Kinetic resolution of 3-hydroxymethylbenzocycloalkanols by selective asymmetric hydrogen-transfer oxidation

Article abstract of DOI:10.1016/j.tetasy.2003.08.016

Kinetic resolution of 3-hydroxymethylbenzocycloalkanols was performed by selective asymmetric hydrogen-transfer oxidation using the Ru(II)-(S,S)-TsDPEN catalyst. Thus, several 3-hydroxymethyl-1-tetralols 7a-d afforded (1R,3R)-3-hydroxymethyl-1-tetralols (

Full text of DOI:10.1016/j.tetasy.2003.08.016

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3689–3696
Kinetic resolution of 3-hydroxymethylbenzocycloalkanols by
selective asymmetric hydrogen-transfer oxidation
Yolanda Caro, Mar´ıa Torrado, 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 18 July 2003; accepted 6 August 2003
Abstract—Kinetic resolution of 3-hydroxymethylbenzocycloalkanols was performed by selective asymmetric hydrogen-transfer
oxidation using the Ru(II)-(S,S)-TsDPEN catalyst. Thus, several 3-hydroxymethyl-1-tetralols 7a–d afforded (1R,3R)-3-hydroxy-
methyl-1-tetralols (1R,3R)-7a–d and (S)-3-hydroxymethyl-1-tetralones (S)-9a–d, and 3-hydroxymethyl-1-indanol 7e gave (1R,3S)-
3-hydroxymethyl-1-indanol (1R,3S)-7e and (R)-3-hydroxymethyl-1-indanone (R)-9e, with high enantioselectivities.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
low affinity for 5-HT2A receptors compared to D2
receptors.3 Over the last few years we have been work-
ing on modulation of the butyrophenone system with
the aim of combining antagonism at the 5-HT2 family
and D2 receptors in a single molecule.4 We have
reported the synthesis, pharmacology and molecular
modelling of the aminobutyrophenones QF0104B 1 and
QF0108B 2 (Fig. 1),5–7 which showed high affinity for
the 5-HT2A receptor subtype with Ki values of 1.6 and
2.7 nM, respectively, compound 1 being the most selec-
The introduction of the butyrophenone haloperidol
(Haldol®, Fig. 1) into the clinic in 1959 was a signifi-
cant advance in the treatment of schizophrenia, due to
its efficacy in countering the hallucinatory and delu-
sional (positive) symptoms of the disease.1 However,
haloperidol is ineffective in the treatment of negative
symptoms and neurocognitive deficiencies,2 a therapeu-
tic profile that could be rationalized by the relatively
Figure 1.
* Corresponding author. Tel.: +34 981 594 628; fax: +34 981 594 912; e-mail: qojcfm@usc.es
† Drug Research & Development Group.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.016

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Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 3689–3696
Scheme 1. Reagents and conditions: (i) Pd/C, H2, MeOH, rt, 3 h, 92–96%; (ii) CF3COOH, (CF3CO)2O, rt, 8 h, 50–85%; (iii)
LiAlH4, THF, rt, 12 h, 85–90%.
tive for the serotonin 5-HT2A receptor subtype, with a
5-HT2A/5-HT2C Ki ratio as high as 150.7 These com-
pounds are also potent D2 receptor antagonists,
although they display Ki values higher than those at
5-HT2A receptors.
substrate to acetone has been widely used as a method
for the kinetic resolution of secondary alcohols.10
In particular, Ru(II) complexes of chiral mono-N-tosyl-
1,2-diphenylethylenediamines catalyze the hydrogen
transfer reaction of racemic allylic and benzylic sec-
ondary alcohols to ketones enantioselectively by con-
verting one enantiomer, leaving the other enantiomer
intact. We wished to examine the use of this asymmet-
ric hydrogen-transfer oxidation to the 3-hydroxy-
methyl-1-tetralol system. To this end, a range of 3-
hydroxymethyl-1-tetralols ( )-7a–d were prepared from
dimethylsuccinate and the corresponding benzaldehydes
via Stobbe condensation, hydrogenation of the benzyli-
denhemisuccinates 4 obtained, cyclization with trifl-
uoroacetic anhydride in trifluoroacetic acid, and
subsequent lithium aluminum hydride reduction
(Scheme 1). Diols ( )-7a–d were obtained in 50–70%
overall yield as white crystalline solids.
The known chiral discriminatory properties of drug-
receptor interactions have prompted us to investigate
further whether the receptor affinities of these com-
pounds are associated with chirality, specifically, the
effect of the stereochemistry at C-3 of the tetralone on
the in vitro affinities and selectivities of 1 and 2 at
5-HT2 and D2 receptors.
Recently, we have reported the preparation of (+)- and
(−)-3-hydroxymethyl-1-tetralone tosylates as single
enantiomers by resolution of synthetic precursors,8 in
order to obtain enantiomerically pure aminobutyrophe-
nones 1 and 2. Herein we report a new methodology for
the kinetic resolution of 3-hydroxymethyl-1-tetralol 7a,
an intermediate in the synthesis of the aminobutyrophe-
nones 1 and 2, by selective asymmetric hydrogen-trans-
The cis-relative stereochemistry between the C1
hydroxyl and the C3 hydroxymethyl groups in diols
( )-7a–d was evident from the proton NMR spectrum.
In the spectrum of the previously reported tetralol
cis-( )-7a,8 the signal of the H1 proton appears as a
double doublet (J=10.5, 5.8 Hz). The magnitude of the
largest vicinal coupling constant (J=10.5 Hz) indicates
a trans-diaxial relationship between H2ax and H1 in a
preferred half-chair conformation that places the
hydroxy group at C1 (and consequently the hydroxy-
methyl group at C3) in an equatorial position (Fig. 2).
fer
oxidation
using
Noyori’s
catalyst
[Ru(II)(p-cymene)-TsDPEN], (TsDPEN=N-tosyl-1,2-
diphenylethylenediamine). We have extended our study
to mono- and dimethoxy-substituted 3-hydroxymethyl-
1-tetralols 7c–d, precursors of new series of butyrophe-
nones
under
development,
and
to
the
3-hydroxymethyl-1-indanol 7e, in turn, the precursor of
pyridylpiperazine derivative QF0504B 3, which is a
5-HT2C selective ligand, with a 5-HT2A/5-HT2C Ki ratio
of 0.027.7
2. Results and discussion
A large number of kinetic resolution strategies that rely
on the use of chiral catalysts for the enantioselective
oxidation of one enantiomer of a racemic secondary
alcohol to its corresponding ketone have been reported
to date.9 Since Noyori’s report on reversible catalytic
asymmetric transfer hydrogenation complexes for
asymmetric catalysis, the use of chiral diamine Ru(II)
complexes to transfer hydride from a racemic alcohol
Figure 2.
In the NMR spectra (CD3OD) of tetralols 7b–d, the
signal of the H1 protons appears as a double doublet

Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 3689–3696
3691
(JH1–H2ax=10.1–10.6). As in the above mentioned com-
pound 7a and other previously reported tetralols,11
consideration of the Karplus relationship suggest that
the H1 protons of the hydroxymethyltetralols exist in a
quasi-axial conformation on a half-chair ring. Assum-
ing that the conformation of hydroxymethyl groups is
equatorial in these compounds, these results indicate a
cis relation between the 3-hydroxymethyl group and the
1-hydroxy group.
Scheme 2. Reagents and conditions: (i) MeOH, p-TsOH,
reflux, 5 h, 90%; (ii) LiAlH4, THF, rt, 12 h, 70%.
The study of the resolution of the 3-hydroxymethyl-1-
tetralols was extended to an 1-indanol derivative. Thus,
3-hydroxymethyl-1-indanol ( )-7e was prepared by
esterification and subsequent lithium aluminum hydride
reduction of the known 3-oxo-1-indancarboxylic acid
812 (Scheme 2). Lithium aluminum hydride reduction of
3-substituted-1-indanones has been described to give
cis-products.13 In our case, almost pure cis-3-hydroxy-
methyl-1-indanol was obtained. Stereochemical assign-
ment was further supported by the study of the 1H
NMR spectrum, where the signals of the protons at C2
appear at different chemical shifts (two signals at 1.87
and 2.61 ppm) due to the shielding of C1 and C3
substituents over H2 cis.14
For the kinetic resolution of the intermediates in the
synthesis of our previously mentioned aminobutyrophe-
nones by asymmetric hydrogen-transfer oxidation, we
first examined the hydrogen transfer reaction of the diol
( )-7a in acetone at 28°C in the presence of the Ru(II)-
(1S,2S) - N - p - toluenesulfonyl - 1,2 - diphenylethylenedi-
amine [Ru(II)-(S,S)-TsDPEN] catalyst prepared from
[RuCl2(h6-p-cymene].10 The reaction was found to
occur chemoselectively at the secondary centre to give
the chiral ketone (+)-9a leaving the chiral diol (−)-7a
without affecting the hydroxy functionalities (Table 1,
entries 1–4). The enantioselective oxidation occurred to
the
(1S)-stereoisomer,
affording
the
(S)-3-
hydroxymethyltetralone (+)-9a8 with 99.9% e.e., and the
Table 1. Kinetic resolution of diols 7a–e by chiral Ru(II) complex
Entry
Substrate
Concentr. (M)
Solvent systema S/Cb
Time (h)
Ketone
Unreact. substr.
n
R1
R2
Yieldc
E.e.
45d
Yieldc
E.e.d
1
2
3
4
5
6
7
8
( )-7a
( )-7a
( )-7a
( )-7a
( )-7b
( )-7b
( )-7b
( )-7c
( )-7c
( )-7c
( )-7d
( )-7d
( )-7d
( )-7e
( )-7e
( )-7e
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
0
H
H
H
H
OCH3
OCH3
OCH3
H
H
H
OCH3 OCH3
OCH3 OCH3
OCH3 OCH3
H
H
H
H
H
H
H
H
H
H
OCH3
OCH3
OCH3
0.50
0.50
0.50
0.50
0.75
0.75
0.75
0.50
0.50
0.50
0.20
0.60
0.60
1.20
1.20
1.20
A
A
A
A
B
500
200
100
50
100
50
48
48
28
36
21
24
36
36
72
96
48
24
38
24
18
40
3
16
48
42
45
48.5
47
30
40
42
—
34
44
38
30
44
90
—
99.9d 70
99.9d 43
23e
95e
99.9e
96e
97e
99.9e
46e
80e
86e
95d
40
93.5d 40
B
B
95d
40
50
99.9d 40
99.9d 50
99.9d 45
C
C
C
A
C
C
A
A
A
100
100
50
100
50
50
100
50
9
10
11
12
13
14
15
16
95d
—
44
96d
48
51e
99.9d 42
99.9e
78d
60d
84d
H
H
H
62
90
80
47
57
38
50
a Solvent system: A: acetone; B: acetone/MeOH (4:1); C: acetone/MeOH (3:2).
b Substrate to catalyst ratio.
c Yields after purification.
d Determined by HPLC analysis using a Daicel Chiralcel OD-H column.
e Determined by HPLC analysis using a Daicel Chiralcel OD-H column, after oxidation with MnO2.

3692
Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 3689–3696
(1R,3R)-diol (−)-7a with 95% e.e., using a substrate to
catalyst (S/C) ratio of 100 (entry 3). The enantiopurity
of the unreacted diol could be increased to 99.9% e.e.
when the S/C ratio was decreased from 100 to 50, the
enantiomeric excess of the oxidated compound being
95% (entry 4).
lution of ( )-1-tetralol using Ru(II)-(S,S)-TsDPEN cat-
alyst, where the (S)-enantiomer was converted to the
corresponding ketone, leaving the unreacted (R)-enan-
tiomer.10b In addition, comparison of both chiroptical
properties and chiral HPLC elution orders of the tetra-
lones 9c–d with those of 9a–b [(S)-enantiomers are
eluted faster, and good resolutions were obtained] sup-
ports our assignment (Table 2).
Excellent enantioselectivities (>99% e.e.) with high
chemical yields were obtained when the 6-methoxy- and
the 6,7-dimethoxy- derivatives ( )-7b and ( )-7d,
respectively, were treated with 2% (S/C=50) Ru(II)-
(S,S)-TsDPEN at 28°C for 36–38 h (entries 8 and 14).
Decreasing the catalyst concentration (entries 6 and 12)
or the reaction time (entries 7 and 13) resulted in lower
enantioselectivity.
Table 2. Optical and chiral HPLC properties of hydroxy-
ketones 9a–da
b
Compound
[h]2D0
tR (min)
RS
2.6
1.1
1.2
1.1
(S)-(+)-9ac
(R)-(−)-9a
(S)-(+)-9bc
(R)-(−)-9b
(S)-(+)-9cd
(R)-(−)-9c
(S)-(+)-9dd
(R)-(−)-9d
+28.5
−28.3
+37.0
−36.3
+35.3
−28.2e
+53.1
−53.0
44
49
59
64
64
70
98
104
For the 7-methoxytetralol derivative ( )-7c, the best
result was obtained using a S/C ratio of 100 for 72 h
(entry 9). Under these conditions ketone (+)-9c and diol
(−)-7c were isolated in 40% yield (99.9% e.e.) and 45%
yield (80% e.e.), respectively. By increasing the amount
of Ru(II)-(S,S)-TsDPEN to 2% (S/C=50) and the reac-
tion time to 96 h (entry 10), we only could raise the diol
enantiopurity to 85% e.e.
a Analytical HPLC was performed on Daicel Chiralcel® OD-H, 5 m,
250×4.6 mm column.
b Resolution between HPLC peaks: RS=(tR2−tR1)/0.5(w1−w2).
c Absolute configuration established by X-ray crystallography of their
tosylates [for tosylate (S)-(+)-10a see Ref. 8].
d Proposed absolute configuration.
The kinetic resolution of the indanol ( )-7e proceeded
with slightly lower enantioselectivity, affording, in the
best case, the indanone (+)-9e with 90% e.e. (30% yield)
after 18 h by using S/C of 50 (entry 15). When the
reaction time was increased to 40 h, both the ketone
yield and the enantiopurity of the unreacted indanol
were improved to 44% and 84% e.e., respectively (entry
16); on the contrary, the enantiomeric purity of the
hydroxymethylindanone (+)-9e decreased to 80% e.e.
e 80% e.e.
The absolute configuration of the C3 in the indane
derivatives was established by chemical correlation of
the (−)-3-hydroxymethyl-1-indanol (−)-7e with the
known (S)-1-indanylmethanol,15 as shown in Scheme 3.
To this end, (−)-7e was dehydroxylated by hydrogena-
tion on palladium/carbon to afford (S)-1-indanyl-
methanol. The same absolute configuration, which
turned out to be (S), could be attributed to C3 in the
parent indanol, and hence, the absolute configuration
of cis-(−)-7e is (1R,3S), and that of hydroxyindanone
(+)-9e is (3R).
The absolute configuration of the hydroxymethyltetra-
lones (+)-9a and (+)-9b was confirmed by X-ray crystal-
lographic analysis of their tosylates (+)-10a8 (+)-10b,
respectively, in turn obtained by treatment of the
hydroxyketone with tosyl chloride in pyridine. Figure 3
shows the crystal structure of (+)-10b is (S).
Scheme 3. Reagents and conditions: H2, Pd–C, HClO4,
AcOH, rt, 2 h, 55%.
In summary, we have accomplished the resolution of
Figure 3. ORTEP drawing of (+)-10b.
racemic 3-hydroxymethylbenzocycloalkanols by
a
Although the absolute configuration of hydroxyketones
(+)-9c and (+)-9d could not be determined by X-ray
crystallography, we assumed that these enantiomers
have the (S)-configuration according to the above
established stereochemical course of kinetic resolution
of ( )-7a and ( )-7b, and the previously reported reso-
Ru(II)-chiral amine complex-mediated selective asym-
metric hydrogen-transfer oxidation to give precursors
of potent CNS chiral agents in high enantiomeric
excess. Receptor binding assays and behavioural studies
of these CNS agents as single enantiomers are now in
progress and will be reported in due course.

Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 3689–3696
3693
3. Experimental
3.3. General procedure for the cyclization of the benzyl
hemiesters 5a–d. Preparation of the tetralones 6a–d
3.1. General
To
a solution of the hemiester (9.0 mmol) in
CF3COOH (41.5 mL) was added at 0°C (CF3CO)2O
(4.0 mL). After 8 h of stirring at room temperature, the
mixture was poured into ice water, basified with
NaHCO3 and extracted with EtOAc. The organic phase
was dried (Na2SO4) and concentrated under vacuum to
afford a residue, which was purified by column
chromatography.
Melting points were determined with a Gallenkamp
capillary melting point apparatus and are uncorrected.
Infrared spectra were recorded with a Perkin Elmer
1600 FTIR spectrophotometer; the main bands are
1
given in cm−1. H NMR spectra were recorded with a
Bruker WM AMX (300 MHz); chemical shifts are
recorded in parts per million (l) downfield from tetra-
methylsilane (TMS). Mass spectra were performed on a
Hewlett-Packard HP5988A mass spectrometer by elec-
tron impact (EI), or on a Finnigan Trace-MS mass
spectrometer by chemical ionization (CI). Optical rota-
tions 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 u
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.
3.3.1. Methyl (4-oxo-1,2,3,4-tetrahydronaphthalen-2-
yl)carboxylate, 6a.20 Yellow oil (70% yield).
3.3.2. Methyl (7-methoxy-4-oxo-1,2,3,4-tetrahydro-
naphthalen-2-yl)carboxylate, 6b. Yellow solid (85%
yield); mp 107–108°C (EtOAc/hexane). IR: 1733, 1684,
1654 cm−1; 1H NMR (CDCl3): l 2.75–2.93 (m, 2H, H1),
3.00–3.20 (m, 3H, H2, H3), 3.72 (s, 3H, CO2CH3), 3.85
(s, 3H, OCH3), 6.72 (d, 1H, J=2.3 Hz, H8), 6.84 (dd,
1H, J=8.7, 2.5 Hz, H6), 8.00 (d, 1H, J=8.75 Hz, H5);
MS (EI, m/z): 234 (M+). Anal. calcd for C13H14O4: C,
66.66; H, 6.02. Found: C, 66.30, H, 6.09%.
3.3.3. Methyl (6-methoxy-4-oxo-1,2,3,4-tetrahydro-
naphthalen-2-yl)carboxylate, 6c.21 White solid (50%
yield); mp 77–79°C. Lit.21 mp 76–78°C.
3.2. General procedure for the preparation of the ben-
zyl hemiesters 5a–d
3.3.4. Methyl (6,7-dimetoxy-4-oxo-1,2,3,4-tetrahydro-
naphthalen-2-yl)carboxylate, 6d. Yellowish solid (85%
A mixture of the hemisuccinate 4a–d (14.5 mmol) and
10% palladium on activated carbon (0.3 g) in anhy-
drous methanol (50 mL) was stirred at room tempera-
ture under H2 for 3 h. The reaction mixture was filtered
through Celite® and the solvent was evaporated under
reduced pressure to give pure benzylsuccinic-hemiesters.
1
yield); mp 147–148°C. IR: 1730, 1718, 1667 cm−1; H
NMR (CDCl3): l 2.75–2.98 (m, 2H, H1), 3.14–3.20 (m,
3H, H2, H3), 3.72 (s, 3H, CO2CH3), 3.91, 3.94 (s, 3H,
2×OCH3), 6.68 (s, 1H, H8), 7.50 (s, 1H, H5); MS (EI,
m/z): 264 (M+). Anal. calcd for C14H16O5: C, 63.63; H,
6.10. Found: C, 63.61; H, 6.17%.
3.2.1. 2-Benzylsuccinic acid 1-methyl ester, 5a.16
Obtained from hemisuccinate 4a16 as yellowish-brown
oil (92% yield).
3.4. Synthesis of the diols 7a–e
Ketoester 6 (5 mmol) was dissolved in anhydrous THF
(50 mL) and added dropwise to a stirred suspension of
LiAlH4 (1.90 g, 50 mmol) in anhydrous THF (80 mL)
under Ar. 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.
3.2.2. 2-(3-Methoxybenzyl)succinic acid 1-methyl ester,
5b. Obtained from hemisuccinate 4b17 as yellow solid
(95% yield); mp 76–79°C. Lit.17 mp 77–78°C.
3.2.3. 2-(4-Methoxybenzyl)succinic acid 1-methyl ester,
5c. Prepared from hemisuccinate 4c18 as yellow solid
(96% yield); mp 77–79°C (CH2Cl2/hexane). IR: 2953,
1
1732, 1613, 1514 cm−1; H NMR (CD3OD): l 2.43 (dd,
1H, J=16.9, 4.9 Hz, H3), 2.58–2.67 (m, 1H, H3), 2.77
(dd, 1H, J=13.5, 7.6 Hz, Ph-HCH-), 2.91 (dd, 1H,
J=13.6, 6.8 Hz, Ph-HCH-), 3.01–3.09 (m, 1H, H2),
3.63 (s, 3H, COOCH3), 3.77 (s, 3H, Ph-OCH3), 6.85 (d,
2H, J=8.6 Hz, H3 and H5 Ph), 7.09 (d, 2H, J=8.6 Hz,
H2 and H6 Ph); MS (EI, m/z): 252 (M+). Anal. calcd
for C13H16O5: C, 61.90; H, 6.39. Found: C, 61.61; H,
6.17%.
3.4.1. 3-Hydroxymethyl-1,2,3,4-tetrahydronaphthalen-1-
ol, 7a. White solid (85% yield); mp 104–105°C. Lit.8 mp
103–105°C.
3.4.2. 3-Hydroxymethyl-6-methoxy-1,2,3,4-tetrahydro-
naphthalen-1-ol, 7b. White solid (85% yield); mp 130–
131°C. IR: 3268, 2956, 1616, 1499 cm−1; 1H NMR
(CDCl3): l 1.47–1.58 (m, 1H, H4), 2.04–2.28 (m, 2H,
H3, H4), 2.61 (dd, 1H, J=16.5, 9.3 Hz, 1H2), 2.80 (dd,
1H, J=16.1, 5.2 Hz, 1H2), 3.63 (d, 2H, J=6.1 Hz,
CH2OH), 3.78 (s, 3H, OCH3), 4.75–4.84 (m, 1H, H1),
6.62 (d, 1H, J=2.4 Hz, H5), 6.78 (dd, 1H, J=8.5, 2.4
3.2.4. 2-(3,4-Dimethoxybenzyl)succinic acid 1-methyl
ester, 5d. Prepared from hemisuccinate 4d19 as yellowish
solid (94% yield); mp 108–110°C (hexane). Lit.19 mp
108–109°C.

3694
Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 3689–3696
Hz, H7), 7.41 (d, 1H, J=8.5 Hz, H8); MS (EI, m/z):
208 (M+). Anal. calcd for C12H16O3·1/6H2O: C, 68.22;
H, 7.79. Found: C, 68.13; H, 7.60%.
TsDPEN10b was stirred at 28°C in the solvent and
conditions indicated in Table 1. Then, the mixture was
filtered and the solvent was evaporated under reduced
pressure to give a residue which was purified by chro-
matography (silica gel, CH2Cl2:MeOH or hex-
ane:EtOAc) to give the diols (−)-7a–e and the ketones
(+)-9a–e.
3.4.3.
3-Hydroxymethyl-7-methoxy-1,2,3,4-tetra-
hydronaphthalen-1-ol, 7c. White solid (90% yield); mp
1
118–119°C. IR: 3398, 3342, 2934, 1611, 1499 cm−1; H
NMR (CDCl3): l 1.48–1.63 (m, 1H, H4), 2.09–2.17 (m,
1H, H3), 2.26–2.34 (m, 1H, H4), 2.53 (dd, 1H, J=16.2,
9.9 Hz, H2), 2.83 (dd, 1H, J=16.2, 5.3 Hz, H2), 3.66
(d, 2H, J=6.2 Hz, -CH2-OH), 3.81 (s, 3H, CH3O-),
4.79–4.84 (m, 1H, H1), 6,78 (dd, 1H, J=8.4, 2.7 Hz,
H6), 7.03 (d, 1H, J=8.4 Hz, H5), 7.09 (d, 1H, J=2.6
Hz, H8); MS (EI, m/z): 208 (M+). Anal. calcd for
C12H16O3: C, 69.21; H, 7.74. Found: C, 69.42; H,
7.99%.
3.5.1.
(1R,3R)-3-Hydroxymethyl-1,2,3,4-tetrahydro-
naphthalen-1-ol, (−)-7a.8 [h]D20=−104 (c 1.0, EtOAc),
99.9% e.e. Lit.8 [h]2D0=−103 (c 1.0, EtOAc).
3.5.2.
(S)-3-Hydroxymethyl-1,2,3,4-tetrahydro-
naphthalen-1-one, (+)-9a. [h]2D0=+28.5 (c 0.5, AcOEt),
99.9% e.e. Chiralcel® OD-H, hexane:propan-2-ol, 94:6,
flow 0.5 mL/min, u 254 nm. tR=44 min.
3.4.4.
6,7-Dimethoxy-3-hydroxymethyl-1,2,3,4-tetra-
hydronaphthalen-1-ol, 7d. White solid (85% yield); mp
3.5.3. (1R,3R)-3-Hydroxymethyl-6-methoxy-1,2,3,4-tet-
rahydronaphthalen-1-ol, (−)-7b. [h]2D0=−97.3 (c 0.5,
EtOAc), 99.9% e.e.
115–116°C. IR: 1609, 1515, 1459, 1257, 1218 cm−1; H
1
NMR (CDCl3): l 1.47–1.58 (m, 1H, H4), 2.16 (m, 1H,
H3), 2.24–2.32 (m, 1H, H4), 2.53 (dd, 1H, J=16.1, 9.6
Hz, 1H2), 2.80 (dd, 1H, J=16.1, 5.2 Hz, 1H2), (d, 2H,
J=6.1 Hz, CH2OH), 3.84, 3.87 (s, 3H, 2×OCH3), 4.77–
4.81 (m, 1H, H1), 6.57 (s, 1H, H5), 7.05 (s, 1H, H8);
MS (EI, m/z): 238 (M+). Anal. calcd for C13H18O2·1/2
H2O: C, 64.31; H, 7.68. Found: C, 64.03; H, 7.45%.
3.5.4.
(S)-3-Hydroxymethyl-6-methoxy-1,2,3,4-tetra-
hydronaphthalen-1-one, (+)-9b. Yellow solid, mp 70–
72°C; [h]2D0=+37.0 (c 0.5, EtOAc), 99.9% e.e. Chiralcel®
OD-H, hexane:propan-2-ol, 90:10, flow 0.3 mL/min, u
254 nm. tR=59 min. IR: 3258, 2925, 1670, 1598 cm−1;
1H NMR (CDCl3): l 2.35–2.46 (m, 2H, H4), 2.66–2.87
(m, 2H, 1H2, H3), 3.03 (dd, 1H, J=16.4, 1.9 Hz, 1H2),
3.68–3.78 (m, 2H, CH2OH), 3.85 (s, 3H, OCH3), 6.72
(d, 1H, J=2.2 Hz, H5), 6.83 (dd, 1H, J=8.7, 2.4 Hz,
H7), 8.00 (d, 1H, J=8.7 Hz, H8); MS (EI, m/z): 206
(M+).
3.4.5. 3-Hydroxymethylindan-1-ol, 7e. A solution of 3-
oxo-1-indancarboxylic acid12 8 (2.5 g, 0.014 mol) and
p-TsOH (catalytic) in methanol (15 mL) was refluxed
with stirring for 5 h. After cooling, the solvent was
distilled off under reduced pressure. The residue was
dissolved in CH2Cl2, and the resulting solution was
washed with 10% NaHCO3 and water and then dried
(Na2SO4). After removal of the solvent in vacuo the
resulting orange oil was ball-to-ball distilled (130–
133°C/0.4 mmHg) to give methyl 3-oxo-1-indancar-
boxylate (2.4 g, 90%) as a colourless oil. The ketoester
(5 mmol) was dissolved in anhydrous THF (125 mL)
and added dropwise to a stirred suspension of LiAlH4
(4.90 g, 0.129 mol) in anhydrous THF (200 mL) under
Ar. After stirring for 12 h at room temperature, water
(5 mL), 5% NaOH (8 mL) and water (30 mL) were
added dropwise. The precipitate was removed by filtra-
tion and washed with EtOAc. The filtrate was concen-
trated in vacuo to give a residue, which was dissolved in
CH2Cl2, dried (Na2SO4), concentrated at reduced pres-
sure. The resulting yellow oil was purified by column
chromatography (silica gel, EtOAc:hexane, 2:1) to
afford cis-( )-7e (0.57 g, 70%) as a white solid, mp
86–87°C; IR: 3316, 2957, 1461 cm−1; 1H NMR (CDCl3):
l 1.87 (dt, 1H, J=14.2, 2.5 Hz, 1H2), 2.61 (ddd, 1H,
J=14.2, 8.7, 6.9 Hz, 1H2), 2.28–3.34 (m, 1H, H3),
3.81–3.93 (m, 2H, CH2OH), 5.05 (dd, 1H, J=6.8, 1.8
Hz, H1), 7.24–7.34 (m, 3H, H4, H5, H6), 7.41 (dd, 1H,
J=7.6, 1.4 Hz, H7); MS (EI, m/z): 164 (M+). Anal.
calcd for C10H12O2: C, 73.15; H, 7.37. Found: C, 73.29;
H, 7.10%.
3.5.5. (1R,3R)-3-Hydroxymethyl-7-methoxy-1,2,3,4-tet-
rahydronaphtalen-1-ol, (−)-7c. [h]2D0=−94.0 (c 0.5,
EtOAc), 80% e.e.
3.5.6.
(S)-3-Hydroxymethyl-7-methoxy-1,2,3,4-tetra-
hydronaphthalen-1-one, (+)-9c. Colourless oil; [h]2D0=
+35.3 (c 0.5, EtOAc), 99.9% e.e. Chiralcel® OD-H,
hexane:propan-2-ol, 90:10, flow 0.3 mL/min, u 254 nm.
tR=64 min. IR: 3422, 2930, 1668, 1608 cm−1; H NMR
1
(CDCl3): l 2.40–2.48 (m, 2H, H4), 2.75–2.83 (m, 2H,
H2, H3), 2.99–3.05 (m, 1H, H2), 3.63–3.74 (m, 2H,
-CH2-OH), 3.83 (s, 3H, CH3O-), 7.07 (dd, 1H, J=8.4,
2.8 Hz, H6), 7.19 (d, 1H, J=8.4 Hz, H5), 7.50 (d, 1H,
J=2.8 Hz, H8); MS (CI, m/z): 207 (MH+).
3.5.7. (1R,3R)-6,7-Dimethoxy-3-hydroxymethyl-1,2,3,4-
tetrahydronaphthalen-1-ol, (−)-7d. [h]2D0=−98.0 (c 0.5,
EtOAc), 99.9% e.e.
3.5.8. (S)-6,7-Dimethoxy-3-hydroxymethyl-1,2,3,4-tetra-
hydronaphthalen-1-one, (+)-9d. White solid, mp 122–
123°C; [h]2D0=+53.1 (c 0.5, EtOAc), 99.9% e.e.
Chiralcel® OD-H, hexane:propan-2-ol, 90:10, flow 0.3
mL/min, u 254 nm. tR=98 min. IR: 1654, 1598, 1508
cm−1; 1H NMR (CDCl3): l 2.35–2.43 (m, 2H, H4),
2.62–2.65 (m, 2H, 1H2, H3), 3.00 (dd, 1H, J=16.0, 4.0
Hz, 1H2), 3.71–3.77 (m, 2H, CH2OH), 3.91, 3.94 (s,
3.5. General procedure for resolution of diols 7a–e
A mixture of diol 7a–e (1 mmol) and Ru(II)-(S,S)-

Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 3689–3696
3695
3H, 2×OCH3), 6.70 (s, 1H, H5), 7.50 (s, 1H, H8); MS
(EI, m/z): 236 (M+). Anal. calcd for C13H16O4: C,
66.09; H, 6.83. Found: C, 66.01; H, 6.87%.
was added to a cooled solution of the hydroxyketone
(+)-9b (0.1 g, 0.48 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 (+)-10b (0.13 g, 75%) as a
white solid, mp 108–109°C (cyclohexane); [h]2D0=+9.2 (c
1.0, EtOAc); IR: 1676, 1601, 1358 cm−1; 1H NMR
(CDCl3): l 2.27–2.36 (m, 1H, H4), 2.45 (s, 3H, CH3-
Ph), 2.50–2.64 (m, 2H, H3, H4), 2.75–2.83 (m, 1H,
1H2), 2.98 (dd, 1H, J=17.7, 2.0 Hz, 1H2), 3.84 (s, 3H,
OCH3), 4.01–4.07 (m, 1H, CH2O-), 6.66 (d, 1H, J=2.2
Hz, H5), 6.81 (dd, 1H, J=8.7, 2.4 Hz, H7), 7.35 (d, 2H,
J=8.0 Hz, H3, H5 Ph), 7.78 (d, 2H, J=8.2 Hz, H2, H6
Ph), (d, 1H, J=8.7 Hz, H8); MS (EI, m/z): 360 (M+).
Anal. calcd for C19H20O5S: C, 63.32; H, 5.59; S, 8.90.
Found: C, 63.26; H, 5.63; S, 8.65%.
3.5.9.
(1R,3S)-3-Hydroxymethylindan-1-ol,
(−)-7e.
[h]2D0=−13.6 (c 0.5, EtOAc), 85% e.e. Chiralcel® OD-H,
hexane:propan-2-ol, 95:5, flow 0.5 mL/min, u 254 nm.
tR=40 min.
3.5.10.
(R)-3-Hydroxymethyl-1-indanone,
(+)-9e.
Colourless oil. [h]2D0=+14.0 (c 0.5, EtOAc), 90% e.e. IR:
3394, 1701, 1605 cm−1; H NMR (CDCl3): l 2.57 (dd,
1
1H, J=19.1, 3.1 Hz, 1H2), 2.85 (dd, 1H, J=19.1, 7.7
Hz, 1H2), 3.55–3.63 (m, 1H, H3), 3.90 (d, 2H, J=5.7
Hz, CH2OH), 7.39–7.44 (m, 1H, H6), 7.59–7.65 (m, 2H,
H4, H5), 7.76 (d, 1H, J=7.7 Hz, H7); MS (EI, m/z):
162 (M+).
3.6. General procedure for oxidation of diols (−)-7a–e:
preparation of hydroxyketones (−)-9a–e
Diol (−)-7a–e (1.0 mmol) was dissolved in CHCl3 (15
mL) and MnO2 (2.17 g, 25 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 chromatogra-
phy (silica gel, EtOAc/hexane, 1:1) to give the hydroxy-
ketone (−)-9a–e.
3.7.2. Crystallographic analysis of (+)-10b. Suitable crys-
tals of (+)-10b (C19H20O5S) were obtained from Et2O at
room temperature by slow evaporation of the solvent,
C19H20O5S, M=360.41, a=6.4662(8), b=32.467(4), c=
3
,
,
8.4901(11) A, space group P21, V=1764.0(4) A , T=
293(2) K, Z=4, Dcalcd=1.357 Mg/m3, F(000)=760.
Final goodness-of-fit=1.023, R=0.0459, wR=0.1001.
Absolute structure determination was completed using
the Flack parameter.22 Crystallographic data (excluding
structure factors) for (S)-(+)-10b have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 211912.
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].
3.6.1.
(R)-3-Hydroxymethyl-1,2,3,4-tetrahydro-
naphthalen-1-one, (−)-9a. 75% Yield. [h]2D0=−28.3 (c 1.0,
AcOEt), 99.9% e.e. Chiralcel® OD-H, hexane:propan-2-
ol, 94:6, flow 0.5 mL/min, u 254 nm. tR=49 min.
3.6.2.
(R)-3-Hydroxymethyl-6-methoxy-1,2,3,4-tetra-
hydronaphthalen-1-one, (−)-9b. 85% Yield. [h]2D0=−36.3
(c 0.5, EtOAc), 99.9% e.e. Chiralcel® OD-H, hex-
ane:propan-2-ol, 90:10, flow 0.3 mL/min, u 254 nm.
tR=64 min.
3.8. Determination of the absolute configuration of cis-
hydroxymethylindanol (−)-7e
3.6.3.
(R)-3-Hydroxymethyl-7-methoxy-1,2,3,4-tetra-
hydronaphthalen-1-one, (−)-9c. 86% Yield. [h]2D0=−28.2
(c 0.5, EtOAc), 80% e.e. Chiralcel® OD-H, hex-
ane:propan-2-ol, 90:10, flow 0.3 mL/min, u 254 nm.
tR=70 min.
A mixture of cis-hydroxymethylindanol (−)-7e ([h]2D0=
−13.6, 85% ee) (80 mg, 0.49 mmol) and 10% palladium
on carbon (10 mg) in glacial acetic acid (10 mL)
containing 70% aqueous perchloric acid (one drop) was
stirred under hydrogen for 2 h. Filtration through
Celite® and concentration gave the crude product,
which was purified by chromatography (silica gel,
CH2Cl2) to give (S)-1-indanylmethanol (40 mg, 55%
yield) as a colourless oil. [h]2D0=−14.3 (c 1.0, benzene);
lit.15 [h]2D0=−11.6 (benzene), 68% e.e.
3.6.4. (R)-6,7-Dimethoxy-3-hydroxymethyl 1,2,3,4-tetra-
hydronaphthalen-1-one, (−)-9d. 90% Yield. [h]2D0=−53.0
(c 0.5, EtOAc), 99.9% e.e. Chiralcel® OD-H, hex-
ane:propan-2-ol, 90:10, flow 0.3 mL/min, u 254 nm.
tR=104 min.
3.6.5. (S)-3-Hydroxymethyl-1-indanone, (−)-9e. 80%
Yield. [h]2D0=−13.5 (c 0.5, EtOAc), 85% e.e.
Acknowledgements
3.7. Determination of the absolute configuration of
hydroxyketone (+)-9b
This work was supported by Spanish Comisio´n Inter-
ministerial de Ciencia y Tecnolog´ıa (CICYT) under
Grants SAF98-0148-C04-04 and SAF2002-04195-C03-
01, and by Xunta de Galicia under Grant PGIDT01-
PXI20309PR.
3.7.1. Preparation of (S)-(6-methoxy-4-oxo-1,2,3,4-tetra-
hydronaphthalen-2-yl)methyl 4-methylbenzenesulfonate,
(+)-10b. p-Toluenesulfonyl chloride (0.12 g, 0.60 mmol)

3696
Y. Caro et al. / Tetrahedron: Asymmetry 14 (2003) 3689–3696
11. Eirin, A. M.; Ravin˜a, E.; Montan˜e´s, J. M.; Calleja, J. M.
References
Eur. J. Med. Chem. 1976, 11, 29–32.
1. Holstein, A. P.; Chen, C. H. Am. J. Psychiatry 1965, 122,
462–463.
12. Hashimoto, I.; Takatsuka, R. Bull. Chem. Soc. Jpn. 1977,
50, 2495–2496.
2. King, D. J. Eur. Neuropsychopharmacol. 1998, 8, 33–42.
3. Capuano, B.; Crosby, I. T.; Lloyd, E. J. Curr. Med.
Chem. 2002, 9, 521–548.
13. Miura, M.; Yoshida, M.; Nojima, M.; Kusabayashi, S. J.
Chem. Soc., Perkin Trans. 1 1982, 79–83.
14. Alesso, E. N.; Moltrasio Iglesias, G. Y.; Aguirre, J. M.
An. Quim. 1993, 89, 242–245.
15. (S)-1-Indanylmethanol: [h]D=−11.6 (c 0.71, benzene),
68% e.e. Lorentzen, R. J.; Brewster, J. H.; Smith, H. E. J.
Am. Chem. Soc. 1992, 114, 2181–2187. (R)-1-Indanyl-
methanol: [h]D=+17 (c 0.4, benzene). Battail-Robert, M.
D.; Gagnaire, D. B. Soc. Chim. Fr. 1966, 208–210.
16. Cohen, S. G.; Milovanovic, A. J. Am. Chem. Soc. 1968,
90, 3495–3502.
17. Barnier, J. P.; Blanco, L.; Guibe-Jampel, E.; Rousseau,
G. Tetrahedron 1989, 45, 5051–5058.
18. Guirguis, N. R.; Awad, B. M.; Saad, H. A. Liebigs Ann.
1986, 1003–1011.
19. Ganeshpure, P. A.; Stevenson, R. J. Chem. Soc., Perkin
Trans. 1 1981, 1681–1684.
20. Horning, E. C.; Walker, G. N. J. Am. Chem. Soc. 1952,
74, 5147–5151.
4. Ravin˜a, E.; Masaguer, C. F. Curr. Med. Chem.: Central
Nervous System Agents 2001, 1, 43–62.
5. Cortizo, L.; Santana, L.; Ravina, E.; Orallo, F.;
Fontenla, J. A.; Castro, E.; Calleja, J. M.; De Ceballos,
M. L. J. Med. Chem. 1991, 34, 2242–2247.
6. 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.
7. 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.
8. Caro, Y.; Masaguer, C. F.; Ravina, E. Tetrahedron:
Asymmetry 2003, 14, 381–387.
9. (a) Robinson, D. E. J. E.; Bull, S. D. Tetrahedron:
Asymmetry 2003, 14, 1407–1446; (b) Arterburn, J. B.
Tetrahedron 2001, 57, 9765–9788.
10. (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.;
Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285–
288; (b) Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Mat-
sumura, K.; Ikariya, T.; Noyori, R. Angew. Chem., Int.
Ed. Engl. 1997, 36, 288–290.
21. Kometani, T.; Shiotani, S. J. Med. Chem. 1978, 21,
1105–1110.
22. (a) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39,
876–881; (b) Bernardinelli, G.; Flack, H. D. Acta Crys-
tallogr., Sect. A 1985, 41, 500–511.