A new stereocontrolled entry into the anthracyclinone families. Part 1: Synthesis of bicyclic precursors of 4-demethoxy-7-deoxy-derivatives

Article abstract of DOI:10.1016/S0957-4166(99)00280-3

A new and versatile strategy to obtain enantiomerically pure bicyclic precursors of compounds belonging to different anthracyclinone families is reported. Completely stereoselective hydrocyanation of (R)-4-(2,5-dimethoxyphenyl)-1-p-tolysulfinyl-2-butanone

Full text of DOI:10.1016/S0957-4166(99)00280-3

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2935–2944
A new stereocontrolled entry into the anthracyclinone families.
Part 1: Synthesis of bicyclic precursors of 4-demethoxy-7-deoxy-
derivatives
José L. García Ruano,∗ Cristina García Paredes and Chafiq Hamdouchi
Departamento de Química Orgánica, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
Received 15 June 1999; accepted 5 July 1999
Abstract
A new and versatile strategy to obtain enantiomerically pure bicyclic precursors of compounds belon-
ging to different anthracyclinone families is reported. Completely stereoselective hydrocyanation of (R)-4-(2,5-
dimethoxyphenyl)-1-p-tolylsulfinyl-2-butanone and further intramolecular capture of the Pummerer intermediate
generated from the resulting sulfinylcyanohydrin are the key steps to obtain the bicyclic nitrile 2 with the proper
configuration and functionality at C-9. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Anthracyclinone antibiotics, the powerful antitumor substances assembled by fermentation,1 have
received great attention because of their clinical usefulness in the treatment of a large variety of
human cancers.2 Thus, the naturally occurring daunomycin and adriamycin (1a and 1b, Scheme 1) are
increasingly used for the treatment of breast and lung cancers as well as lymphocytic and myelocytic
leukemias. However, cardiotoxicity of these natural products, as well as development of resistance
(acquired resistance) after initially effective systemic chemotherapy,3 often limit the scope of their
effectiveness. As a result, there has been a considerable interest in the search for new analogues, with
lower undesired side effects. This is the case of the demethoxy derivatives 1c and 1d which exhibit lower
toxicity, and 9-alkylanthracyclines,4 1e, which show a clear trend for decreasing resistance factors as
the 9-alkyl side-chain increases. It is therefore desirable to have a general method for the synthesis of
these families of compounds, but it is more significant to be able to extend the same strategy to a large
variety of analogues in all their possible configurations. Although many approaches to this end have been
∗
Corresponding author. E-mail: joseluis.garcia.ruano@uam.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00280-3

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screened,5 most of them showed the drawback of the low flexibility and the moderate stereoselectivity,
as well as of lengthy sequences.
Scheme 1.
As a part of our research program directed to the use of chiral sulfoxide groups for the construction
of important chiral building blocks, potentially useful in the total synthesis of a broad range of natural
and non-natural products,6 we have undertaken the synthesis of the anthracyclinone family. We have
envisioned that starting from the intermediate 2 (Scheme 2) with the correct configuration at the
hydroxylated carbon (which will become C-9 in anthracyclinones), we would be able to obtain many such
compounds, taking advantage of the fact that the problems of the creation of the hydroxylic stereogenic
center at C-7,7 the introduction of the sugar moiety8 and the formation of the tetracyclic skeletons from
the bicyclic ones9 have been successfully solved in racemic series. In this paper we describe the synthesis
of enantiomerically pure compound 2, as well as the transformation of its CN group into the moieties
usually present at C-9 in the bicyclic precursor of the different anthracyclinones.
Scheme 2.
2. Results and discussion
Two different strategies were designed to prepare compound 2 (Scheme 2), starting from monocyclic
and bicyclic compounds (3 and 4, Scheme 2) making use of the highly diastereoselective hydrocyanation
of β-ketosulfoxides10 as the key step for the preparation of the stereogenic center.
Taking into account the successful results obtained in the hydrocyanation reactions of 2-p-tolylsulfinyl
cyclohexanone,10b the most direct strategy is that involving the reactions of compound 3 (prepared by
sulfinylation of 5,8-dimethoxy-2-tetralone) with Et2AlCN, yielding the sulfinyl cyanohydrin 5, eventually
easily transformed into 2 (Scheme 3). The instability of compounds 3 and 5 (prone to pyrolysis of the
sulfinyl group and further aromatization) and their low enantiomeric excess (<20%) led us to abandon
this strategy.
Scheme 3.
Therefore the synthesis of the key intermediate 2 was carried out starting from monocyclic β-
ketosulfoxide 4 (Scheme 4), which was prepared by orthometallation of 1,4-dimethoxybenzene, sub-

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2937
sequent copper–lithium exchange prior to the 1,4-addition of the aryl copper to methyl acrylate, and
final reaction of the ester with the α-lithio derivative of (R)-methyl p-tolyl sulfoxide. Reaction of 4 with
Et2AlCN in the previously reported10a mild conditions affords sulfinylcyanohydrin 6 in 97% yield as the
sole diastereomer. The configuration of 6 was assigned as (S)- according to the stereochemical behavior
of other acyclic β-ketosulfoxides previously studied.10
Scheme 4.
The intramolecular capture of the thionium cations, generated from sulfoxides under Pummerer
conditions, has been used to form tetrahydronaphthalene derivatives in the case of activated aromatic
rings.11 On the basis of this precedent, we treated compound 6 with TMSOTf and iPr2NEt, according
to the procedure reported by Craig but slightly modified.12 The nature of the product isolated in the
process of the ring closure was dependent on the method of performing the hydrolysis (Scheme 4). When
the resulting reaction mixture was quenched by addition of a solution of sodium hydrogencarbonate, the
alcohol 7 was isolated in 75% yield, but injecting the reaction mixture to the same basic solution afforded
the silyl derivative 211 in almost quantitative yield as a 9:1 mixture of two diastereoisomers, the epimers
at C-1. The higher stability of the silylated cyanohydrins to dehydrocyanation made it advisable to follow
the sequence with the protected alcohol.
With compound 2 in hand, we focused on some possible conversions of CN group in order to
synthesize a series of bicyclic derivatives, direct precursors of 4-demethoxyanthracyclinones. The results
obtained from such transformations are depicted in Scheme 5. The DIBAL reduction of the cyano group
at 2 yielded the aldehyde 8,11 which could be used to prepare the corresponding tetracyclic aldehyde, a
key intermediate in the synthesis of 14,14-difluoridarubicin.13 The reaction of 8 with MeMgBr yielded
a mixture of epimeric alcohols, which was treated with Raney-Ni to eliminate the Stol14 group, and
further oxidized to acetyl derivative 1015 using the conditions reported by Tomioka et al.5c Specific
rotation of the obtained compound 10 {[α]D20=−46.2 (c 1 CHCl3); lit.16a [α]D20=−46.3 (CHCl3), and
lit.16b [α]D20=−47.1 (c 1.11 CHCl3)} indicates that it was essentially optically pure and had the right
configuration.
Obtention of chiral precursors of 9-alkyl anthracyclines 1e (R=Me, Et) (Scheme 1) was carried out
from 12 (Scheme 6), obtained by reduction of compound 8 with NaBH4 followed by desulfenylation
with Raney-Ni and further desylilation. Tosylation of the CH2OH group of 12 and treatment with LiAlH4
gave methyl derivative 14 {[α]D20=−26.2 (c 1.09 CHCl3), 86% ee}. Reaction of 13 with NaOH in iPrOH
afforded the epoxide 15, which can be used as precursor of any 9-alkyl derivative. Thus, its reaction with
Me2Cu(CN)Li yielded ethyl carbinol 16 {[α]D20=−22.8 (c 1.4 CHCl3) 90% ee; lit.17 [α]D20=−24.5 (c
1.31 CHCl3)}. The loss of optical purity observed for compounds 14 and 16 could have occurred during
the desulfenylation step.18

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Scheme 5. (i) (a) DIBAL-H (70%); (ii) MeMgBr (70%); (iii) Raney-Ni (90%); (iv) SO3·Py, DMSO, Et3N (61%)
Scheme 6. (i) NaBH4 (80%); (ii) Raney-Ni (72%); (iii) nBu4NF (98%); (iv) TsCl, Py (97%); (v) LiAlH4 (90%) (vi) NaOH,
iPrOH (92%); (vii) Me2Cu(CN)Li (83%)
In summary we have presented herein a convergent synthetic approach to a series of chiral bicyclic
precursors of 4-demethoxyanthracyclinones. The successful approach expanded and took advantage of
our earlier studies on the stereoselective hydrocyanation mediated by a chiral sulfoxide group. This step
has been efficiently coupled to the intramolecular trapping of the Pummerer intermediate generated from
the sulfinylcyanohydrin to assemble the bicyclic compound 2 with the desired configuration at C-9.
Modifications of these bicyclic structures in the sense the proper way for them to evolve into tetracyclic
structures with X=H (Scheme 1) in a highly regioselective manner, as well as the introduction of
functionalities such as OH and CO2R at C-10 (present in rhodomycins and aclavinomycins respectively)
will be published in due course.
3. Experimental
3.1. General
All reagents were purchased from commercial suppliers and were used without further purification,
unless stated otherwise. THF and ether were dried by refluxing and distilling from sodium-benzophenone
ketyl immediately prior to use. Diisopropylamine and diisopropylethylamine were distilled from sodium
hydroxide, methylene chloride and pyridine were distilled from calcium hydride. Chlorotrimethylsilane
was distilled from calcium hydride immediately prior to use. All experiments were conducted in a dry
argon atmosphere. All melting points are given uncorrected. IR spectra were taken on a Perkin–Elmer
1
257 spectrophotometer. H and 13C NMR spectra were recorded at 200 MHz and 300 MHz with CDCl3

J. L. García Ruano et al. / Tetrahedron: Asymmetry 10 (1999) 2935–2944
2939
as solvent, and tetramethylsilane as an internal standard. Mass spectra were determined at an ionization
voltage of 70 eV. Microanalyses were performed by CONSEJO Laboratories, Madrid, Spain.
3.2. Methyl-3-(2,5-dimethoxyphenyl)propionate 30
A solution of 1,4-dimethoxybenzene (10 g, 72 mmol) in 55 mL of dry THF was added to a solution of
nBuLi (29 mL, 72.5 mmol, 2.5 M in hexane) in THF at 23°C under an argon atmosphere. After stirring
for 1 h, the reaction mixture was transferred via cannula to a stirred suspension of CuI (13.78 g, 72.5
mmol) in 30 mL of dry THF at 0°C. The reaction mixture was stirred at 0°C for 1 h and the resulting
green solution was cooled to −78°C before adding successively, TMSCl (50 mL, 0.36 mol), methyl
acrylate (6.5 mL, 68 mmol) and Et3N (10 mL, 72 mmol). The mixture was stirred for 48 h from −78°C
to rt, hydrolyzed with 10% NH3 in saturated aqueous NH4Cl solution and extracted with 2×200 mL of
ether. The combined extracts were washed with the ammoniacal solution until no blue color remained
and finally washed with brine. The resulting colorless solution was dried over Na2SO4 and concentrated
in vacuo. The residue was purified by flash chromatography (hexane/AcOEt, 95/5) to give 30 (16 g, 70%
yield) as colorless oil. IR (film, cm−1) 1720, 1430. 1H NMR (CDCl3) δ 6.73 (m, 3H), 3.77 (s, 3H), 3.75
(s, 3H), 3.67 (s, 3H), 2.91 (t, J=8.3 Hz, 2H), 2.6 (t, J=8.3 Hz, 2H); 13C NMR (CDCl3) δ 172.9, 153.02,
151.20, 129.43, 115.81, 110.89, 110.51, 55.06, 54.89, 50.82, 33.45, 25.73. MS, m/z 224 (M+, 100), 193
(95.9), 167 (25.4), 151 (61.28), 135 (9.47), 121 (34.63). Anal. calcd for C12H16O4: C: 64.27, H: 7.19.
Found: C: 64.20, H: 6.84%.
3.3. (RS)-4-(2,5-Dimethoxyphenyl)-1-p-tolylsulfinyl-2-butanone 4
To a solution of LDA (20 mmol) in 20 mL of THF was added a solution of (R)-methyl-p-tolyl
sulfoxide19 (3.16 g, 20 mmol) in 20 mL of THF at −78°C. After 90 min a solution of 3 (2.2 g, 9.8
mmol) in 10 mL of THF was added dropwise. After 2 h sat. NH4Cl (20 mL) was added and the cool
bath was removed. The mixture was stirred for 10 min and then acidified with 7% HCl. Ether (30 mL)
was added and the phases were separated. The aqueous phases were combined and extracted twice with
ether (20 mL). The combined organic layers were washed with brine and dried over Na2SO4. Solvent was
removed in vacuo and the residue was purified by flash chromatography (50% AcOEt/hexane) yielding 4
(2.7 g, 80% yield) as a white solid. Mp=78–80°C, [α]D20=+149 (c 1.01 CHCl3). IR (film, cm−1): 1700,
1
1040. H NMR (CDCl3) δ 7.41 (AA0BB0, J=8.1 Hz, 4H), 6.71 (m, 3H), 3.8 (AB, JAB=13.5 Hz, 2H),
3.75 (s, 3H), 3.74 (s, 3H), 2.77 (m, 4H, 2×CH2), 2.41 (s, 3H). 13C NMR (CDCl3) δ 201, 151.48, 142.04,
139.62, 129.98, 129.53, 123.94, 116.36, 111.45, 110.95, 68.11, 55.56, 44.74, 24.51, 21.32. MS, m/z 346
(M+, 17.5), 330 (9.3), 222 (8.9), 207 (19.5), 165 (14.8), 151 (100), 121 (35.8), 105 (6.1), 91 (34.9) 77
(22.9). Anal. calcd for C19H22O4S: C, 65.88; H, 6.40. Found: C, 66.01; H, 6.37%.
3.4. (2S,RS)-2-Cyano-4-(2,5-dimethoxyphenyl)-1-(p-tolylsulfinyl)-2-butanol 6
A solution of 4 (3.5 g, 10 mmol) in 30 mL of dry THF was added dropwise to Et2AlCN (20 mL, 20
mmol, 1 M in toluene) under argon at −35°C. The mixture was stirred for 5 min and then transferred via
cannula into 60 mL of MeOH/HClconc. 1/1 at −78°C. The resulting mixture was stirred for 15 min and
poured carefully into 200 g of ice with 30 mL of HClconc.. CH2Cl2 (50 mL) was added and the phases
were separated. The aqueous phase was extracted with 2×50 mL of CH2Cl2. The organic phases were
combined, dried over Na2SO4 and evaporated in vacuo yielding pure 5 (3.6 g, 97% yield) as a white solid.
1
Mp=119–120°C, [α]D20=+144 (c 1 CHCl3). IR. (film, cm−1): 3500–3300, 1500, 1200, 1050. H NMR

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(CDCl3) δ 7.48 (AA0BB0, J=8.2 Hz, 4H), 6.73 (m, 3H), 5.99 (s, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.0 (AB,
AB=13.2 Hz, 2H), 2.86 (m, 2H), 2.45 (s, 3H), 2.07 (m, 2H, CH2). 13C NMR (CDCl3) δ 153.41, 151.47,
J
142.99, 138.91, 130.42, 123.96, 119.33, 116.13, 11.73, 11.12, 70.81, 62.50, 55.62 (2C), 41.05, 24.88,
21.43. Anal. calcd for C20H18SO4N: C, 64.33%; H, 6.20%; S, 8.58%; N, 3.75%. Found: C, 64.52%; H,
6.50%; S, 8.28%; N, 3.55%.
3.5. (1S,2S)-2-Cyano-1,2,3,4-tetrahydro-5,8-dimethoxy-O-trimethylsilyl-1-(p-tolylthio)-2-naphthol 2
To a solution of 6 (3.6 g, 9.6 mmol) in 30 mL of dry CH2Cl2 under argon at 0°C was added TMSOTf
(8.4 mL, 43.2 mmol, 4.5 equiv.) and iPr2NEt (7.5 mL, 43.2 mmol, 4.5 equiv.). The cold bath was removed
and the mixture was stirred for 30 min. The mixture was transferred via a cannula into a saturated aqueous
solution of NaHCO3. The organic phase was separated and the aqueous phase was extracted with 2×10
mL of CH2Cl2. The organic phases were combined and washed with brine, dried over Na2SO4 and
evaporated in vacuo. Purification by flash chromatography (hexane/AcOE, 14/1) yielded 2 (4 g, 97%
yield) as a mixture of epimers at C-1 (9/1). Mp=142–144°C, major isomer [α]D20=+288.6 (c 0.5 CHCl3).
IR (film, cm−1): 2950, 1480, 1260, 1140, 1090. 1H NMR (CDCl3) δ 7.27 (AA0BB0, J=8.0 Hz, 4H), 6.69
(s, 2H), 4.96 (d, JW=2.3 Hz, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 2.74 (m, 2H, CH2), 2.33 (s, 3H, Me), 2.16
(m, 2H, CH2). 13C NMR (CDCl3) δ 150.72, 150.56, 136.76, 133.69, 132.73, 132.0, 129.40 (2C), 129.12,
108.92, 108.29, 72.26, 55.67, 55.34, 53.57, 29.72, 22.10, 21.15, 1.07. MS, m/z 427 (M+, 34.6), 304
(100), 263 (8.8), 205 (94.4), 177 (87.9), 123 (15.6), 91 (17.9), 73 (64.2). Anal. calcd for C23H19SO3NSi:
C, 64.61%; H, 6.83%; S, 7.49%; N, 3.27%. Found: C, 64.39%; H, 7.02%; S, 7.23%; N, 3.09%.
3.6. (1S,2S)-2-Cyano-1,2,3,4-tetrahydro-5,8-dimethoxy-1-(p-tolylthio)-2-naphthol 7
When the reaction mixture was hydrolyzed by addition of a solution of NaHCO3 the unprotected
product was obtained. After chromatography purification (hexane/AcOEt, 7/3) 6 was obtained as a solid
1
in 75% yield. Mp=134–136°C. IR (film, cm−1) 2940, 1480, 1260, 1110, 1070. H NMR (CDCl3) δ 7.3
(AA0BB0, J=8.0 Hz, 4H), 6.72 (s, 2H), 4.96 (s, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.16–2.7 (m, 3H), 2.35 (s,
3H), 2.33 (m, 2H).
3.7. (1S,2R)-2-Formyl-1,2,3,4-tetrahydro-5,8-dimethoxy-O-trimethylsilyl-1-(p-tolylthio)-2-naphthol 8
To a solution of 2 (4.2 g, 9.8 mmol) in 40 mL of dry THF at room temperature was added DIBAL-
H (14.7 mL, 1.5 equiv., 1 M in toluene). The mixture was stirred 1 h and then poured carefully into
100 mL of 5% H2SO4. CH2Cl2 (50 mL) was added and the phases were separated. The aqueous phase
was extracted with 2×25 mL of CH2Cl2. The organic phases were combined, washed with brine, dried
over Na2SO4 and evaporated in vacuo. The residue was crystallized from ether/hexane. Compound
8 was obtained as a white solid (3.2 g, 76% yield, mixture of epimers at C-1 (9/1)). Major isomer:
mp=134.4–135.7°C, [α]D20=+280.6 (c 0.24 CHCl3). IR (film, cm−1): 2950, 1730, 1480, 1260, 1080. 1H
NMR (CDCl3) δ 9.35 (d, J=1.4 Hz, 1H), 7.27 (AA0BB0, JAB=8.1 Hz, 4H), 6.63 (s, 2H), 4.81 (d, J=2.3 Hz,
1H), 3.75 (s, 3H), 3.74 (s, 3H), 3–2.4 (m, 4H), 2.3 (m, 5H). 13C NMR (CDCl3) δ 198.62, 150.73, 150.33,
136.11, 134.08, 132.67, 132.05, 131.77, 128.84, 125.00, 124.16, 108.42, 107.63, 80.38, 55.45, 55.17,
49.30, 25.27, 21.66, 20.87, 2.03, 0.73. MS, m/z 430 (M+ 3.17), 307 (27.3), 279 (71.3), 189.1 (21.4), 91
(10.0), 73 (100). Anal. calcd for C23H30SO4Si: C, 64.15%; H, 7.02%; S, 7.44%. Found: C, 63.88%; H,
7.03%; S, 7.45%.

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3.8. (1S,2R,10R), (1S,2R,10S)-1,2,3,4-Tetrahydro-2-(1-hydroxyethyl)-5,8-dimethoxy-O-trimethylsilyl-
1-(p-tolyl thio)-2-naphthol 9
To a solution of 8 (3.2 g, 7.4 mmol) in 30 mL of dry THF under argon at 0°C was added MeMgBr
(5 mL, 2 equiv., 3 M in ether). The ice bath was removed and the mixture was stirred for 4 h. The
mixture was cooled at 0°C and 10 mL of sat. NH4Cl was added. CH2Cl2 (15 mL) was added and the
phases were separated. The aqueous phase was extracted with CH2Cl2 (2×15 mL). The organic phases
were combined, washed with brine, dried over Na2SO4 and evaporated in vacuo. Purification by flash
chromatography (hexane/AcOEt, 9/1) afforded diol 9 (2.2 g, 68% yield) as a mixture 1/1 of epimers
at the secondary hydroxylic center. Mp=130–132°C, [α]D20=+200.2 (c 0.55 CHCl3). IR (film, cm−1):
1
3500, 2920, 1250, 1080. H NMR (CDCl3) δ 7.15 (m, 8H, 2×AA0BB0), 6.59 (m, 4H), 5.20 (d, J=2.4
Hz, 1H), 4.67 (d, J=2.0 Hz, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.59 (s, 3H), 3.56 (s, 3H), 3.1–2.85 (m, 2H),
2.8–2.2 (m, 12H), 1.9 (m, 2H), 1.47 (d, J=9.5 Hz, 1H), 1.17 (d, J=6.4 Hz, 3H), 1.11 (d, J=6.2 Hz, 3H),
0.14 (m, 18H). 13C NMR (CDCl3) δ 151.29, 151.01, 150.61, 135.66, 135.32, 135.10, 134.59, 129.80,
128.95, 128.84, 128.44, 127.09, 126.69, 124.94, 123.99, 108.08, 107.96, 107.80, 80.38, 80.21, 68.76,
68.25, 55.62, 55.50, 50.09, 48.73, 27.47, 26.85, 22.39, 21.99, 20.98, 17.26, 3.10, 2.93. MS, m/z 446 (M+,
6.3), 279 (100), 264 (16.6), 189 (16.8), 124 (7.1), 91 (11.3), 73 (49.1). Anal. calcd for C24H34SO4Si: C,
64.55%; H, 7.68%; S, 7.17%. Found C, 64.75%; H, 7.37%; S, 7.17%.
3.9. (R)-(−)-2-Acetyl-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthol 10
To a solution of 8 (98 mg, 0.22 mmol) in 5 mL of EtOH at room temperature was added Raney-Ni
under argon atmosphere. The mixture was stirred for 90 min. The mixture was filtered through a pad of
Celite and the solvent was evaporated under reduced pressure. The resulting oil was dissolved in ether
and 5 mL of 7% HCl was added. It was stirred for 5 min and the phases were separated. The aqueous
phase was washed with 2×10 mL of ether. The organic phases were combined, dried over Na2SO4 and
evaporated in vacuo. Purification by flash chromatography (hexane/AcOEt, 1/1) afforded 9 (50 mg, 90%
yield) as a white solid. Diol 9 was oxidized as described5c (SO3·Py (318 mg, 10.25 equiv.), Et3N (0.7
mL), DMSO (0.7 mL)). Purification by flash chromatography (AcOEt/hexane, 3/7) yielded 10 as a solid
(21.6 mg, 56% yield) [α]D20=−46.2 (c 1 CHCl3) (lit.16a [α]D20=−46.3 (CHCl3), lit.16b [α]D20=−47.1 (c
1.11 CHCl3). IR (film, cm−1): 3500, 1700, 1480, 1260, 1090. 1H NMR (CDCl3) δ 6.66 (s, 2H), 3.79 (s,
3H), 3.76 (s, 3H), 3.65 (br s, 1H, OH), 3.1–2.7 (m, 4H), 2.32 (s, 3H), 1.95 (m, 2H).
3.10. (1S,2R)-(+)-1,2,3,4-Tetrahydro-2-hydroxymethyl-5,8-dimethoxy-O-trimethylsilyl-1-p-tolylthio-
2-naphthol 11
To a solution of 8 (640 mg, 1.48 mmol) in 5 mL of absolute EtOH at 0°C was added NaBH4 (1.5
equiv.). The mixture was stirred for 30 min and two drops of AcOH were added. EtOH was removed
in vacuo and the residue was dissolved in 10 mL of CH2Cl2 and washed with brine. The phases
were separated and the aqueous phase was extracted with 10 mL of CH2Cl2. The organic phases were
combined and dried over Na2SO4. The solvent was evaporated in vacuo yielding 11 (570 mg, 90% yield)
as a white solid. Mp=122.8–123.4°C, [α]D20=+120 (c 0.7 CHCl3). IR (film, cm−1): 2940, 1480, 1150.
1H NMR (CDCl3) δ 7.19 (AA0BB0, J=8.1 Hz, 4H), 6.62 (s, 2H), 4.9 (d, J=2.1 Hz, 1H), 3.75 (s, 3H),
3.69 (s, 3H), 3.46 (m, 3H), 2.96 (m, 1H), 2.53 (m, 2H), 2.30 (s, 3H), 1.9 (m, 1H), 0.11 (s, 9H, TMS). 13
C
NMR (CDCl3) δ 150.66, 150.45, 135.22, 134.82, 129.81, 128.56, 126.09, 123.55, 107.74, 107.63, 77.95,
66.22, 55.22, 54.99, 48.87, 27.46, 21.70, 20.64, 2.19. MS, m/z 432 (M+, 16.34), 309 (31), 278 (56.5),

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J. L. García Ruano et al. / Tetrahedron: Asymmetry 10 (1999) 2935–2944
219 (100), 177 (90.8), 124 (21.4), 91 (30.7), 73 (92.1). Anal. calcd for C23H30SO4SiC: C, 63.87%; H,
7.45%; S, 7.39%. Found: C, 63.98%; H, 7.41%; S, 7.63%.
3.11. (R)-(−)-1,2,3,4-Tetrahydro-2-(hydroxymethyl)-5,8-dimethoxy-2-naphthol 12
To a solution of 11 (460 mg, 1.06 mmol) in 20 mL of EtOH was added Raney-Ni in excess under
argon. The mixture was stirred overnight, filtered through a pad of Celite and the solvent was removed in
vacuo. The solid was dissolved in 5 mL of THF under argon. At 0°C, 1.1 equiv. of nBu4NF (1 M in THF)
was added dropwise. After 3 min water (5 mL) and 5 mL of ether were added and the organic phases were
separated. The aqueous phase was extracted with 2×10 mL of ether. The organic phases were combined
and dried over Na2SO4. The solvent was evaporated in vacuo yielding diol 12 (182 mg, 72% yield) as
a white solid. Mp=145.5–146.5°C, [α]D20=−27.4 (c 0.55 acetone). IR (film, cm−1): 3600–3400, 1480,
1240, 1100.1H NMR (CDCl3) δ 6.64 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 3.53 (m, 3H), 2.76 (m, 5H), 1.7
(m, 2H). 13C NMR (CD3OD) δ 153.98, 153.43, 126.58 (2C), 108.83 (2C), 72.33, 71.18, 56.84, 34.24,
31.32, 22.00. MS, m/z 238 (M+ 89.3), 220 (25.9), 207 (84.7), 189 (100), 177 (23.5), 164 (39.1), 149
(35.4), 131 (12.5), 91 (24.8), 77 (21.1). Anal. calcd for C13H18O4: C, 65.53%; H, 7.61%. Found: C,
65.40%; H, 7.59%.
3.12. (R)-(−)-1,2,3,4-Tetrahydro-5,8-dimethoxy-2-methyl-2-naphthol 14
To a solution of 12 (217 mg, 0.9 mmol) in 7 mL of pyridine at rt was added TsCl (1.5 equiv.). After 15
h, pyridine was evaporated in vacuo. The oil obtained was dissolved in 10 mL of CH2Cl2 and washed with
7% HCl and NaHCO3 several times and finally with sat. NaCl. The organic phase was then dried over
Na2SO4. The solvent was evaporated in vacuo yielding pure 13 (346 mg, 97% yield). 1H NMR (CDCl3)
δ 7.57 (4H, AB, JAB=8.3 Hz), 6.6 (s, 2H, AB), 4.0 (2H, AB), 3.76 (s, 3H), 3.74 (s, 3H), 2.72 (m, 4H),
2.44 (s, 3H), 1.79 (m, 2H). A solution of 13 (85 mg) in 4 mL of ether was added to a stirring suspension
of LiAlH4 (30 mg in 2 mL of dry ether) under argon at rt. After 16 h, 5 mL of water and 5 mL of 1 M
NaOH were added. The mixture was stirred for 10 min and the phases were separated. The aqueous phase
was extracted with 2×10 mL of benzene. The organic phases were combined and dried over Na2SO4.
The solvent was evaporated in vacuo to yield 14 (43.5 mg, 90% yield) as an oil that crystallized in the
cold. [α]D20=−26.2 (c 1.09 CHCl3) (86% ee determined by chiral HPLC, Chiracel OD, hexane/iPrOH,
9/1, (S)-13 t=7.22 min, (R)-13 t=10.86 min. IR (film, cm−1): 3500–3430, 1470, 1240. 1H NMR (CDCl3)
δ 6.63 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 2.77 (m, 4H), 1.80 (m, 2H), 1.66 (br s, 1H, OH), 1.35 (s, 3H).
13C NMR (CDCl3) δ 151.46, 151.18, 125.46, 125.0, 106.73, 68.19, 55.42, 37.57, 34.52, 28.71, 20.87.
MS, m/z 222 (M+, 100), 204 (49.7), 189 (62.6), 164 (68.9), 149 (56.6), 121 (20.2), 91 (28.2), 77 (18.3).
Anal. calcd for C13H18O3: C, 70.23%; H, 8.17%. Found: C, 69.90%; H, 8.10%.
3.13. (R)-(+)-Epoxide 15
To a solution of tosyl derivative of 13 (260 mg, 1 mmol) in 5 mL of iPrOH was added NaOH (60
mg). After 1 h, water (5 mL) was added and the phases were separated. The aqueous phase was extracted
with 2×10 mL CH2Cl2. The organic phases were combined and dried over Na2SO4. The solvent was
evaporated in vacuo yielding epoxide 15 (134 mg, 92% yield) as an oil. [α]D20=+4 (c 1 CHCl3). IR (film,
1
cm−1): 2940, 1480, 1250, 980. H NMR (CDCl3) δ 6.65 (2H, AB), 3.79, 3.76 (6H), 2.8 (m, 6H), 1.84
(m, 2H). 13C NMR (CDCl3) δ 151.12 (2C), 126.24, 125.06, 107.23, 106.89, 57.08, 55.62, 55.45, 54.15,
31.13, 29.05, 22.11. MS, m/z 220 (M+, 100), 205 (41.4), 190 (38.3), 189 (39.1), 175 (51.6), 159 (35.1),

J. L. García Ruano et al. / Tetrahedron: Asymmetry 10 (1999) 2935–2944
2943
147 (27.4), 131 (29.7), 115 (70.2), 103 (33.5), 91 (43.2), 77 (45). Anal. calcd for C13H16O3: C, 70.87%;
H, 7.33%. Found: C, 71.14%; H, 7.11%.
3.14. (R)-(−)-2-Ethyl-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthol 16
To a solution of Me2Cu(CN)Li (prepared from 0.21 mmol CuCN in 1 mL dry ether and 0.44 mmol
MeLi (1.6 M in ether) from −78°C to −50°C) at −78°C was added dropwise a solution of epoxide 15 (31
mg, 0.14 mmol) in 1 mL dry ether. The temperature was allow to rise to −20°C. After 2.5 h, 10 mL of a
solution of 10% NH4OH/sat. NH4Cl was added. The phases were separated and the organic phase was
washed with 2×10 mL of 10% NH4OH/sat. NH4Cl until total elimination of the blue color. The organic
phases were combined and dried over Na2SO4. Evaporation of the solvent in vacuo yielded 27.6 mg
(83% yield) of pure 16 as a liquid. [α]D20=−22.8, (c 1.4 CHCl3). (90% ee determined by chiral HPLC,
Chiracel OD, hexane/iPrOH, 9/1, (S)-15 t=7.07 min, (R)-15 t=13.18 min) (lit.17 [α]D20=−24.5, (c 1.31
1
CHCl3)). IR (film, cm−1) 3620–3400, 2920, 1480, 1240. H NMR δ 6.63 (s, 2H, AB), 3.79, 3.77 (2s,
6H, 2×MeO), 2.8–2.6 (m, 4H, 2×CH2-Ar), 1.8–1.6 (m, 5H, 2×CH2, OH), 1.05 (t, 3H, CH3). 13C NMR
(CDCl3) δ 151.75, 151.23, 125.95, 124.83, 106.95, 106.84, 70.11, 55.56, 35.65, 34.12, 32.04, 20.47,
7.50.
Acknowledgements
Financial support from the DGICYT, Spain (Project PB96-0035), is gratefully acknowledged.
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