The first total synthesis of racemic 3,4-dihydroxy-2-(3-methylbut-2-enyl)- 3,4-dihydronaphthalen-1(2 H)-one

Article abstract of DOI:10.1055/s-0029-1219761

Racemic 3,4-dihydroxy-2-(3-methylbut-2-enyl)-3,4-dihydronaphthalen-1(2H)- one is synthesized for the first time, in seven steps, starting from commercially available -tetralone. The key steps in this process are dihydroxylation using osmium tetroxide, benzylic oxidation mediated by sodium chlorite-tert-butyl hydroperoxide, and prenylation. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219761

SHORT PAPER
1763
The First Total Synthesis of Racemic 3,4-Dihydroxy-2-(3-methylbut-2-enyl)-
3,4-dihydronaphthalen-1(2H)-one
S
ynthesis of
a
Ra
c
a
emic
N
apht
n
halenone
D
e
g
rivative aru Suresh, Jondass Jon Paul Selvam, Karuturi Rajesh, Vanam Shekhar, Dokuburra Chanti Babu, Yenamandra
Venkateswarlu*
Organic Chemistry Division-I, Natural Products Laboratory, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: luchem@iict.res.in
Received 19 February 2010; revised 1 March 2010
The biological potential of these natural products has
Abstract: Racemic 3,4-dihydroxy-2-(3-methylbut-2-enyl)-3,4-di-
stimulated significant interest in the preparation of 2 and
hydronaphthalen-1(2H)-one is synthesized for the first time, in sev-
3, and to the best of our knowledge, there are no reports
on the total synthesis of these compounds. Herein, we re-
en steps, starting from commercially available a-tetralone. The key
steps in this process are dihydroxylation using osmium tetroxide,
benzylic oxidation mediated by sodium chlorite–tert-butyl hydro- port the first racemic total synthesis of 3,4-dihydroxy-2-
peroxide, and prenylation.
(3-methylbut-2-enyl)-3,4-dihydronaphthalen-1(2H)-one
(1) via osmium tetroxide (OsO4) dihydroxylation, benzyl-
ic oxidation using sodium chlorite–tert-butyl hydroperox-
ide (NaClO2–t-BuOOH) and prenylation, as key steps.
Key words: racemic, natural products, dihydroxylation, benzylic
oxidation, prenylation
Our synthesis of compound 1 (Scheme 1) started from
commercially available a-tetralone (4) which was reduced
with sodium borohydride in methanol at room tempera-
ture for 30 minutes to afford 1,2,3,4-tetrahydronaphtha-
len-1-ol (5) in 95% yield. Dehydration of alcohol 5 with
p-toluenesulfonic acid in anhydrous tetrahydrofuran at re-
flux temperature for 10 hours gave alkene 6 in 90% yield.
Reaction of 6 with a catalytic amount of osmium tetrox-
ide, in the presence of excess N-methylmorpholine N-ox-
ide, in acetone–water (5:1) at room temperature for 8
hours gave the corresponding diol 7 in 75% yield.7
Naphthoquinones are present in different plant families.
Their molecular structures endow them with redox prop-
erties making them active in various oxidative biological
processes. In traditional medicine, often originating
among native Amerindian populations, plants containing
naphthoquinones have been employed for the treatment of
a number of diseases including cancer.1,2 The toxicity and
therapeutic activities of these compounds involves the
formation of oxygen-reactive species.3–5 Two cytotoxic
natural products, (2R,3R,4R)-3,4-dihydro-3,4-dihydroxy-
2-(3-methylbut-2-enyl)-1(2H)-naphthalenone (2) and
(2S,3R,4R)-3,4-dihydro-3,4-dihydroxy-2-(3-methylbut-2-
enyl)-1(2H)-naphthalenone (3) (Figure 1), were isolated
by Kinghorn et al. from the chloroform-soluble extract of
the roots of Ekmanianthe longiflora.6 Interestingly, both
compounds 2 and 3 exhibited in vitro cytotoxicity to a
small panel of human tumor cell lines.6
b
a
4
5
OH
O
6
c
d
O
O
OH
OTBS
OH
OTBS
O
7
8
OH
OH
O
OH
OH
e
1
2
f
O
OTBS
OTBS
OTBS
OTBS
9
10
OH
OH
3
O
g
Figure 1 Structures of cytotoxic natural products 2 and 3 and race-
mic 1
OH
1
OH
Scheme 1 Reagents and conditions: (a) NaBH4, MeOH, r.t., 30 min,
95%; (b) PTSA (5 mol%), THF, reflux, 10 h, 90%; (c) OsO4, NMO,
acetone–H2O (5:1), r.t., 8 h, 75%; (d) TBSCl, imidazole, CH2Cl2, r.t.,
8 h, 90%; (e) NaClO2, t-BuOOH, MeCN–H2O (3:1), reflux, 8 h, 75%;
(f) LDA, prenyl bromide, THF–HMPA, –78 °C, 5 h, 60%; (g) HF–py,
THF, r.t., 4 h, 80%.
SYNTHESIS 2010, No. 11, pp 1763–1765
Advanced online publication: 06.04.2010
DOI: 10.1055/s-0029-1219761; Art ID: Z04210SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

1764
V. Suresh et al.
SHORT PAPER
ESI-MS: m/z = 149 [M + H]+.
The two hydroxy groups in compound 7 were protected
using two equivalents of tert-butyldimethylsilyl chloride
and imidazole in dichloromethane, at room temperature
over eight hours, to afford bis-silyl ether 8 in 90% yield.
Benzylic oxidation of compound 8 was attempted using
various oxidizing agents; these included chromium(VI)-
based reagents such as the chromium trioxide–pyridine
complex,8 chromium trioxide and 3,5-dimethylpyrazole,9
pyridinium chlorochromate,10 pyridinium dichromate,11
pyridinium dichromate–tert-butyl hydroperoxide,12 sodi-
um chromate13 and sodium dichromate in acetic acid,14
but without success. However, the benzylic oxidation was
achieved using sodium chlorite and tert-butyl hydroper-
oxide in acetonitrile–water (3:1) at reflux temperature to
give ketone 9 in 75% yield.15 Compound 9 was deproto-
nated using lithium diisopropylamide, and then alkylated
with prenyl bromide in anhydrous tetrahydrofuran–hexa-
methylphosphoramide, at –78 °C for five hours, to give 10
in 60% yield.16 Finally, removal of the silyl protecting
groups in 10 was achieved with hydrogen fluoride–pyri-
dine in tetrahydrofuran at room temperature to afford
racemic 3,4-dihydroxy-2-(3-methylbut-2-enyl)-3,4-di-
hydronaphthalen-1(2H)-one (1) in 80% yield. The spec-
troscopic data (IR, 1H and 13C NMR and MS) for 1 were
found to be analogous with those reported for natural
products 2 and 3.6
1,2-Dihydronaphthalene (6)
To a stirred soln of alcohol 5 (2.3 g, 15.4 mmol) in anhyd THF (10
mL) was added PTSA (5 mol%, 120 mg, 0.77 mmol) at r.t. and the
resulting mixture was stirred at reflux for 10 h. After completion,
the reaction was quenched with sat. aq NaHCO3 soln (20 mL) and
extracted with EtOAc (2 × 30 mL). The combined organic layer was
washed with brine (20 mL), dried over anhyd Na2SO4, the solvent
removed under reduced pressure and the crude residue purified by
silica gel column chromatography (hexane–EtOAc, 49:1) to afford
alkene 6.
Colorless liquid; yield: 1.8 g (90%).
1H NMR (400 MHz, CDCl3): d = 7.61–7.51 (m, 1 H), 7.27–7.23
(m, 2 H), 7.10–6.91 (m, 1 H), 6.32 (d, J = 7.0 Hz, 1 H), 5.83–5.81
(m, 1 H), 2.62 (t, J = 8.2 Hz, 2 H), 2.10–2.06 (m, 2 H).
ESI-MS: m/z = 153 [M + Na]+.
CAS No. 447-53-0.
1,2,3,4-Tetrahydronaphthalene-1,2-diol (7)
To a soln of alkene 6 (1.75 g, 13.5 mmol) in acetone–H2O (40 mL,
5:1) was added NMO (3.6 g, 26.5 mmol, 2 equiv) followed by OsO4
(2.5 wt% in t-BuOH, 1.7 mL, 0.13 mmol, 0.1 equiv). The reaction
mixture was stirred at r.t. for 8 h and then concd in vacuo. The res-
idue was purified by silica gel column chromatography (hexane–
EtOAc, 1:1) to afford diol 7.
Colorless liquid; yield: 1.66 g (75%); [a]D –10.4 (c 1.2, CHCl3).
IR (KBr): 3303, 2920, 1049, 1029, 742 cm–1.
In conclusion, we have reported a simple and efficient
method for the first total synthesis of racemic 3,4-di-
hydroxy-2-(3-methylbut-2-enyl)-3,4-dihydronaphthalen-
1(2H)-one (1), in seven steps, starting from readily avail-
able a-tetralone (4).
1H NMR (400 MHz, CDCl3): d = 7.44–7.41 (m, 1 H), 7.31–7.10
(m, 3 H), 4.70–4.68 (m, 1 H), 4.04–3.98 (m, 1 H), 2.97–2.89 (m,
1 H), 2.90–2.72 (m, 1 H), 2.44–2.38 (m, 2 H), 2.18–1.88 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 136.3, 136.1, 129.8, 128.4, 127.9,
126.2, 69.8, 69.4, 26.8, 25.9.
ESI-MS: m/z = 187 [M + Na]+.
All solvents and reagents were purified by standard techniques.
Crude products were purified by column chromatography on silica
gel (Acheme Chemical, 60–120 mesh). Melting points were ob-
tained using a Büchi 535 melting point apparatus and are uncorrect-
ed. Optical rotations were recorded on a Horiba polarimeter using a
10 mm cell. FT-IR spectra were obtained using a Thermo Nicolet
Nexus 670 spectrometer. 1H and 13C NMR spectra were recorded on
Bruker Avance 300 and Varian Gemini 200 and 400 spectrometers
using CDCl3 as the solvent. Chemical shifts are reported in ppm
with respect to TMS as the internal standard. Coupling constants (J)
are quoted in Hz. Mass spectra were obtained using a Micromass
Quattro micro™ API (Waters) spectrometer or a High resolution
QSTARXL Hybrid MS/MS system (Applied Biosystems, US)
spectrometer.
CAS No. 21016-53-5.
1,2-Bis[(tert-butyldimethylsilyl)oxy]-1,2,3,4-tetrahydronaph-
thalene (8)
To a cooled (0 °C) soln of diol 7 (1.5 g, 9.14 mmol) and imidazole
(1.55 g, 22.8 mmol) in anhyd CH2Cl2 (20 mL) was added a soln of
TBSCl (3.42 g, 22.8 mmol) in anhyd CH2Cl2 (5 mL). The mixture
was stirred at r.t. for 8 h, diluted with H2O (30 mL) and extracted
with CH2Cl2 (3 × 30 mL). The combined organic phase was washed
with brine (30 mL), dried over anhyd Na2SO4 and the solvent re-
moved under reduced pressure. The residue was purified by silica
gel column chromatography (hexane–EtOAc, 19:1) to afford bis-
silyl ether 8.
Colorless liquid; yield: 3.22 g (90%); [a]D –4.33 (c 2.4, CHCl3).
IR (KBr): 2932, 2857, 1070, 836, 774 cm–1.
1,2,3,4-Tetrahydronaphthalen-1-ol (5)
To a stirred soln of a-tetralone (4) (3.0 g, 20.5 mmol) in MeOH (20
mL) was slowly added NaBH4 (1.89 g, 51.3 mmol) at r.t. and the re-
sulting mixture was stirred for 30 min at r.t. After completion, the
mixture was diluted with H2O (20 mL) and extracted with EtOAc (4
× 60 mL). The combined organic layer was washed with brine (15
mL), dried over anhyd Na2SO4 and concd under reduced pressure.
The crude residue was purified by silica gel column chromatogra-
phy (hexane–EtOAc, 9:1) to give alcohol 5.
1H NMR (300 MHz, CDCl3): d = 7.39–6.89 (m, 4 H), 4.47–4.45
(m, 1 H), 3.90–3.89 (m, 1 H), 3.02–2.88 (m, 1 H), 2.79–2.61 (m,
1 H), 2.20–2.05 (m, 1 H), 1.75–1.67 (m, 1 H), 0.84 (br d, J = 1.3 Hz,
9 H), 0.82 (br d, J = 1.1 Hz, 9 H), 0.12 (s, 3 H), 0.02 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 138.5, 136.0, 129.1, 128.4, 127.4,
125.4, 73.2, 72.1, 27.6, 26.1, 26.0, 25.8, 18.4, 18.2, –4.0, –4.3, –4.4,
–4.5.
ESI-MS: m/z = 410 [M + NH4]+.
Colorless liquid; yield: 2.90 g (95%).
1H NMR (400 MHz, CDCl3): d = 7.30–7.28 (m, 1 H), 7.18–7.06 (m,
2 H), 6.98–6.70 (m, 1 H), 4.60 (t, J = 4.5 Hz, 1 H), 2.82–2.61 (m,
2 H), 2.37 (br s, 1 H), 1.98–1.60 (m, 4 H).
HRMS (EI): m/z calcd for C22H40NaO2Si2: 415.2459; found:
415.2469.
Synthesis 2010, No. 11, 1763–1765 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of a Racemic Naphthalenone Derivative
1765
3,4-Bis[(tert-butyldimethylsilyl)oxy]-3,4-dihydronaphthalen-
1(2H)-one (9)
by column chromatography (hexane–EtOAc, 7:3) gave 3,4-dihy-
droxy-2-(3-methylbut-2-enyl)-3,4-dihydronaphthalen-1(2H)-one
(1).
To a soln of bis-TBS ether 8 (1.0 g, 2.54 mmol) in MeCN–H2O (45
mL, 3:1) was added a 70% aq soln of tert-butyl hydroperoxide (2.7
g, 29.97 mmol) followed by the slow addition of 80% NaClO2 (0.51
g, 5.65 mmol) at r.t. The resulting mixture was stirred at reflux tem-
perature for 8 h. After completion, the reaction mixture was poured
onto 10% Na2SO3 aq soln (30 mL) and extracted with Et2O (3 × 80
mL). The combined organic phase was washed with brine (50 mL),
dried over anhyd Na2SO4 and the solvent was removed under re-
duced pressure. The residue was purified by column chromatogra-
phy (hexane–EtOAc, 22:1) to yield ketone 9.
White solid; yield: 41 mg (80%); mp 138 °C; [a]D –58.1 (c 1.0,
CHCl3).
IR (KBr): 3312, 2923, 2855, 1688, 1109, 1066 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.04 (d, J = 7.6 Hz, 1 H), 7.70–
7.57 (m, 2 H), 7.50–7.45 (m, 1 H), 5.20 (t, J = 6.8 Hz, 1 H), 4.97 (d,
J = 1.5 Hz, 1 H), 4.29–4.23 (m, 1 H), 3.02 (q, J = 6.8 Hz, 1 H),
2.62–2.50 (m, 2 H), 1.70 (s, 3 H), 1.67 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 197.6, 140.4, 134.7, 134.3, 130.8,
129.0, 128.9, 127.2, 120.7, 72.3, 68.8, 50.8, 25.8, 25.7, 17.8.
Pale-yellow solid; yield: 773 mg (75%); mp 70 °C; [a]D –37.5 (c 1.0,
CHCl3).
IR (KBr): 2955, 2930, 2892, 2857, 1691, 1254, 836 cm–1.
HRMS (EI): m/z [M + Na]+ calcd for C15H18O3Na: 269.1154; found:
269.1159.
1H NMR (300 MHz, CDCl3): d = 7.98 (d, J = 7.6 Hz, 1 H), 7.57–
7.51 (m, 1 H), 7.42–7.31 (m, 2 H), 4.85–4.78 (m, 1 H), 4.28–4.15
(m, 1 H), 3.20–3.00 (br m, 1 H), 2.71–2.61 (m, 1 H), 1.22–0.61 (br
m, 18 H), 0.18 (s, 3 H), 0.07 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 196.6, 142.0, 133.5, 131.7, 129.5,
128.1, 126.4, 72.0, 71.8, 42.2, 25.6, 25.5, 17.9, 17.8, –4.3, –4.4, –4.7,
–4.8.
Acknowledgment
The authors are grateful to UGC, CSIR, New Delhi, Ministry of
Earth Sciences (MoES) and the Department of Biotechnology
(DBT), New Delhi, India, for financial support, and to Dr. J. S.
Yadav, Director, Indian Institute of Chemical Technology (IICT),
for his encouragement.
ESI-MS: m/z = 429 [M + Na]+.
HRMS (EI): m/z [M + Na]+ calcd for C22H38NaO3Si2: 429.2252;
found: 429.2245.
References
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3,4-Bis[(tert-butyldimethylsilyl)oxy]-2-(3-methylbut-2-enyl)-
3,4-dihydronaphthalen-1(2H)-one (10)
To a soln of LDA (315 mg, 1.0 mol, 2.94 mmol) in anhyd THF (3
mL) at –78 °C was added a soln of ketone 9 (500 mg, 1.23 mmol)
in anhyd THF (3 mL), and the reaction mixture warmed to 0 °C for
1 h. The mixture was cooled to –78 °C and treated with HMPA (1
mL) and prenyl bromide (0.34 mL, 2.94 mmol), in a dropwise fash-
ion, to afford an orange soln which was stirred at –78 °C for 5 h.
Next, the reaction mixture was quenched with sat. aq NH4Cl soln
(20 mL) and extracted with Et2O (3 × 30 mL). The combined organ-
ic phase was washed with brine (50 mL), dried over anhyd Na2SO4
and the solvent removed under reduced pressure. Purification of the
residue by column chromatography (hexane–EtOAc, 20:1) gave
prenylated compound 10.
Pale-yellow liquid; yield: 350 mg (60%); [a]D –10.35 (c 1.5,
CHCl3).
IR (KBr): 2929, 2857, 1687, 1254, 835, 773 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.94 (d, J = 8.1 Hz, 1 H), 7.57–
7.28 (m, 3 H), 5.16–4.86 (m, 2 H), 4.34–3.91 (m, 1 H), 2.87–2.65
(m, 1 H), 2.41–2.19 (m, 2 H), 1.69–1.58 (m, 6 H), 1.26 (s, 3 H), 0.89
(m, 18 H), 0.61 (s, 3 H), 0.15 (s, 3 H), 0.04 (s, 3 H).
ESI-MS: m/z = 475 [M + H]+.
HRMS (EI): m/z [M + Na]+ calcd for C27H46NaO3Si2: 497.2878;
(8) (a) Dauben, W. G.; Lorber, M.; Fullerton, D. S. J. Org.
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found: 497.2877.
3,4-Dihydroxy-2-(3-methylbut-2-enyl)-3,4-dihydronaphthalen-
1(2H)-one (1)
To a soln of 10 (100 mg, 0.21 mmol) in anhyd THF (3 mL), in a
polypropylene vial, was slowly added HF–pyridine (0.8 mL) at 0
°C. The reaction mixture was stirred at r.t. for 4 h, transferred into a
separating funnel, quenched with sat. aq NaHCO3 soln (10 mL) and
extracted with EtOAc (3 × 10 mL). The combined organic phase
was washed with brine (10 mL), dried over anhyd Na2SO4 and the
solvent removed under reduced pressure. Purification of the residue
Synthesis 2010, No. 11, 1763–1765 © Thieme Stuttgart · New York