMP, p-TsOH,
cyclohexane, reflux, 24 h; (ii) aq. oxalic acid, hexane, rt, 18 h.

384
Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 381–387
and (R)-(−)-3-carboxymethyltetralone were obtained in
90% yield, upon hydrolysis of the corresponding
SAMP-hydrazones with oxalic acid.23 The SAMP can
be recovered in about 80% yield, with sufficient purity
to be used again for preparation of hydrazones. There-
fore, diastereomeric separation via the SAMP-hydra-
zone has proven to be a good alternative to obtain both
tosylates in enantiopure form and good chemical yields.
mercially available lipases were obtained as gift samples
from Amano Pharmaceutical Co., Ltd. (Nagoya,
Japan) and Novo Nordisk Bioindustrial, S.A. (Madrid,
Spain), and used as received.
4.2. Preparation of the racemic tosylate, ( )-3
4.2.1. Benzylidensuccinic acid, 4. A solution of benzalde-
hyde (15 g, 141 mmol) and dimethyl succinate (25.76 g,
176 mmol) in t-BuOH (20 mL) was added dropwise
within 3 h to a refluxing mixture of t-BuOK (17.4 g,
155 mmol) and t-BuOH (100 mL). Reflux was contin-
ued for another 3 h, and t-BuOH was removed in
vacuo. The residue obtained was dissolved in 1N aq.
HCl (100 mL), and the aqueous solution was extracted
with EtOAc (3×25 mL). The combined organic layers
were dried (Na2SO4) and concentrated in vacuo to yield
an oily crude product. This oil was dissolved in MeOH
(60 mL), a 15% solution of NaOH in MeOH (100 mL,
375 mmol) was added and the mixture was refluxed for
12 h. The resulting suspension was concentrated under
reduced pressure, and the residue dissolved in water
(150 mL). The solution was washed with EtOAc (3×100
mL), acidified with concentrated HCl and extracted
with EtOAc (3×50 mL). The organic extracts were dried
(Na2SO4) and concentrated in vacuo to afford a solid
which was crystallized from EtOAc/hexane to give 4
(20.4 g, 70%) as a white crystalline solid; mp 180–
182°C. Lit.24 mp 174–176°C.
The absolute configuration of the tosylates was unam-
biguously confirmed by X-ray crystallography analysis.
Fig. 2 shows the crystal structure of (+)-3 is (S).
Figure 2. ORTEP drawing of (+)-3.
3. Conclusion
In summary, three different resolution methods for the
preparation of tosylates (+)-3 and (−)-3 were used. Both
compounds, (R)-(−)-3 and (S)-(+)-3, could be obtained
in high enantiomeric excess allowing to synthesize the
new CNS drugs 1 and 2 in enantiopure form. Binding
assays and behavioural studies of these butyrophenones
as single enantiomers are now in progress and will be
reported in due course.
4.2.2. Benzylsuccinic acid, ( )-5. A mixture of benzyli-
densuccinic acid 4 (3.0 g, 14.5 mmol) and 10% palla-
dium on activated carbon (0.3 g) in acetic acid (30 mL)
was heated at 75°C under H2 for 3 h. After cooling, the
reaction mixture was filtered through Celite® and the
acetic acid was evaporated under reduced pressure to
give pure benzylsuccinic acid (2.97 g, 98%) as a white
solid; mp 165–167°C. Lit.25 mp 160–161°C (H2O).
4. Experimental
4.1. General
4.2.3. 4-Oxo-1,2,3,4-tetrahydronaphtalen-2-ylcarboxylic
acid, ( )-6. Benzylsuccinic acid (2.7 g, 12.9 mmol) was
dissolved in concentrated H2SO4 (55 g) and stirred at
room temperature for 8 h. The red reaction mixture
was carefully poured over crushed ice (110 g) and
allowed to crystallize overnight at 5°C. The resulting
crystals were filtered, washed with water, dried in vacuo
and recrystallized from EtOH/H2O to give 6 (1.8 g,
73%) as white crystals; mp 155–157°C. Lit.15 mp 152–
Melting points were determined with a Kofler hot stage
instrument or a Gallenkamp capillary melting point
apparatus and are uncorrected. Infrared spectra were
recorded with a Perkin–Elmer 1600 FTIR spectropho-
tometer; the main bands are given in cm−1. H NMR
1
spectra were recorded with a Bruker WM AMX (300
MHz); chemical shifts are recorded in parts per million
(l) downfield from tetramethylsilane (TMS). Mass
1
154°C; IR: 2970, 1686, 1600 cm−1; H NMR (acetone-
d6): l 2.82–2.86 (m, 2H, 2×H4), 3.19–3.34 (m, 3H,
2×H2, H3), 7.33–7.40 (m, 2H, H3, H5), 7.56 (t, 1H,
J=7.4, H6), 7.92 (d, 1H, J=7.9, H8); MS (EI, m/z): 190
(M+). Anal. calcd. for C11H10O3: C, 69.46; H, 5.30.
Found: C, 69.20; H, 5.16%.
spectra were performed on
a
Hewlett–Packard
HP5988A mass spectrometer by electron impact (EI).
Optical rotations at the sodium D-line were determined
using a Perkin–Elmer 241 polarimeter. HPLC analyses
were performed with an instrument that consisted of a
Waters 1525 binary pump, a Waters 2487 dual l
absorbance detector, a Waters 2414 refractive index
detector, and Breeze® data processor. Flash column
chromatography was performed using Kieselgel 60 (60–
200 mesh, E. Merck AG, Darmstadt, Germany). Reac-
tions were monitored by thin-layer chromatography
(TLC) on Merck 60 GF254 chromatogram sheets using
iodine vapour and/or UV light for detection. The com-
4.2.4. Methyl 4-oxo-1,2,3,4-tetrahydronaphtalen-2-ylcar-
boxylate, ( )-7. A solution of 3-carboxy-1-tetralone 6
(1.0 g, 5.2 mmol) in anhydrous diethyl ether (25 mL)
was saturated with a solution of diazomethane in ether
under cooling in an ice-bath, and then allowed to stand
at room temperature for 2 h. After evaporating the
solvent, the residual oil was distilled under reduced
pressure, giving 3-carboxy-1-tetralone methyl ester (1.0

Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 381–387
385
1
g, 93%) as colourless oil; IR: 2953, 1734, 1685 cm−1; H
4.3. Preparation of the tosylates (+)-3 and (−)-3 via
resolution of benzylsuccinic acid, ( )-5
NMR (CDCl3): l 2.78–2.99 (m, 2H, H4), 3.18–3.23 (m,
3H, H2, H3), 3.73 (s, 3H, CH3), 7.28 (d, 1H, J=7.6,
H5), 7.34 (t, 1H, J=7.6, H7), 7.51 (dt, 1H, J=7.5, 1.4,
H6), 8.03 (dd, 1H, J=7.8, 1.0, H8); MS (EI, m/z): 204
(M+).
4.3.1. Resolution of ( )-5. Benzylsuccinic acid ( )-5 was
resolved following the method reported by Yamaguchi
and co-workers.16 The acid ( )-5 (10.58 g, 50 mmol)
and (R)-(+)-a-methylbenzylamine (6.06 g, 50 mmol)
were dissolved in hot ethanol and allowed to stand at
room temperature. The precipitate was collected and
then recrystallized three times. The salt (mp 176–178°C)
was dissolved in water and acidified with 2N HCl. After
stirring for 2 h at room temperature, the mixture was
extracted with EtOAc. The combined organic layers
were dried (Na2SO4) and concentrated to give (S)-(−)-
benzylsuccinic acid (−)-5 (1 g, 10%), mp 168–169°C,
[h]2D0 −26 (c 0.5, EtOAc).
4.2.5. 3-Hydroxymethyl-1,2,3,4-tetrahydronaphtalen-1-
ol, ( )-8. 3-Carboxy-1-tetralone, methyl ester 7 (1.0 g,
4.9 mmol) was dissolved in anhydrous THF (50 mL)
and added dropwise to a stirred suspension of LiAlH4
(1.86 g, 49 mmol) in anhydrous THF (80 mL) under
argon. After stirring for 12 h at room temperature,
water (2.0 mL), 5% NaOH (3.0 mL) and water (12.0
mL) were added dropwise. The precipitate was removed
by filtration and washed with EtOAc. The filtrate was
concentrated in vacuo to give a residue, which was
dissolved in CH2Cl2, dried (Na2SO4) and concentrated
at reduced pressure to afford the cis-diol ( )-8 (0.75 g,
85%) as a white solid; mp 103–105°C (Et2O); IR: 3338,
In a similar way, (R)-(+)-benzylsuccinic acid (+)-5 (1 g,
10%), mp 167–169°C, [h]2D0 +26 (c 0.5, EtOAc), was
achieved from the benzylsuccinic acid ([h]2D0 +8 (c 0.5,
EtOAc)) obtained from the filtrate of the above first
recrystallization (after concentration and quantitative
HCl hydrolysis of the salt), using (S)-(−)-a-methylben-
zylamine. Lit.26 [h]D25 +26.3 (c 1.5, EtOAc), 99.2% ee.
1
1044, 1012 cm−1; H NMR (CDCl3): l 1.53–1.64 (m,
1H, H4), 2.12–2.17 (m, 1H, H3), 2.26–2.32 (m, 1H, H4),
2.58–2.67 (dd, 1H, J=16.6, 9.6 Hz, H2), 2.85–2.93 (dd,
1H, J=16.6, 5.2 Hz, H2), 3.65–3.69 (d, 2H, J=6.2 Hz,
-CH2-OH), 4.83–4.88 (m, 1H, H1), 7.10–7.54 (m, 4H,
Ph); MS (EI, m/z): 178 (M+). Anal. calcd for C11H14O2:
C, 74.13; H, 7.92. Found: C, 74.01; H, 7.97%.
The enantiomeric purity of the benzylsuccinic acids was
determined by HPLC (Chiralcel® OD-H, hex-
ane:propan-2-ol, 97:3, flow 0.7 mL/min, u 254 nm) after
their transformation to the corresponding dimethyl
esters by treatment with methanol/p-TsOH:
4.2.6. 3-Hydroxymethyl-1,2,3,4-tetrahydronaphtalen-1-
one, ( )-9. Diol 8 (0.75 g, 4.2 mmol) was dissolved in
CHCl3 (50 mL) and MnO2 (9.1 g, 105 mmol) was
added. The mixture was stirred at room temperature
for 4 h, and then filtered through silica gel, eluted with
EtOAc and the combined filtrates were concentrated in
vacuo to give an oil which was purified by column
chromatography (silica gel, EtOAc/hexane, 1:1) to give
( )-9 (0.56 g, 75%) as a colourless oil; IR: 3420, 2925,
Dimethyl (S)-(−)-benzylsuccinate: [h]2D0 −26.4 (c 1,
EtOAc), tR=23.65 min, ee >99%.
Dimethyl (R)-(+)-benzylsuccinate: [h]2D0 +26.5 (c 0.5,
EtOAc), tR=19.81 min, ee >99%.
1
1683, 1601 cm−1; H NMR (CDCl3): l 2.40–2.51 (m,
4.3.2.
(S)-4-Oxo-1,2,3,4-tetrahydronaphtalen-2-ylcar-
2H, 2×H4), 2.73–2.91 (m, 2H, H2, H3), 3.04–3.11 (m,
1H, H2), 3.65–3.76 (m, 2H, -CH2-OH), 7.29–7.34 (m,
2H, H5, H7), 7.49 (dt, 1H, J=7.5, 1.4, H6), 8.02 (dd,
1H, J=7.7, 1.0, H8); MS (EI, m/z): 176 (M+).
boxylic acid, (+)-6. Obtained from (S)-(−)-benzylsuc-
cinic acid (−)-5 by cyclization with sulfuric acid as
previously described. [h]2D0 +40.6 (c 1.3, MeOH). Lit.17
[h]2D0 +39.48 (c 1.5, MeOH).
4.2.7. (4-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl)methyl
4-methylbenzenesulfonate, ( )-314. p-Toluenesulfonyl
chloride (0.68 g, 3.5 mmol) was added to a cooled
solution of the hydroxyketone 9 (0.5 g, 2.8 mmol) in
dry pyridine (5 ml) and the mixture stirred at 0°C for
48 h. Ice water (40 mL) was then added to the reaction,
and the resultant mixture was extracted with CH2Cl2
(3×50 mL). The organic extracts were dried (Na2SO4),
filtered and concentrated at reduced pressure to give an
oil, which was purified by column chromatography
(silica gel, EtOAc/hexane 1:4) to afford the tosylate
( )-3 (0.65 g, 70%) as a white solid, mp 95–96°C (Et2O);
4.3.3.
(R)-4-Oxo-1,2,3,4-tetrahydronaphtalen-2-ylcar-
boxylic acid, (−)-6. [h]2D0 −41.0 (c 1, MeOH). Lit.17 [h]2D0
−39.3 (c 1.5, MeOH).
4.3.4. (S)-Methyl 4-oxo-1,2,3,4-tetrahydronaphtalen-2-
ylcarboxylate, (+)-7. Obtained from (+)-6 by diazo-
methane esterification. [h]2D0 +27.0 (c 0.5, EtOAc).
4.3.5. (R)-Methyl 4-oxo-1,2,3,4-tetrahydronaphtalen-2-
ylcarboxylate, (−)-7. [h]2D0 −28 (c 0.5, EtOAc).
1
IR: 1674, 1598, 1361, 1182 cm−1; H NMR (CDCl3): l
2.38 (dd, 1H, J=16.0, 1.6, H4), 2.46 (s, 3H, Ph-CH3),
2.57–3.07 (m, 4H, 2×H2, H3, H4), 4.02–4.07 (m, 2H,
-CH2-O-), 7.22–7.32 (m, 2H, H5, H7), 7.36 (d, 2H,
J=8.2, H3%, H5%), 7.49 (t, 1H, J=7.5, H6), 7.80 (d, 2H,
J=8.1, H2%, H6%), 8.00 (d, 1H, J=8.0, H8); MS (EI,
m/z): 330 (M+). Anal. calcd for C18H18O4S: C, 65.43;
H, 5.49; S, 9.71. Found: C, 65.26; H, 5.59; S, 9.44%.
4.3.6.
(1S,3S)-3-Hydroxymethyl-1,2,3,4-tetrahydrona-
phtalen-1-ol, (+)-8. Obtained by LiAlH4 reduction of
(+)-7. [h]2D0 +102 (c 1.0, EtOAc)
4.3.7. (1R,3R)-3-Hydroxymethyl-1,2,3,4-tetrahydrona-
phtalen-1-ol, (−)-8. [h]2D0 −103 (c 1, EtOAc).

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Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 381–387
4.3.8. (S)-3-Hydroxymethyl-1,2,3,4-tetrahydronaphtalen-
1-one, (+)-9. Prepared from (+)-8 by oxidation with
MnO2. [h]2D0 +28.1 (c 0.5, EtOAc), 98% ee. Chiralcel®
OD-H, hexane:propan-2-ol, 94:6, flow 0.5 mL/min, u
254 nm; tR=44 min.
4.5. Resolution of the racemic ester ( )-7 via SAMP-
hydrazones
A mixture of racemic ester ( )-7 (0.5 g, 2.45 mmol),
SAMP (0.33 mL, 2.45 mmol) and p-TsOH (catalytic) in
cyclohexane (6 mL) was stirred at reflux under argon
for 24 h. After cooling, the mixture was diluted with
CH2Cl2 (25 mL) and washed with 10% Na2CO3 solu-
tion. The organic layer was separated, dried (Na2SO4)
and concentrated under vacuo to give a residue which
was purified by column chromatography (silica gel,
EtOAc:hexane, 1:7) to afford the SAMP-hydrazones
(R,S)-12 (280 mg, 36%) and (S,S)-12 (290 mg, 37%) as
brown oils.
4.3.9.
(R)-3-Hydroxymethyl-1,2,3,4-tetrahydrona
phtalen-1-one, (−)-9. [h]2D0 −27.7 (c 0.5, EtOAc), 97% ee.
Chiralcel® OD-H, hexane:propan-2-ol, 94:6, flow 0.5
mL/min, u 254 nm; tR=49 min.
4.3.10. (S)-(4-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-
methyl 4-methylbenzenesulfonate, (+)-3. Prepared by
tosylation of (+)-9. [h]2D0 +11.8 (c 0.5, EtOAc).
4.5.1. Methyl (R,S)-4-{[2-(methoxymethyl)pyrrolidin-1-
yl]imino}-1,2,3,4-tetrahydronaphthalene-2-carboxylate:
SAMP-hydrazone, (R,S)-12. [h]D +375 (c 1, EtOAc); IR
4.3.11. (R)-(4-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-
methyl 4-methylbenzenesulfonate, (−)-3. [h]2D0 −12.0 (c
0.5, EtOAc).
1
(film): w 2950, 2874, 1736 cm−1; H NMR (CDCl3): l
1.40–1.60 (m, 1H, H-3%), 1.71–1.96 (m, 2H, Hs-4%),
2.02–2.12 (m, 1H, H-3%), 2.70 (ddd, J=9.4, 7.8, 7.8, 1H,
H-5%), 2.88–3.07 (m, 5H, Hs-2, H-3, Hs-4), 3.25–3.29
(m, 1H, H-5%), 3.33 (dd, J=9.1, 7.2, 1H, -CH2O-), 3.36
(s, 3H, CH3-O), 3.37–3.49 (m, 1H, H-2%), 3.56 (dd,
J=9.1, 4.0, 1H, -CH2O-), 3.68 (s, 3H, COOCH3), 7.12–
7.25 (m, 3H, H-5, H-6, H-7), 8.08 (dd, J=7.6, 1.5, 1H,
H-8); MS (EI, m/z): 316 (M+).
4.4. Procedure for the lipase-catalyzed acylation of the
hydroxyketone, ( )-9
To a solution of the hydroxymethyltetralone ( )-9 (176
mg, 1.0 mmol) in benzene, vinyl acetate (55 mL, 0.6
mmol), and Pseudomonas fluorescens lipase on Celite®
(100 mg) was added. The mixture was stirred for 7 h at
room temperature, filtered through Celite® and concen-
trated in vacuo. The residue was purified by flash
column chromatography (silica gel, EtOAc:hexane, 1:3)
to give (R)-3-hydroxymethyltetralone (−)-9 (60 mg,
35%) and the (S)-acetate (+)-11 (85 mg, 40%).
4.5.2. Methyl (S,S)-4-{[2-(methoxymethyl)pyrrolidin-1-
yl]imino}-1,2,3,4-tetrahydronaphthalene-2-carboxylate:
SAMP-hydrazone, (S,S)-12. [h]2D0 +906 (c 1, EtOAc); IR
1
(film): w 2950, 2874, 1736 cm−1; H NMR (CDCl3): l
1.67–1.84 (m, 1H, H-3%), 1.85–1.94 (m, 2H, Hs-4%),
2.02–2.14 (m, 1H, H-3%), 2.40 (dd, J=12.5, 16.2, 1H,
H-2), 2.45 (dd, J=8.8, 16.2, 1H, H-5%), 2.81–2.87 (m,
1H, H-3), 2.97–3.07 (m, 2H, Hs-4), 3.31–3.41 (m, 2H,
H-2, -CH2O-), 3.37 (s, 3H, CH3O-), 3.41–3.48 (m, 1H,
H-5%), 3.53–3.59 (m, 2H, H-2%, -CH2O-), 3.75 (s, 3H,
COOCH3), 7.10–7.24 (m, 3H, H-5, H-6, H-7), 8.17 (d,
J=7.6, 1H, H-8).
4.4.1.
(R)-3-Hydroxymethyl-1,2,3,4-tetrahydrona-
phthalen-4-one, (−)-9. [h]2D0 −26.5 (c 1.0, EtOAc), 93%
ee. Chiralcel® OD-H, hexane:propan-2-ol, 94:6, flow 0.5
mL/min, u 254 nm; tR=49.4 min.
4.4.2. (S)-(1-Oxo-1,2,3,4-tetrahydro-3-naphthyl)methyl
acetate, (+)-11. Mp 77–79°C; [h]2D0 +24.2 (c 1.0, EtOAc),
91% ee; IR (film): w 1732, 1683, 1246, 1039 cm−1; H
1
NMR: l 2.06 (s, 3H, CH3), 2.42 (dd, 1H, J=16.1, 11.9,
H2), 2.50–2.61 (m, 1H, H3), 2.74–2.86 (m, 2H, H4), 3.00
(dd, 1H, J=16.2, 2.5, H2), 4.10 (d, 2H, J=5.9, CH2O),
7.25 (d, 1H, J=7.9, H5), 7.30 (t, 1H, J=7.6, H7), 7.47
(dt, 1H, J=7.4, 1.2, H6), 8.00 (d, 1H, J=7.6, H8); MS
(EI, m/z): 218 (M+). Anal. calcd for C13H14O3: C,
71.54; H, 6.47. Found: C, 71.80; H, 6.51%.
4.5.3. (S)-Methyl 4-oxo-1,2,3,4-tetrahydronaphtalen-2-
ylcarboxylate, (+)-7. A solution of the SAMP-hydra-
zone (S,S)-12 (100 mg, 0.32 mmol) in hexane (3 mL)
was stirred at room temperature with a saturated
aqueous solution of oxalic acid (0.5 mL) for 18 h. The
aqueous layer was separated, extracted with hexane and
the organic extracts were combined, dried (Na2SO4)
and concentrated under vacuum. The residue was
purified by column chromatography (silica gel,
EtOAc:hexane, 1:4) to give the (S)-ketoester (+)-7 (58
mg, 90%). [h]2D0 +27.9 (c 0.5, EtOAc)
4.4.3.
(S)-3-Hydroxymethyl-1,2,3,4-tetrahydrona-
phthalen-4-one, (+)-9. To a solution of acetate (S)-(+)-
11 (65 mg, 0.3 mmol) in dimethoxyethane (10 mL), 1N
aq. LiOH (3.6 mL, 3.6 mmol) was added. The mixture
was refluxed for 2.5 h and then cooled, diluted with
Et2O (25 mL), and acidified with 1N HCl. The organic
phase was separated and the aqueous layer was
extracted with ether. The combined organic extracts
were dried (Na2SO4) and concentrated in vacuo to give
a residue which was purified by column chromatogra-
phy (silica gel, EtOAc:hexane, 1:1) to afford 48 mg
(91% yield) of (S)-(+)-9. [h]2D0 +26.0 (c 1.0, EtOAc), 91%
ee. Chiralcel® OD-H, hexane:propan-2-ol, 94:6, flow 0.5
mL/min, u 254 nm; tR=44.2 min.
4.5.4. (R)-Methyl 4-oxo-1,2,3,4-tetrahydronaphtalen-2-
ylcarboxylate, (−)-7. (R)-Ketoester (−)-7 was similarly
obtained from the SAMP-hydrazone (R,S)-12 in 91%
yield. [h]2D0 −27.8 (c 0.5, EtOAc)
4.6. Crystallographic analysis of (+)-3
Suitable crystals of (+)-3 (C18H8O4S) were obtained
from Et2O at room temperature by slow evaporation of
the solvent, C18H18O4S, M=330.38, a=22.6414(8), b=

Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 381–387
387
,
6.3824(2), c=23.4726(8) A, space group I2, V=
3312.85(19) A , T=293(2) K, Z=8, Dcalcd=1.325 Mg/
Fontenla, J. A.; Castro, E.; Calleja, J. M.; De Ceballos,
M. L. J. Med. Chem. 1991, 34, 2242–2247.
3
,
m3, F(000)=1392. Final goodness-of-fit=1.060,
R=0.0392, wR=0.1015. Absolute structure determina-
tion was completed using the Flack parameter.27 Crys-
tallographic data (excluding structure factors) for
(S)-(+)-3 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publi-
cation number CCDC 196442. Copies of the data can
be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK [fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
13. Loza, M.; Verde, I.; Castro, M. E.; Orallo, F.; Fontenla,
J. A.; Calleja, J. M.; Ravina, E.; Cortizo, L.; De Cebal-
los, M. L. Bioorg. Med. Chem. Lett. 1991, 1, 717–720.
14. Brea, J.; Rodrigo, J.; Carrieri, A.; Sanz, F.; Cadavid, M.
I.; Enguix, M. J.; Villazo´n, M.; Mengod, G.; Caro, Y.;
Masaguer, C. F.; Ravin˜a, E.; Centeno, N. B.; Carotti, A.;
Loza, M. I. J. Med. Chem. 2002, 45, 54–71.
15. Hathaway, B. A.; Nichols, D. E.; Nichols, M. B.; Yim,
G. K. W. J. Med. Chem. 1982, 25, 535–538.
16. Yamaguchi, T.; Yanagi, T.; Hokari, H.; Mukaiyama, Y.;
Kamijo, T.; Yamamoto, I. Chem. Pharm. Bull. 1998, 46,
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17. Barloco, D.; Cignarella, G.; Giardina, G. A. M.; Grugni,
M.; Ronzoni, S. WO 0027815. CAN 132:347490.
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19. Enantioselectivity was calculated from the formula E=
ln[(1−c)(1−ees)]/ln[(1−c)(1+ees)]. See: Chen, C.-S.; Fuji-
moto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc.
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Acknowledgements
This work was supported by Spanish Comisio´n Inter-
ministerial de Ciencia y Tecnolog´ıa (CICYT) under
Grant SAF98-0148-C04-04, and Xunta de Galicia
under Grant PGIDT01-PXI20309PR. We would like to
thank Amano Pharmaceutical Co. Ltd (Nagoya, Japan)
and Novo Nordisk Bioindustrial, S.A. (Madrid, Spain)
for their generous gifts of lipases.
20. Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253–2329.
21. (a) Djuric, S. W.; Docter, S. H.; Yu, S. S.; Spangler, D.;
Tsai, B.-S.; Anglin, C. P.; Gaginella, T. S.; Kachur, J. F.;
Keith, R. H.; Maziasz, T. J.; Villani-Price, D.; Rao, T. S.;
Walsh, R. E.; Widomski, D. L.; Fretland, D. J. Bioorg.
Med. Chem. Lett. 1994, 4, 811–816; (b) Herold, P.;
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