Efficient enantioselective synthesis of (R)-2-acetyl-2-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, the key intermediate in the synthesis of anthracycline antibiotics

Article abstract of DOI:10.1016/S0957-4166(01)00531-6

A simple, efficient, enantioselective synthesis of (R)-2-acetyl-2-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, the key intermediate in the synthesis of anthracycline antibiotics, is described. The synthetic procedure starts with the Sharpless asymmetric dihydroxylation of 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene: the diol obtained is regioselectively transformed into the corresponding chloroacetate which is dehalogenated and saponified to give the desired title compound in four steps with satisfactory yield (52%). No separation step is necessary at any point of the synthetic process. An efficient procedure for the synthesis of the starting enone and the stereoselectivity of the methanolysis of the intermediate chloroacetate are also reported.

Full text of DOI:10.1016/S0957-4166(01)00531-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3155–3161
Efficient enantioselective synthesis of
(
R)-2-acetyl-2-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydro-
naphthalene, the key intermediate in the synthesis of
†
anthracycline antibiotics
a
a,
b,
b
a
Fabrizio Badalassi, Paolo Crotti, * Cristina Di Bugno, * Fabio D’Arata, Lucilla Favero and
b
Alessio Ramacciotti
a
Dipartimento di Chimica Bioorganica e Biofarmacia, Universit a` di Pisa, Via Bonanno 33, 56126 Pisa, Italy
b
Menarini Ricerche SpA, Via Livornese 897, La Vettola, 56010 Pisa, Italy
Received 13 November 2001; accepted 22 November 2001
Abstract—A simple, efficient, enantioselective synthesis of (R)-2-acetyl-2-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene,
the key intermediate in the synthesis of anthracycline antibiotics, is described. The synthetic procedure starts with the Sharpless
asymmetric dihydroxylation of 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene: the diol obtained is regioselectively transformed
into the corresponding chloroacetate which is dehalogenated and saponified to give the desired title compound in four steps with
satisfactory yield (52%). No separation step is necessary at any point of the synthetic process. An efficient procedure for the
synthesis of the starting enone and the stereoselectivity of the methanolysis of the intermediate chloroacetate are also reported.
©
2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
C(9) of the corresponding anthracyclinones 1–4 (R =
3
H) is very important as only compounds with (S)-
configuration at this 1position show the desired
pharmacological activity.
Compounds which belong to the class of anthracycline
antibiotics, such as daunomycin 1, doxorubicin 2,
hydarubicin 3, and epirubicin 4 have widespread thera-
peutic use as antineoplastic agents. The configuration at
1,2,3,4-Tetrahydronaphthalene-derived hydroxy ketone
(
R)-5 (Scheme 1), which possesses the requisite configu-
ration at C(2), corresponding to the C(9) carbon of
anthracyclines 1–4, is a key intermediate in the indus-
trial synthesis of these important pharmacologically
2,3
active compounds. As a consequence, an efficient and
straightforward method for the synthesis of (R)-5 con-
stitutes a point of sure interest.
2
3
Since the pioneering work of Wong and Arcamone,
several stereoselective procedures have been described
for the synthesis of hydroxy ketone (R)-5 with good e.e.
Some of these procedures utilize:
(
a) Sharpless asymmetric epoxidation (SAE) of racemic
4 5
allylic alcohols (±)-6 and (±)-7 with concomitant
kinetic resolution or SAE or TBHP/VO(acac) oxida-
2
*
†
Corresponding authors. Fax: +39 050 43321 (P.C.); fax: +39 050
61171 (C.D.B.); e-mail: crotti@farm.unipi.it; cdibugno@
labguidotti.it
6
7
tion of non-racemic allylic alcohols (S)-6 and (R)-7
9
followed by
protocol;
a typical LAH-reduction/reoxidation
Dedicated to the memory of Dr. Raffaello Giorgi.
0
957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00531-6

3
156
F. Badalassi et al. / Tetrahedron: Asymmetry 12 (2001) 3155–3161
Scheme 1.
(
b) SAE of allylic alcohol 8 followed by a Payne
turn has been prepared in a straightforward way also.
Several procedures are known for the synthesis of
enone 9, starting from the corresponding unsaturated
rearrangement (PhSNa) and a final desulfurization and
oxidation;
8
6a
14
15
carboxylic acid 14, aldehyde 15, 1-tetralone 16 and
16
(
c) bromolactonization of chiral acetals and amides
2-tetralone 17 or based on acylation (AcCl/AlCl ) of
9,17
3
9
10
derived from unsaturated ketone 9 and acid 10
5,8-diacetoxy-3,4-dihydronaphthalene 18.
However,
respectively, followed by appropriate debromination
and other necessary transformations;
in some cases the yields are poor or the protocol
decidedly complex (Scheme 2).
(
d) microbial reduction of (±)-5 with fermenting baker’s
We have found that direct acylation of 5,8-dimethoxy-
4
yeast followed by separation of diastereoisomeric diols
and a necessary final reoxidation;
3,4-dihydronaphthalene 19 with AcCl in the presence
1
1
of an excess of AlCl (8 equiv./mol) allows the direct
3
preparation of enone 9 by a very simple protocol with
(
e) hydroxylation of the potassium enolate of b-keto
a
satisfactory yield (70% after recrystallization)
ester 11 using a chiral N-sulfonyl oxaziridine, followed
by reduction of the carbonyl group and transformation
of the methoxycarbonyl group into an acetyl group
(Scheme 3).
We made use of the Sharpless asymmetric dihydroxyl-
ation (SAD) for the introduction of the required
configuration of the target compound into the skeleton
of enone 9, by means of an enriched [1% K OsO (OH) ]
1
2,13
(
Scheme 1).
However, these procedures are often complex and gen-
erally difficult to transfer to large scale to the point that
hydroxy ketone (R)-5 has been commonly prepared on
an industrial scale by resolution of the corresponding
racemic mixture obtained by a-hydroxylation (t-BuOK/
2
2
4
AD-mix-a in the presence of methanesulfonamide
18
(Scheme 3). Diol (1S,2R)-13 was obtained in satisfac-
tory yield (71%, after recrystallization) and excellent
e.e. (98%). This first part of our synthetic approach to
compound (R)-5 had also been previously utilized by
Tomioka, even if in less effective and more drastic
2
,3a
O ) of ketone 12 (Scheme 1).
2
19
operating conditions. However, in that case, diol
2
. Results and discussion
(1S,2R)-13 was reductively dehydroxylated (Et SiH/
3
CF COOH) at the benzylic position with concomitant
3
We describe herein a new and simple protocol for the
enantioselective synthesis of (R)-5 starting from 2-acet-
yl-5,8-dimethoxy-3,4-dihydronaphthalene 9, which in
reduction of the carbonyl group to the corresponding
secondary alcohol, which then had to be reoxidized in
order to form the target compound (R)-5.

F. Badalassi et al. / Tetrahedron: Asymmetry 12 (2001) 3155–3161
3157
Scheme 2.
Scheme 3.
In our present approach, we took advantage of the
Sharpless procedure for transforming a diol into the
IRA-400 (OH) afforded (R)-5 in workable yield (52%
from enone 9) and excellent e.e. (99%) (Scheme 3).
18,20
corresponding epoxide.
Treatment of the diol
(
1S,2R)-13 with MeC(OMe) in CH Cl in the presence
In our preliminary, more tedious synthetic approach to
(R)-5, subsequently abandoned, it was decided to trans-
form chloroacetate (1R,2S)-21 into the corresponding
epoxide (1S,2R)-23. However, when chloroacetate
(1R,2S)-21 was treated with Amberlyst IRA-400 (OH) in
MeOH, instead of the expected epoxide (1S,2R)-23,
the cis-methoxy alcohol (1S,2R)-25 was obtained as the
main product (87%), accompanied by a small amount
(13%) of the trans-diastereoisomer (1R,2R)-24 (Scheme
3
2
2
of PPTS for 24 h led to the sufficiently stable cyclic
orthoester intermediate 20 ( H NMR), which was exposed
to Me SiCl for 1 h to give the chloroacetate (1R,2S)-21
as the only reaction product. Chloroacetate (1R,2S)-21
has the desired substitution and stereochemistry at C(2)
for the target compound (R)-5. Treatment of (1R,2S)-21
with Bu SnH in the presence of AIBN under irradiation
from a common 200 Watt electric light bulb yielded the
1
3
3
21
acetate (R)-22. Saponification of (R)-22 with Amberlyst
4).

3
158
F. Badalassi et al. / Tetrahedron: Asymmetry 12 (2001) 3155–3161
Scheme 4.
This result indicated that rapid methanolysis had
occurred at the benzylic chloro-substituted position,
largely with inversion of configuration, impeding
cyclization. The exact structure and configuration of
the cis-methoxy alcohol (1S,2R)-25 was unequivocally
demonstrated by its stability under acetylation condi-
antibiotics, in a decidedly efficient and straightforward
way. The process requires four simple steps starting
from enone 9, without the necessity of any chromato-
graphic separation, and the target compound (R)-5 is
obtained in good overall yield (52%) and excellent
enantioselectivity (99% e.e.). The method appears to be
decidedly competitive with, and even superior to, other
previously described procedures and is thus a candidate
2
2
tions (Ac O/Py) and by the fact that (1S,2R)-25 is also
2
obtained, together with the dimethoxy derivative
24
(
(
1S,2R)-26, in the methylation (MeI/Ag CO ) of diol
for application on a large scale. Moreover, a simple
and efficient procedure for the synthesis of the starting
material, enone 9, is described.
2
3
8,19
1
1S,2R)-13, whose configuration is certain.
As for
the trans-methoxy alcohol (1R,2R)-24, its structure and
configuration were demonstrated by preparing it, for
comparison, in a rigidly stereocontrolled way by ring-
opening reaction of epoxide (1S,2R)-23 under alkaline
conditions. For this purpose, chloroacetate (1R,2S)-21
was cyclized to the corresponding epoxide (1S,2R)-23
by treatment with 10% aqueous NaOH in THF. Subse-
quent treatment of epoxide (1S,2R)-23 with catalytic
MeONa in anhydrous methanol afforded the methoxy
alcohol (1R,2R)-24 as the only reaction product, by a
4
. Experimental
4
.1. General
1
13
H and C NMR spectra were determined with a
Bruker AC-200 spectrometer on CDCl solutions using
3
Me Si as the internal standard. Optical rotations were
4
well-known S 2 opening process with nucleophilic
N
measured with a Perkin–Elmer 241 digital polarimeter
with a 1 dm cell. E.e. Values for diol (1S,2R)-13 and
hydroxy ketone (R)-5 were determined by HPLC on a
Chiracel OD-H chiral column [(25 cm×0.46 cm (i.d.)].
All reactions were followed by TLC on Alugram SIL
G/UV254 silica gel sheets (Macherey–Nagel) with
detection by UV and/or spraying with 20% phospho-
molybdic acid in EtOH. Toluene and CH Cl were
attack on the benzylic less substituted oxirane carbon
(
(
Scheme 4). The formation of both (1R,2R)-24 and
1S,2R)-25 in the acid methanolysis of epoxide (1S,2R)-
2
3 (24/25 ratio=72:28) further confirmed the trans-/cis-
23
diastereoisomeric relationship between these products.
2
2
3. Conclusion
distilled under nitrogen from sodium/benzophenone
ketyl and CaH , respectively. Commercially available
2
In conclusion, our procedure makes it possible to
obtain the tetraline-derived hydroxy ketone (R)-5, the
key intermediate for the synthesis of anthracycline
Amberlyst IRA-400 (Aldrich) was activated by treat-
ment with 30% aqueous NaOH, followed by washings
with water and MeOH.

F. Badalassi et al. / Tetrahedron: Asymmetry 12 (2001) 3155–3161
3159
4.2. 2-Acetyl-5,8-dimethoxy-3,4-dihydronaphthalene 9
gen with MeC(OMe) (5.60 g, 0.046 mol) and PPTS
3
(
0.20 g, 0.079 mmol) and the resulting reaction mixture
AcCl (41.9 g, 0.53 mol) was dropwise added at 0°C
was maintained at the same temperature for 24 h.
Evaporation of the organic solvent afforded a crude
solid product consisting of intermediate 20 (9.35 g) [ H
under nitrogen to a suspension of AlCl (44.9 g, 0.33
3
1
mol) in anhydrous CH Cl (200 mL). After stirring for
2
2
3
0 min at the same temperature, a solution of 5,8-
NMR l 6.70 (t, 2H, J=6.5 Hz), 5.77 (s, 1H), 3.78 (s,
3H), 3.73 (s, 3H), 3.27 (s, 3H), 2.85–3.05 (m, 2H), 2.34
(s, 3H), 1.95–2.19 (m, 2H), 1.54 (s, 3H)], which was
taken up in anhydrous CH Cl (60 mL) and treated
4
dimethoxy-3,4-dihydronaphthalene 19 (8.0 g, 0.042
mol) in anhydrous CH Cl (250 mL) was slowly added
2
2
and the resulting reaction mixture was further stirred
for 30 min at 0°C. Ice was cautiously added and the
organic phase was separated. Evaporation of the
washed (5% aqueous HCl, water and brine) afforded a
crude solid product (9.80 g) which was recrystallized
from AcOEt to give pure 9 as a solid (6.83 g, 70%
2
2
with Me SiCl (5.56 g, 0.051 mol). The reaction mixture
3
was stirred at rt for 1 h, then the solvent was evapo-
rated to give a solid residue. Hexane (100 mL) was
added and the resulting suspension was vigorously
stirred for 3 h, then filtered to give pure chloroacetate
(1R,2S)-21 as a solid (9.41 g, 99% yield), mp 125–
6
a
yield), mp 105–106°C (lit. mp 106–107°C): IR 1650
−
1
1
25
cm (CꢀO); H NMR l 7.81 (t, 1H, J=1.4 Hz), 6.84
127°C: [h] =−16.2 (c 1.0, CH Cl ): IR 1737 and 1714
D
2
2
−
1
1
(
d, 1H, J=8.9 Hz), 6.69 (d, 1H, J=8.9 Hz), 3.84 (s,
cm (CꢀO); H NMR l 6.72 (d, 1H, J=8.9 Hz), 6.65
(d, 1H, J=8.9 Hz) 5.27 (d, 1H, J=1.7 Hz), 3.79 (s,
3H), 3.73 (s, 3H), 2.98 (ddd, 1H, J=17.5, 5.5, 1.6 Hz),
3
2
1
1
H), 3.80 (s, 3H), 2.75–2.83 (m, 2H), 2.47–2.56 (m, 2H),
13
.45 (s, 3H). C NMR l 198.8, 151.0, 150.4, 137.2,
31.5, 127.2, 122.6, 113.2, 108.5, 56.1, 55.9, 25.3, 20.5,
9.9. Anal. calcd for C H O : C, 72.39; H, 6.94.
13
2.30 (s, 3H), 2.13–2.73 (m, 3H), 1.89 (s, 3H). C NMR
l 204.2, 169.6, 151.6, 150.7, 125.4, 123.2, 110.1, 108.3,
82.9, 56.0, 55.6, 52.9, 26.3, 20.5, 20.2, 19.6. Anal. calcd
for C H O Cl: C, 58.81; H, 5.86. Found: C, 58.98; H,
14
16
3
Found: C, 72.64; H, 7.02%.
16
19
5
4
.3. (1S,2R)-2-Acetyl-5,8-dimethoxy-1,2,3,4-tetra-
5.57%.
hydronaphthalen-1,2-diol 13
4
.5. (R)-2-Acetoxy-2-acetyl-5,8-dimethoxy-1,2,3,4-tetra-
A solution of commercial AD-mix-a (60.0 g) (Aldrich),
previously enriched with K OsO (OH) (0.10 g), in a
hydronaphthalene 22
2
2
4
1
:1 H O/t-BuOH mixture (400 mL) was treated with
A solution of chloroacetate (1R,2S)-21 (9.80 g, 0.030
mol) in toluene (200 mL) was treated under nitrogen
2
NaHCO (10.9 g) and MeSO NH (4.07 g, 0.043 mol)
3
2
2
with AIBN (0.15 g) and Bu SnH (24.3 g, 0.083 mol)
3
and the reaction mixture was stirred for 24 h at rt under
the irradiation of a 200 Watt electric light bulb. Evapo-
ration of the washed (water) organic solvent afforded a
solid residue, which was repeatedly washed with hex-
ane, then filtered to give pure acetate (R)-22 as a white
2
5
solid (7.04 g, 80% yield), mp 116–118°C, [h] =−46.3 (c
D
−
1
1
1.0, CHCl ): IR 1733 and 1720 cm (CꢀO); H NMR
3
l 6.65 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.02 (ABdd,
2H, J=18.3 Hz), 2.80–2.90 (m, 1H), 2.37–2.62 (m, 2H),
2.21 (s, 3H), 2.04 (s, 3H), 1.85–2.02 (m, 1H). C NMR
l 206.5, 170.5, 151.4, 150.9, 125.1, 122.7, 107.2, 107.0,
83.6, 55.5, 55.6, 30.2, 26.7, 24.0, 21.0, 19.5. Anal. calcd
for C H O : C, 65.74; H, 6.90. Found: C, 65.56; H,
13
16
20
5
(
1S,2R)-13, which was recrystallized from 1:1 AcOEt/
6.69%.
hexane to give pure diol (1S,2R)-13 as a clear crys-
talline product (8.07 g, 71% yield), mp 141–143°C,
4.6. (R)-2-Acetyl-2-hydroxy-5,8-dimethoxy-1,2,3,4-tetra-
2
5
19b
25
[
(
1
4
h] =−21.9 (c 1.0, CHCl ), 98% e.e. [lit. [h] =−17.6
hydronaphthalene 5
D
3
D
c 1.10, CHCl ), 82% e.e.]: IR 3531 and 3450 (OH) and
3
−1 1
714 cm (CꢀO); H NMR l 6.71 (s, 2H), 5.30 (s, 1H),
.48 (d, 1H, J=1.3 Hz), 3.84 (s, 3H), 3.82 (d, 1H,
A solution of acetate (R)-22 (6.72 g, 0.023 mol) in
MeOH (400 mL) was treated under stirring at rt with
Amberlyst IRA-400 (OH) (13.40 g) and the suspension
was stirred for 18 h at the same temperature. Evapora-
tion of the filtered organic solution afforded a solid
residue, which was recrystallized from hexane/AcOEt to
give pure (R)-5 as a solid (5.30 g, 92% yield), mp
J=1.8 Hz), 3.78 (s, 3H), 2.75–2.82 (m, 2H), 2.39 (s,
H), 2.01 (dt, 1H, J=13.5, 4.0 Hz), 1.79 (ddd, 1H,
3
13
J=13.6, 9.5, 8.0 Hz). C NMR l 215.1, 152.9, 151.8,
1
27.7, 126.4, 109.4, 108.6, 79.4, 69.2, 56.4, 56.3, 29.4,
26.6, 19.8. Anal. calcd for C H O : C, 63.15; H, 6.81.
14
18
5
2
5
9
Found: C, 63.44; H, 6.72%.
128–129°C, [h] =−46.2 (c 1.0, CHCl ), 99% e.e. [lit.
D 3
20
mp 129.5–130.5°C, [h] =−48.7 (c 0.368, CHCl ), 100%
D
3
−
1
1
4
.4. (1R,2S)-2-Acetoxy-2-acetyl-1-chloro-5,8-dimethoxy-
,2,3,4-tetrahydronaphthalene 21
e.e.]: IR 1701 cm (CꢀO); H NMR l 6.66 (s, 2H), 3.79
(s, 3H), 3.76 (s, 3H), 3.63 (s, 1H), 2.95 (ABdd, 2H,
J=17.3 Hz), 2.68–3.00 (m, 2H), 2.32 (s, 3H), 1.78–2.04
1
13
A stirred solution of the diol (1S,2R)-13 (7.72 g, 0.029
(m, 2H). C NMR l 212.3, 151.6, 151.1, 125.5, 122.7,
mol) in CH Cl (60 mL) was treated at rt under nitro-
107.4, 107.0, 76.4, 55.6, 55.5, 32.4, 29.7, 23.9, 19.2.
2
2

3
160
F. Badalassi et al. / Tetrahedron: Asymmetry 12 (2001) 3155–3161
Anal. calcd for C H O : C, 67.18; H, 7.25. Found:
C, 67.01; H, 7.10%.
NMR l 6.61 (s, 2H), 4.99 (s, 1H), 3.75 (s, 3H), 3.66
(s, 3H), 3.37 (s, 3H), 3.23 (s, 3H), 2.84 (ddd, 1H,
J=18.5, 5.9, 3.9 Hz), 2.51 (ddd, 1H, J=18.5, 10.2,
14
18
4
13
8
.1 Hz), 2.11–2.19 (m, 2H), 2.03 (s, 3H). C NMR l
4
.7. Treatment of chloroacetate (1R,2S)-21 with
207.6, 152.0, 151.9, 127.0, 125.0, 110.2, 108.4, 85.0,
70.7, 58.2, 56.5, 55.9, 52.5, 25.2, 22.3, 21.8. Anal.
calcd for C H O : C, 65.29; H, 7.53. Found: C,
MeOH
16
22
5
A solution of chloroacetate (1R,2S)-21 (0.326 g, 1.0
64.98; H, 7.26%.
mmol) in MeOH (30 mL) containing CH Cl (2 mL)
2
2
was stirred at rt for 18 h. Dilution with ether and
evaporation of the washed (saturated aqueous
4
.9. (1S,2R)-2-Acetyl-1,2-epoxy-5,8-dimethoxy-1,2,3,4-
tetrahydronaphthalene 23
NaHCO and water) organic solution afforded a liq-
3
uid product (0.25 g) consisting of a 90:10 mixture of
methoxy alcohols (1S,2R)-25 and (1R,2R)-24 ( H
NMR), which was subjected to preparative TLC (a
A solution of chloroacetate (1R,2S)-21 (0.22 g, 0.67
mmol) in THF (16 mL) was treated with 10%
aqueous NaOH (2 mL) and the reaction mixture was
stirred at 50°C for 5 h, then at rt for 20 h. Dilution
with ether and evaporation of the washed (water)
organic solvent afforded a solid (0.16 g) of practically
pure epoxide (1S,2R)-23, which was recrystallized
1
9
8:2 mixture of CH Cl and Et O was used as the
2 2 2
eluant). Extraction of the most intense band afforded
pure (1S,2R)-2-acetyl-2-hydroxy-1,5,8-trimethoxy-
,2,3,4-tetrahydronaphthalene 25 as a liquid (0.20 g,
1
7
2
5
1% yield), [h] =+44.7 (c 1.3, CHCl ): IR 3475
D
3
from hexane to give pure (1S,2R)-23 as a solid (0.12
−
1
1
(
OH) and 1712 cm (CꢀO); H NMR l 6.63 (s, 2H),
25
g, 72% yield), mp 109–111°C, [h] =−209.3 (c 2.3,
D
4
3
2
1
.83 (s, 1H), 3.75 (s, 3H), 3.68 (s, 1H), 3.57 (s, 3H),
.42 (s, 3H), 2.74 (ddd, 1H, J=17.7, 7.5, 5.9 Hz),
.55 (dt, 1H, J=17.7, 6.1 Hz), 2.26 (s, 3H), 1.97 (dt,
H, J=13.2, 6.2 Hz), 1.74 (ddd, 1H, J=13.2, 7.5, 6.0
−1
1
CHCl ): IR 1706 cm (CꢀO); H NMR l 6.70 (d,
H, J=9.0 Hz), 6.62 (d, 1H, J=9.0 Hz), 4.50 (s, 1H),
.73 (s, 3H), 3.67 (s, 3H), 2.92–3.08 (m, 2H), 2.03–
.30 (m, 2H), 2.12 (s, 3H). C NMR l 208.2, 153.8,
3
1
3
2
1
2
13
1
3
Hz). C NMR l 212.5, 153.3, 151.3, 127.9, 125.3,
51.0, 127.8, 120.7, 112.0, 109.1, 66.8, 56.6, 51.9,
4.4, 20.9, 18.0. Anal. calcd for C H O : C, 67.73;
1
2
10.1, 108.7, 78.9, 75.0, 59.8, 56.4, 56.2, 29.8, 25.7,
0.3. Anal. calcd for C H O : C, 64.27; H, 7.19.
14
16
4
15
20
5
H, 6.50. Found: C, 67.84; H, 6.19%.
Found: C, 64.61; H, 7.44%.
4.10. (1R,2R)-2-Acetyl-2-hydroxy-1,5,8-trimethoxy-
1,2,3,4-tetrahydronaphthalene 24
Methoxy alcohol (1S,2R)-25 was recovered completely
unreacted when subjected to acetylation conditions
(
Ac O/Py) for 24 h at rt.
2
A solution of epoxide (1S,2R)-23 (0.070 g, 0.28
mmol) in MeOH (3.5 mL) was treated with a cata-
lytic amount of MeONa (7 mg) and the reaction mix-
ture was stirred at 80°C for 72 h. After cooling,
evaporation of the solvent afforded a crude reaction
mixture (0.065 g) mostly consisting of methoxy alco-
hols (1R,2R)-24 (94%) [unreacted epoxide (6%) was
also present], which was subjected to preparative TLC
In an attempt to prepare epoxide (1S,2R)-23, a solu-
tion of chloroacetate (1R,2S)-21 (0.10 g, 0.30 mmol)
in MeOH (6 mL) containing a few drops of CH Cl2
was treated with Amberlyst IRA-400 (OH) (0.050 g)
and the resulting suspension was stirred at rt for 20
h. Evaporation of the filtered organic solution
afforded a crude liquid product consisting of a 13:87
2
(
a 98:2 mixture of CH Cl and Et O was used as the
2 2 2
mixture of methoxy alcohols (1R,2R)-24 and (1S,2R)-
2
1
eluant). Extraction of the most intense band afforded
5 ( H NMR).
pure (1R,2R)-24 (0.048 g, 60% yield) as a liquid,
2
5
[
h] =−113.1 (c 1.2, CHCl ): IR 3465 (OH) and 1708
D 3
−1 1
cm (CꢀO); H NMR l 6.68 (d, 1H, J=9.0 Hz),
.63 (d, 1H, J=9.0 Hz), 4.31 (d, 1H, J=1.4 Hz), 3.71
s, 6H), 3.53 (s, 1H), 3.28 (s, 3H), 2.82–2.94 (m, 1H),
4
.8. Methylation reaction of diol (1S,2R)-13
6
(
A solution of diol (1S,2R)-13 (0.134 g, 0.50 mmol) in
anhydrous MeCN (1.5 mL) was treated with Ag CO3
2
.41–2.70 (m, 2H), 2.38 (s, 3H), 1.74–1.84 (m, 1H).
C NMR l 214.4, 153.1, 151.8, 127.1, 124.5, 110.1,
08.2, 77.7, 76.1, 58.6, 56.2, 27.4, 24.9, 20.6, 20.1
2
1
3
(
0.276 g, 1.0 mmol) and MeI (0.290 g, 2.0 mmol) and
the resulting reaction mixture was stirred at 80°C for
8 h. After cooling, evaporation of the filtered
1
Anal. calcd for C H O : C, 64.27; H, 7.19. Found:
15
20
5
1
C, 64.41; H, 6.95%.
organic solvent afforded a crude product (0.13 g)
consisting of an almost 1:1 mixture of methoxy
derivatives (1S,2R)-25 and (1S,2R)-26 ( H NMR),
1
4.11. Acid methanolysis of epoxide (1S,2R)-23
which was subjected to preparative TLC (an 8:2 mix-
ture of hexane and AcOEt was used as the eluant).
Extraction of the two most intense bands (the faster
moving band contained 26) afforded methoxy alcohol
A solution of epoxide (1S,2R)-23 (0.050 g, 0.20
mmol) in 0.2N H SO in anhydrous MeOH (5 mL)
2
4
was stirred at rt for 3 h. Dilution with Et O and
2
(
1S,2R)-25 (0.046 g, 33% yield) and (1S,2R)-2-acetyl-
,2,5,8-tetramethoxy-1,2,3,4-tetrahydronaphthalene 26
evaporation of the washed (saturated aqueous
1
NaHCO ) organic solution afforded a crude product
3
2
5
as a solid (0.056 g, 38% yield), mp 74–75°C, [h] =
+
consisting of a 72:28 mixture of methoxy alcohols
D
−
1
1
1
114.7 (c 2.2, CHCl ): IR 1712 cm
(CꢀO);
H
(1R,2R)-24 and (1S,2R)-25 ( H NMR).
3

F. Badalassi et al. / Tetrahedron: Asymmetry 12 (2001) 3155–3161
3161
Acknowledgements
13. For other more complex procedures, see: (a) Theurillat-
Moritz, V.; Guidi, A.; Vogel, P. Tetrahedron: Asymmetry
1997, 8, 3497–3501; (b) Garcia Ruano, J. L.; Garcia
Paredes, C.; Hamdouchi, C. Tetrahedron: Asymmetry
1999, 10, 2935–2944.
Menarini Ricerche Spa (Pomezia, Roma) is gratefully
acknowledged for financial support and a fellowship to
F.B.
14. Parameswara Reddy, M.; Krishna Rao, G. S. Tetra-
hedron Lett. 1981, 22, 3549–3550.
5. Rama Rao, A. V.; Deshpande, V. H.; Ramamohan Rao,
B.; Ravichardran, K. Tetrahedron Lett. 1982, 23, 1115–
1
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1
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1. The methanolysis of chloroacetate (1R,2S)-21 occurs also
in the absence of the resin (see Section 4).
2. If (1S,2R)-25, the inversion product, reasonably derives
3
from an S 2 process by nucleophilic attack of MeOH on
N
the reactive secondary benzylic position of (1R,2S)-21, a
participation of the vicinal OCOMe group could reason-
ably be invoked for the formation of (1R,2R)-24, the
retention product.
1
7
8
2
3. As previously observed in other related 2-aryloxirane
systems, in epoxide (1S,2R)-23 nucleophilic attack occurs
exclusively, under acid ring-opening conditions, at the
electronically more favored benzylic oxirane carbon. See
for example: (a) Chini, M.; Crotti, P.; Minutolo, F.;
Martinelli, A.; Micali, E. Gazz. Chim. Ital. 1994, 124,
27–33; (b) Chini, M.; Crotti, P.; Minutolo, F.; Dezi, E.;
Lombardozzi, A.; Pizzabiocca, A.; Renzi, G. Tetrahedron
1993, 49, 5845–5858; (c) Crotti, P.; Dell’Omodarme, G.;
Ferretti, M.; Macchia, F. J. Am. Chem. Soc. 1987, 109,
1463–1469.
6
497–6500.
9
. Suzuki, M.; Kimura, Y.; Terashima, S. Bull. Soc. Chim.
Jpn. 1986, 59, 3559–3572.
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0. (a) Jew, S.-s.; Terashima, S.; Koga, K. Chem. Pharm.
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Koga, K. Tetrahedron Lett. 1978, 19, 4937–4940; (c)
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1. Tamoto, K.; Terashima, S. Chem. Pharm. Bull. 1984, 32,
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1
1
1
4
24. When the same synthetic procedure was repeated on a
ten-fold scale starting from enone 9, the hydroxy ketone
(R)-5 was obtained in similar yield and enantioselectivity.
1