Synthesis of hydroxylated naphthoquinone derivatives

Article abstract of DOI:10.1002/1099-0690(200210)2002:19<3341::AID-EJOC3341>3.0.CO;2-K

The use of the Stobbe condensation for the synthesis of juglone derivatives is presented, together with studies towards their further functionalization. The regiospecific oxidation of the above products to o- or p-naphthoquinones was also investigated. Finally, the preparation of useful intermediates for the synthesis of related natural products such as alkannin and shikonin is proposed. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200210)2002:19<3341::AID-EJOC3341>3.0.CO;2-K

FULL PAPER
Synthesis of Hydroxylated Naphthoquinone Derivatives
Elias A. Couladouros*[a,b] and Alexandros T. Strongilos[a,b]
Keywords: Natural products / Oxidations / Quinones / Stobbe condensation
The use of the Stobbe condensation for the synthesis of jug-
lone derivatives is presented, together with studies towards
their further functionalization. The regiospecific oxidation of
the above products to o- or p-naphthoquinones was also in-
vestigated. Finally, the preparation of useful intermediates
for the synthesis of related natural products such as alkannin
and shikonin is proposed.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
Hydroxylated naphthoquinone derivatives constitute a
very important class of biologically active compounds in-
cluding juglones and naphthazarines. Even the simplest
homologues of this class are challenging synthetic targets,
due to their high chemical reactivity and polyoxygenated
nature. Consequently, several diversified synthetic ap-
proaches such as DielsϪAlder reaction,[1Ϫ4] Fischer car-
bene complexes,[5Ϫ8] Hauser annulation,[9Ϫ11] o-substituted
tertiary benzamide chemistry,[12,13] cyclobutenedione chem-
istry,[14,15] Stobbe condensation,[16] naphthol oxida-
tion,[17,18] etc. have been reported. The most common syn-
thetic problems associated with these compounds involve
low yields in the final deprotection steps and constraints
on the functionalization of the aromatic skeleton. Stobbe
condensation of various benzaldehydes (1, Scheme 1) with
diethyl succinate (2), employing simple and often commer-
cially available starting materials, may address both prob-
lems. By this approach, the formation of a highly func-
tionalized aromatic skeleton (3) may be achieved in two
steps. These useful synthetic intermediates may, after re-
gioselective oxidization, be successfully converted into p-
and o-naphthoquinones 4 and 5, respectively, of which the
former could be further transformed to the naturally occur-
Scheme 1. Target key intermediates and final products (P1, P2
ϭ
protective groups, R1 ϭ carboxylated or aliphatic side chain)
Results and Discussion
The protected juglone derivatives 3a, 3b, and 3d were pre-
ring compounds alkannin and shikonin. This strategy al- pared by application of standard Stobbe conditions[19] to
lows orthogonal protection of hydroxyl groups, a crucial benzaldehydes 1a, 1b, and 1d (Scheme 2). This method was
prerequisite for efficient deprotection in the final steps. Ad- found to be unsuitable for the preparation of silylated jug-
ditionally, by taking advantage of the carboxyl moiety of lones, since benzaldehyde 1c afforded only the peracetylated
key intermediate 3, several side chains, including β-keto al- compound 3c.
lyl derivatives (6, Scheme 1), may be constructed. The re-
sults of our related studies are presented here.
Side chain modifications followed preparation of the aro-
matic core. Attachment of the prenyl group was considered
to be of high priority, since this group appears in the struc-
ture of many natural products, including the title com-
pounds. However, most reported syntheses concerning α-
prenylation[20Ϫ27] of aldehydes or acid derivatives were ex-
pected to result in multistep and ‘‘tricky’’ synthetic proced-
ures. On the other hand, it has been demonstrated[28] that
[a]
Chemistry Laboratories, Agricultural University of Athens,
Iera Odos 75, Athens 118.55, Greece
Fax: (internat.) ϩ30Ϫ(0)10/677-7849
E-mail: ecoula@chem.demokritos.gr
[b]
Organic and Bioorganic Chemistry Laboratory, NCSR
‘‘Demokritos’’,
153.10 Ag. Paraskevi Attikis, POB 60228, Athens, Greece
Eur. J. Org. Chem. 2002, 3341Ϫ3350  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/1019Ϫ3341 $ 20.00ϩ.50/0
3341

E. A. Couladouros, A. T. Strongilos
FULL PAPER
Scheme 2. Preparation of juglone derivatives; reagents and condi-
tions: i) NaH, cat. EtOH, PhMe or tBuOK, tBuOH, 1 h, then conc.
HCl (or AcOH for substrate 1c); ii) Ac2O, AcONa, 120 °C, 5 h,
37Ϫ55% (based on 1)
the allyl moiety in compounds such as 11 (Scheme 3) is effi-
ciently transformed into the respective prenyl component.
Thus, compound 3a, after saponification and subsequent
selective silylation, was converted through carboxylic acid 7
into the S-pyridin-2-yl ester 8,[29,30] the imidazolide 9,[31,32]
or the Weinreb amide 10,[33,34] functionalities suitable for
monoalkylation (Scheme 3). Controlled allylation of sub-
strates 9 and 10 at low temperature afforded the desired
compound 11 in good to excellent chemical yields. In con-
trast, S-pyridin-2-yl ester 8 remained completely unreactive
at low temperature, while at higher temperature it exclus-
ively furnished the disubstituted derivative 12. Although it
has been reported[35] that such derivatives can be trans-
formed into the corresponding propenyl ketones (similar to
11) upon treatment with a strong base (e.g., tBuOK, DMF,
60 °C), that was not the case with compound 12. Under the
same reaction conditions, benzylated analogue 13 (prepared
in three steps from naphthol 3a) was also unreactive.
The use of benzyl ether as a protective group was thought
to be a highly promising alternative to methyl ether protec-
tion, due to its mild deprotection conditions. Thus, the Cs2CO3, DMF, cat. Bu4NI, 5 h, 87%; ix) Excess allylmagnesium
model compound 16 was synthesized in high yield (77%)
from 3b (Scheme 4). Treatment of 16 with CAN at 25 °C
afforded a mixture of products, among which structures 17
and 18 were identified (yields 20Ϫ40%). The 17/18 ratio
varied according to reaction time and molar equivalents of
Scheme 3. Functionalization of carboxylates; reagents and condi-
tions: i) LiOH aq. 3 /THF/MeOH, 1:1:1, 60 °C, 2 h; ii) TBSCl,
imidazole, cat. DMAP, DMF, 70% (based on 3a); iii) Aldrithiol-
2TM, PPh3, CH3CN, 1 h, 90%; iv) Im2CO, THF, 10 min, 94%;
v) MeONHMe·HCl, CBr4, pyridine, PPh3, CH2Cl2, 30 min, 87%;
vi) Organometallic reagent, Et2O or THF, Ϫ100 or Ϫ20 °C, for
yields see table; vii) EtONa, EtOH, reflux 1 h, 89%; viii) PhCH2Br,
bromide, Et2O, 0 °C, 94%. TBSCl ϭ tert-butylclorodimethylsilane,
DMAP ϭ 4-dimethylaminopyridine, Aldrithiol-2TM ϭ 2,2Ј-dipyri-
dyl disulfide, Im2CO ϭ carbonyldiimidazole
The preparation of o- and/or p-naphthoquinone derivat-
CAN. It should be noted that substrates 20b and 21 ives by the regiospecific oxidation of the corresponding jug-
(Scheme 5) under the same conditions afforded the corres- lones was also investigated. Treatment of acetates 3a and 3b
ponding p-quinones 22b and 22c, respectively, in less than with alkaline ethanol furnished naphthols 20a and 20b in
10% yield, among many other unidentified products. On the almost quantitative yields, whereas exhaustive DIBAL re-
other hand, under radical conditions generated by use of duction of acetate 3a and subsequent selective silylation
4,4Ј-di-tert-butylbiphenyl or naphthalene and lithium provided naphthol 21 (Scheme 5). According to the literat-
metal,[36Ϫ38] complete cleavage of the benzyl ether groups ure, all these juglone derivatives should be transformable
and the aromatic silyl ether occurred, affording juglone de- into the respective naphthazarines upon salcomine-cata-
rivative 19 in 25Ϫ30% yield after aerial oxidation. Several lyzed oxidation.[39] In this respect, the presented synthetic
other trials were even more disappointing, and so the use approach should give rise to either juglone or naphthazar-
of benzyl ethers was not studied further.
ine derivatives. However, as has been recently reported by
3342
Eur. J. Org. Chem. 2002, 3341Ϫ3350

Synthesis of Hydroxylated Naphthoquinone Derivatives
FULL PAPER
Scheme 4. Deprotection attempts on substrate 16; reagents and
conditions: i) EtONa, EtOH, reflux 1 h, 93%; ii) TBSCl, imidazole,
cat. DMAP, DMF, 2 h, 97%; iii) DIBAL, CH2Cl2, Ϫ78 °C, 20 min,
98%; iv) NMO, cat. TPAP, CH2Cl2, 2 h, 98%; v) allylmagnesium
bromide, Et2O, 0 °C, 15 min; vi) TBSCl, imidazole, cat. DMAP,
DMF, 1.5 h, 89% (based on 15); vii) CANaq., CH3CN; viii) Li,
DTBBP, THF, Ϫ78Ǟ0 °C or Li, naphthalene, THF, Ϫ20Ǟ0 °C;
DIBAL ϭ diisobutylaluminium hydride, NMO ϭ 4-methylmor-
pholine N-oxide, TPAP ϭ tetrapropylammonium perruthenate,
CAN ϭ ammonium cerium(IV) nitrate, DTBBP ϭ 4,4Ј-di-tert-bu-
tylbiphenyl
Scheme 5. Oxidation of juglone derivatives to p- or o-quinones;
reagents and conditions: i) EtONa, EtOH, reflux 1 h, 89Ϫ93%;
ii) DIBAL, CH2Cl2, Ϫ78 °C, 2 h, 95%; iii) 1.1 equiv. TBSCl, imida-
zole, DMF, 12 h, 85%
our group,[40] this is not the case, and the corresponding
o-naphthoquinones are exclusively formed in high yields
(Scheme 5; entries 1,4,8). After a number of attempts with
various oxidants on both electron-rich and electron-poor
substrates, it was evident that only hypervalent iodide re-
agents[41] could oxidize the p-position regiospecifically.
According to the most widely accepted mechanism,[41,42]
hypervalent iodide oxidations take place through interme-
diate 24 (Scheme 6), which is attacked by a molecule of
water, preferably at the para position. Thus, the alkyl deriv-
ative 21, upon oxidation with PIFA, furnished the expected
quinone 22c (Scheme 5, entry 7). Surprisingly, oxidation of
the carboxylated analogues 20a and 20b proceeded only up
to the intermediate hydroxy-enones 25a and 25b (Scheme 6;
entries 9, 11Ϫ13).[43] Several attempts to force this oxida-
tion to quinones 22a and 22b respectively, by changing the
reaction conditions, were unsuccessful, and the use of a se-
cond oxidant as well as the addition of a strong mineral
acid was necessary. After experimentation with CAN, CrO3,
HgO, and DDQ, the combination of ferric chloride and
HCl provided the best results (Scheme 6; entries 10,14).
These compounds were efficiently transformed into use-
ful and versatile synthetic intermediates. From quinones
22a and 22b, for example, esters 26 and 27, respectively
(Scheme 7), were produced after reduction with Na2S2O4
and protection of the phenolic groups as silyl ethers. Reduc-
tion of 26 and 27 with DIBAL and subsequent oxidation
of the resulting benzyl alcohols with NMO/TPAP afforded
Scheme 6. Oxidation of juglone derivatives to p-quinones with hy-
aldehydes 28 and 29, respectively, in high yields (based on pervalent iodine reagents
Eur. J. Org. Chem. 2002, 3341Ϫ3350
3343

E. A. Couladouros, A. T. Strongilos
FULL PAPER
struments. The following abbreviations are used to denote NMR
signal multiplicities: s ϭ singlet, d ϭ doublet, t ϭ triplet, q ϭ quad-
ruplet, m ϭ multiplet, dd ϭ doublet of doublets. IR spectra were
recorded on a Nicolet Magna system 550 FT-IR instrument. High-
resolution mass spectra (HRMS) were recorded on a VG ZAB-ZSE
mass spectrometer under fast atom bombardment (FAB) condi-
tions, and matrix-assisted (MALDI-FTMS) mass spectra were re-
corded on a PerSeptive Biosystems Voyager IonSpect mass spectro-
meter. Melting points (m.p.) are uncorrected and were recorded on
a Gallenkamp melting point apparatus.
22a and 22b). These aldehydes resemble the common inter-
mediate of most synthetic schemes so far reported for alk-
annin and shikonin,[44] with the additional advantage of or-
thogonal protection of the aromatic hydroxyl groups. As
has recently been demonstrated,[28] intermediate 29 has
been converted into the above natural products in good
yields.
General Procedure for the Preparation of Compounds 3b؊3d:
tBuOK (2.1 g, 18.8 mmol) was added portionwise to a stirred solu-
tion of benzaldehyde 1b (3.0 g, 9.4 mmol) and diethyl succinate
(4.1 g, 23.6 mmol) in tBuOH (35 mL). Upon completion of the
addition, the mixture was stirred at 25 °C for 1 h, and was then
poured into HCl solution (1 , 60 mL) and extracted with EtOAc
(2 ϫ 40 mL). The organic layer was separated and treated with
saturated aqueous Na2CO3 solution. The aqueous layer was ex-
tracted with EtOAc (30 mL) and then acidified with concentrated
hydrochloric acid until pH ϭ 2. Finally the aqueous layer was ex-
tracted with EtOAc (3 ϫ 30 mL), and the organic extracts were
washed with brine (50 mL), dried with Na2SO4, and evaporated
under reduced pressure to afford crude 4-[2,5-bis(benzyloxy)-
phenyl]-3-(ethoxycarbonyl)-3-butenoic acid. The crude carboxylic
acid was cyclized in boiling acetic anhydride (2.9 g, 28.4 mmol) and
anhydrous sodium acetate (927.0 mg, 11.3 mmol) for 5 h. The mix-
ture was allowed to cool overnight and then poured into ice/water
(150 mL). The yellow-orange amorphous solid was filtered and
washed with water (4 ϫ 80mL). The air-dried crude product was
finally recrystallized from EtOAc and Et2O to afford 3b as a pale
orange, crystalline solid (2.4 g, 53% yield based on 1b). 3b: Rf ϭ
0.55 (hexanes/EtOAc, 8:2); m.p. 178Ϫ180 °C. IR (KBr): ν˜ ϭ 2930,
Scheme 7. Preparation of aldehyde 29; reagents and conditions:
i) Na2S2O4, CHCl3/H2O, 15 min; ii) TBSCl, imidazole, cat. DMAP,
DMF, 89% (22aǞ27); iii) DIBAL, CH2Cl2, Ϫ78 °C, 1 h, 93%;
iv) NMO, cat. TPAP, CH2Cl2, 3 h, 97%
Conclusion
In conclusion, the utility of the Stobbe condensation for
the preparation of naphthoquinone derivatives has been
demonstrated. Functionalization of the side chain and re-
giospecific oxidation of various naphthols was also thor-
oughly investigated. These functionalized and orthogonally
protected naphthoquinones are useful synthetic interme-
diates for biologically important classes of compounds.
Furthermore, several juglone derivatives, as well as o- and
p-naphthoquinones and the naturally occurring alkannin
and shikonin, have been successfully synthesized by this
route.
1751, 1720, 1608, 1454, 1363, 1264, 1225, 1023, 752 cmϪ1 1H
.
NMR (250 MHz, CDCl3, 25 °C): δ ϭ 1.39 (t, J ϭ 7.1 Hz, 3 H,
CH2CH3), 1.66 (s, 3 H, OAc), 4.39 (q, J ϭ 7.1 Hz, 2 H, CH2CH3),
5.01 (s, 2 H, OCH2Ph), 5.22 (s, 2 H, OCH2Ph), 6.83 (ABq, J ϭ
8.8 Hz, ∆v ϭ 23.3 Hz, 2 H, CHnaphth), 7.26Ϫ7.56 (m, 10 H, CHar),
7.64 (s, 1 H, CHnaphth), 9.00 (s, 1 H, CHnaphth) ppm. 13C NMR
(62.9 MHz, CDCl3, 25 °C): δ ϭ 14.3, 20.2, 61.2, 70.7, 71.6, 106.7,
109.5, 119.7, 127.2, 127.9, 128.4, 128.6, 128.7, 128.8, 136.4, 136.9,
146.6, 148.4, 149.5, 165.9, 170.2 ppm. HRMS (MALDI) calcd. for
C29H26O6 ([M ϩ Na]ϩ): 493.1621; found 493.1631.
When the above conditions were applied to benzaldehyde 1c (acetic
acid was used instead of hydrochloric acid during the acidification
step), the only isolated product was triacetate 3c, as a white solid
(55% yield based on 1c). 3c: Rf ϭ 0.40 (hexanes/EtOAc, 8:2); m.p.
154Ϫ156 °C. IR (KBr): ν˜ ϭ 2992, 1772, 1724, 1466, 1366, 1283,
Experimental Section
General Remarks: All reactions were carried out under anhydrous
conditions and argon atmosphere, using dry, freshly distilled solv-
ents, unless otherwise noted. Tetrahydrofuran (THF) and diethyl
ether (Et2O) were distilled from sodium/benzophenone, dichloro-
methane (CH2Cl2) from P2O5, and toluene from sodium. Yields
refer to chromatographically and spectroscopically (1H NMR)
homogeneous materials, unless otherwise stated. All reagents were
purchased at highest commercial quality and used without further
purification, unless otherwise stated. Compound 3a was prepared
according to ref.[19] All reactions were monitored by thin-layer
1188, 1032, 897 cmϪ1 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ
.
1.38 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 2.34 (s, 3 H, OAc), 2.36 (s, 3
H, OAc), 2.44 (s, 3 H, OAc), 4.39 (q, J ϭ 7.1 Hz, 2 H, CH2CH3),
7.26 (ABq, J ϭ 8.4 Hz, ∆v ϭ 31.1 Hz, 2 H, CHar), 7.73 (d, J ϭ
1.5 Hz, 1 H, CHar), 8.55 (d, J ϭ 1.5 Hz, 1 H, CHar) ppm. 13C
NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 14.2, 21.0, 61.5, 119.2, 120.6,
122.4, 122.8, 128.6, 128.9, 142.5, 145.5, 165.1, 168.8, 169.1, 169.2
ppm. HRMS (MALDI) calcd. for C19H18O8 ([M ϩ Na]ϩ):
397.0894; found 397.0898.
chromatography (TLC) carried out on 0.25 mm Merck silica gel For the preparation of compound 3d, sodium hydride was used
plates (60 F254), with use of UV light as visualizing agent and eth-
anolic phosphomolybdic acid or p-anisaldehyde solution and heat
as developing agents. Merck silica gel (60, particle size
0.040Ϫ0.063 mm) was used for flash column chromatography.
NMR spectra were recorded on Bruker AMX 500 or AC 250 in-
instead of tBuOK. A catalytic amount of ethanol (0.1 mL) was
added to stirred solution of sodium hydride (345.6 mg,
14.4 mmol) in toluene (10 mL), followed by dropwise addition of
a solution of benzaldehyde 1d (1 g, 6.0 mmol) in diethyl 2-methyl-
succinate (2.8 g, 15.0 mmol). The reaction mixture was further
a
3344
Eur. J. Org. Chem. 2002, 3341Ϫ3350

Synthesis of Hydroxylated Naphthoquinone Derivatives
FULL PAPER
treated as above to afford 3d as pale orange crystalline solid
(737.8 mg, 37% yield based on 1d). 3d: Rf ϭ 0.40 (hexanes/EtOAc,
stirred at 25 °C for 10 min (monitored by TLC) and the solvent
was then evaporated under reduced pressure. The easily hydrolyzed
8:2); m.p. 128Ϫ130 °C. IR (KBr): ν˜ ϭ 2943, 1764, 1718, 1635, 1430, crude product was purified by small column filtration (silica gel,
1249, 1207, 1156, 1052 cmϪ1. 1H NMR (250 MHz, CDCl3, 25 °C):
hexanes/EtOAc, 6:4) to afford 9 as a yellow solid (101.9 mg, 94%
δ ϭ 1.40 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 2.45 (s, 3 H, CarMe), 2.48 yield). Rf ϭ 0.50 (hexanes/EtOAc, 7:3); m.p. 99Ϫ101 °C. IR (KBr):
(s, 3 H, OAc), 3.87 (s, 3 H, OMe), 3.94 (s, 3 H, OMe), 4.37 (q, J ϭ ν˜ ϭ 3117, 2932, 2858, 1718, 1599, 1362, 1236, 1058, 921, 805 cmϪ1
7.1 Hz, 2 H, CH2CH3), 6.44 (d, J ϭ 2.2 Hz, 1 H, CHar), 6.51 (d, 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 0.21 (s, 6 H, Me2Si), 1.01
J ϭ 2.2 Hz, 1 H, CHar), 8.65 (s, 1 H, CHar) ppm. 13C NMR
(s, 9 H, tBuSi), 3.83 (s, 3 H, OMe), 3.88 (s, 3 H, OMe), 6.78 (ABq,
.
(62.9 MHz, CDCl3, 25 °C): δ ϭ 14.0, 14.4, 20.6, 55.3, 55.7, 60.8, J ϭ 8.6 Hz, ∆v ϭ 19.0 Hz, 2 H, CHar), 7.14 (s, 1 H, CHimid), 7.18
91.4, 97.8, 120.0, 123.9, 125.6, 128.4, 130.7, 144.1, 157.6, 161.0, (s, 1 H, CHar), 7.58 (s, 1 H, CHimid), 8.14 (s, 1 H, CHimid), 8.28 (s,
167.5, 168.8 ppm.
1 H, CHar) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 2.6,
18.4, 25.7, 55.7, 105.2, 107.9, 115.1, 118.1, 118.5, 122.5, 127.8,
128.5, 130.7, 138.3, 149.8, 150.6, 153.3, 165.9 ppm.
Preparation of Acid 7: An aqueous solution of LiOH (3 , 15 mL)
was added to a stirred solution of 3a (700.0 mg, 2.19 mmol) in a
1:1 mixture of THF/MeOH (30 mL) and the mixture was heated
to 60 °C for 2 h. The organic solvents were then evaporated under
reduced pressure and the residue was acidified to pH ϭ 2 with 1 
HCl solution, to form a pale brown solid, which was filtered. The
crude acid was air-dried for 1 h, and then dried under high vacuum
at 40 °C overnight and used in the next step without further puri-
fication. The crude product was dissolved in anhydrous DMF (4.0
mL) and cooled to 0 °C, followed by addition of imidazole
(374.4 mg, 5.50 mmol) and TBSCl (497.4 mg, 3.30 mmol). The ice
bath was removed and the reaction mixture was stirred overnight
at 25 °C. Upon consumption of the starting material (monitored
by TLC) the reaction was quenched with methanol (1.0 mL) and
a saturated aqueous solution of NH4Cl was added (15 mL), fol-
lowed by addition of EtOAc (25 mL). The organic layer was separ-
ated and the aqueous layer was extracted with EtOAc (2 ϫ 15 mL).
The combined organic extracts were washed with brine (20 mL)
and the solvent was evaporated under reduced pressure. The crude
product was purified by flash column chromatography (silica gel,
hexanes/EtOAc, 7:3) to afford 7 as a white solid (556.2 mg, 70%
yield from 3a). Rf ϭ 0.50 (hexanes/EtOAc, 7:3); m.p. 225Ϫ226 °C.
IR (KBr): ν˜ ϭ 2931, 1681, 1598, 1463, 1383, 126, 1065, 838, 784
Preparation of Weinreb Amide 10: N,O-Dimethylhydroxylamine hy-
drochloride (30.4 mg, 0.31 mmol), carbon tetrabromide (103.5 mg,
0.31 mmol), pyridine (25.2 µL, 0.31 mmol), and PPh3 (81.3 mg,
0.31 mmol) in small portions, were added successively, to a stirred
solution of 7 (100.0 mg, 0.26 mmol) in anhydrous CH2Cl2 (5 mL).
The mixture was stirred at 25 °C until no starting material was
observed (monitored by TLC; about 30 min) and the solvent was
then evaporated under reduced pressure. The gummy residue was
purified by flash column chromatography (silica gel, hexanes/
EtOAc, 8:2) to afford 10 as a white solid (91.7 mg, 87% yield). Rf ϭ
0.55 (hexanes/EtOAc, 7:3); m.p. 104Ϫ105 °C. IR (KBr): ν˜ ϭ 2933,
2858, 1651, 1599, 1506, 1463, 1386, 1257, 1101, 1057, 960, 842
cmϪ1 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 0.20 (s, 6 H,
.
Me2Si), 1.02 (s, 9 H, tBuSi), 3.35 (s, 3 H, NMe), 3.52 (s, 3 H,
NOMe), 3.83 (s, 3 H, ArOMe), 3.90 (s, 3 H, ArOMe), 6.70 (s, 2 H,
CHar), 7.14 (s, 1 H, CHar), 8.21 (s, 1 H, CHar) ppm. 13C NMR
(62.9 MHz, CDCl3 25 °C): δ ϭ 2.7, 18.6, 25.9, 33.9, 55.7, 55.8,
61.0, 104.3, 106.1, 115.7, 116.0, 121.2, 131.2, 149.8, 150.6, 151.8,
169.6 ppm. HRMS (MALDI) calcd. for C21H31NO5Si ([M ϩ H]ϩ):
406.2044; found 406.2051.
cmϪ1 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 0.24 (s, 6 H,
.
General Procedure for Alkylation: The organometallic reagent (0.11
to 0.22 mmol) was added dropwise to a stirred solution of 8, 9, or
10 (0.1 mmol) in the appropriate solvent (concentration was be-
tween 0.2Ϫ0.3 ) and at the desired temperature. The reaction mix-
ture was stirred at the same temperature until no starting material
could be observed by TLC analysis and then quenched with a sat-
urated aqueous solution of NH4Cl (3Ϫ4 mL). The organic layer
was separated and washed with brine (7 mL) whereas the aqueous
layer was extracted with EtOAc (2 ϫ 10 mL). The combined or-
ganic extracts were dried with Na2SO4 and the solvent was evapor-
ated under reduced pressure. The crude mixture was purified by
flash column chromatography (silica gel, hexanes/EtOAc, 95:5 to
9:1) to afford 11 and/or 12 as pale yellow solids (for yields see table
in Scheme 3).
Me2Si), 1.04 (s, 9 H, tBuSi), 3.84 (s, 3 H, OMe), 3.94 (s, 3 H, OMe),
6.76 (ABq, J ϭ 8.6 Hz, ∆v ϭ 19.4 Hz, 2 H, CHar), 7.48 (s, 1 H,
CHar), 8.71 (s, 1 H, CHar) ppm. 13C NMR (62.9 MHz, CDCl3, 25
°C): δ ϭ 2.7, 18.6, 25.9, 55.9, 104.6, 107.7, 115.7, 119.2, 126.3,
127.2, 128.3, 150.4, 150.7, 152.6, 171.9 ppm. HRMS (MALDI)
calcd. for C19H26O5Si ([M ϩ H]ϩ): 363.1622; found 363.1634.
Preparation of S-Pyridinyl Ester 8: 2,2Ј-Dipyridyl disulfide
(68.7 mg, 0.31 mmol) and PPh3 (81.3 mg, 0.31 mmol) were added
successively to a stirred solution of 7 (100.0 mg, 0.26 mmol) in an-
hydrous CH3CN (1 mL). The mixture was stirred at 25 °C for 1 h
(reaction progress monitored by TLC) and the solvent was then
evaporated under reduced pressure. The crude product was purified
by flash column chromatography (silica gel, hexanes/EtOAc, 8:2)
to afford 8 as a yellow solid (106.6 mg, 90% yield). Rf ϭ 0.60 (hex-
anes/EtOAc, 7:3); m.p. 92Ϫ94 °C. IR (KBr): ν˜ ϭ 2932, 2858, 1681,
1595, 1507, 1456, 1384, 1282, 918, 834 cmϪ1. 1H NMR (250 MHz,
CDCl3, 25 °C): δ ϭ 0.23 (s, 6 H, Me2Si), 1.02 (s, 9 H, tBuSi), 3.83
(s, 3 H, OMe), 3.94 (s, 3 H, OMe), 6.76 (ABq, J ϭ 8.6 Hz, ∆v ϭ
18.2 Hz, 2 H, CHar), 7.26Ϫ7.33 (m, 1 H, CHar), 7.36 (d, J ϭ
1.5 Hz, 1 H, CHar), 7.75 (m, 2 H, CHar), 8.65 (m, 2 H, CHar) ppm.
13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 2.7, 18.5, 25.8, 55.8,
105.0, 108.0, 112.9, 116.6, 122.9, 123.4, 128.1, 130.8, 133.5, 137.1,
150.2, 150.4, 150.7, 151.7, 153.0, 189.1 ppm. HRMS (MALDI)
calcd. for C24H29NO4SSi ([M ϩ H]ϩ): 456.1659; found 456.1680.
Compound 11: Rf ϭ 0.85 (hexanes/EtOAc, 95:5); m.p. 82Ϫ84 °C.
IR (KBr): ν˜ ϭ 2932, 2858, 1684, 1597, 1508, 1463, 1362, 1257,
1076, 919, 839, 780 cmϪ1 1H NMR (250 MHz, CDCl3, 25 °C):
.
δ ϭ 0.22 (s, 6 H, Me2Si), 1.03 (s, 9 H, tBuSi), 3.77Ϫ3.90 (m, 5 H,
OMe and COCH2), 3.94 (s, 3 H, OMe), 5.17Ϫ5.28 (m, 2 H, ϭ
CH2), 6.02Ϫ6.21 (m, 1 H, CHϭCH2), 6.75 (ABq, J ϭ 8.6 Hz, ∆v ϭ
17.1 Hz, 2 H, CHar), 7.40 (d, J ϭ 1.5 Hz, 1 H, CHar), 8.49 (d, J ϭ
1.5 Hz, 1 H, CHar) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C):
δ ϭ 2.7, 18.6, 25.9, 43.3, 55.8, 104.6, 107.6, 113.8, 117.2, 118.5,
122.6, 128.2, 131.4, 133.8, 150.2, 150.8, 152.9, 197.8 ppm. HRMS
(MALDI) calcd. for C22H30O4Si ([M ϩ H]ϩ): 387.1986; found
387.1974.
Preparation of Imidazolide 9: Carbonyldiimidazole (84.3 mg,
0.52 mmol) was added in one portion to a stirred solution of 7
(100.0 mg, 0.26 mmol) in anhydrous THF (4 mL). The mixture was
Compound 12: Rf ϭ 0.80 (hexanes/EtOAc, 95:5); m.p. 97Ϫ99 °C.
IR (KBr): ν˜ ϭ 3522, 2928, 2860, 1602, 1597, 1507, 1463, 1374,
Eur. J. Org. Chem. 2002, 3341Ϫ3350
3345

E. A. Couladouros, A. T. Strongilos
.
1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ quenched with methanol (0.1 mL) and a saturated aqueous solu-
FULL PAPER
1262, 1058, 842 cmϪ1
0.19 (s, 6 H, Me2Si), 1.04 (s, 9 H, tBuSi), 2.28 (s, 1 H, OH),
2.46Ϫ2.80 (m, 4 H, CH2CHϭ), 3.83 (s, 3 H, OMe), 3.91 (s, 3 H,
tion of NH4Cl was added (7 mL), followed by addition of EtOAc
(8 mL). The organic layer was separated, whereas the aqueous layer
OMe), 4.99Ϫ5.15 (m, 4 H, ϭCH2), 5.49Ϫ5.70 (m, 2 H, CHϭCH2), was extracted with EtOAc (10 mL). The combined organic extracts
6.64 (ABq, J ϭ 8.6 Hz, ∆v ϭ 11.5 Hz, 2 H, CHar), 6.91 (d, J ϭ
were washed with brine (10 mL) and dried with Na2SO4, and the
solvent was evaporated under reduced pressure. The crude product
1.9 Hz, 1 H, CHar), 7.88 (d, J ϭ 1.9 Hz, 1 H, CHar) ppm. 13C
NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 2.7, 18.6, 26.0, 46.8, 55.6, was purified by flash column chromatography (silica gel, hexanes/
75.1, 103.8, 104.2, 111.4, 115.0, 119.0, 128.3, 128.6, 133.4, 143.6, EtOAc, 95:5) to afford ethyl 5,8-bisbenzyloxy-4-(tert-butyldime-
149.3, 150.7, 152.0 ppm. HRMS (MALDI) calcd. for C25H36O4Si
thylsilyloxy)-2-naphthoate as a colorless oil (194.8 mg, 97% yield).
Rf ϭ 0.75 (hexanes/EtOAc, 9:1). IR (film): ν˜ ϭ 2929, 1719, 1597,
1456, 1367, 1231, 1052, 830 cmϪ1. 1H NMR (250 MHz, CDCl3, 25
°C): δ ϭ 0.20 (s, 6 H, Me2Si), 0.99 (s, 9 H, tBuSi), 1.42 (t, J ϭ
7.1 Hz, 3 H, CH2CH3), 4.41 (q, J ϭ 7.1 Hz, 2 H, CH2CH3), 5.18
(s, 4 H, OCH2Ph), 6.69 (ABq, J ϭ 8.6 Hz, ∆v ϭ 12.7 Hz, 2 H,
CHnaphth), 7.26Ϫ7.55 (m, 11 H, CHar), 8.73 (d, J ϭ 1.9 Hz, 1 H,
CHnaphth) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 2.4,
14.3, 18.7, 26.0, 60.9, 70.5, 71.5, 106.3, 109.6, 110.5, 115.4, 118.0,
123.0, 127.1, 127.3, 127.5, 127.8, 128.3, 128.4, 128.5, 137.2, 137.6,
149.5, 149.8, 152.7, 166.6 ppm.
([M ϩ H]ϩ): 429.2455; found 429.2440.
Preparation of Compound 13: Cs2CO3 (94.2 mg, 0.29 mmol), benzyl
bromide (37.9 µL, 0.32 mmol), and a catalytic amount of Bu4NI
were added successively to a stirred solution of 20a (41.0 mg,
0.15 mmol, detailed procedure for the preparation of 20a is given
later in this section) in anhydrous DMF (0.5 mL) at 25 °C. The
mixture was stirred at the same temperature for 5 h (monitored by
TLC) and then diluted with water (4 mL) and EtOAc (5 mL). The
organic layer was separated and the aqueous layer was extracted
with EtOAc (5 mL). The combined organic extracts were washed
with brine (8 mL) and dried with Na2SO4, the solvents were evap-
orated under reduced pressure, and the crude product was purified
by flash column chromatography (silica gel, hexanes/EtOAc, 85:15)
to afford ethyl 4-benzyloxy-5,8-dimethoxy-2-naphthoate as a white
A stirred solution of the above ester (180.1 mg, 0.33 mmol) in an-
hydrous CH2Cl2 (10 mL) was cooled to Ϫ78 °C and a solution of
DIBAL in CH2Cl2 (1 , 0.76 mL, 0.76 mmol) was added dropwise.
The mixture was stirred at the same temperature for 20 min (mon-
solid (47.8 mg, 87% yield). Rf ϭ 0.70 (hexanes/EtOAc, 8:2); m.p. itored by TLC) and then quenched with methanol (0.5 mL). The
98Ϫ100 °C. IR (KBr): ν˜ ϭ 2949, 1714, 1603, 1465, 1365, 1280,
dry ice/acetone bath was removed, allowing the mixture to reach
1
1070, 767 cmϪ1. H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 1.43 (t, 25 °C, and a saturated aqueous solution of sodium potassium tart-
J ϭ 7.1 Hz, 3 H, CH2CH3), 3.85 (s, 3 H, OMe), 3.93 (s, 3 H, OMe), rate (10 mL) was then added. Stirring was continued until the
4.43 (q, J ϭ 7.1 Hz, 2 H, CH2CH3), 5.24 (s, 2 H, OCH2Ph), 6.79
cloudy solution became clear (about 2 h), and the mixture was ex-
(ABq, J ϭ 8.6 Hz, ∆v ϭ 29.4 Hz, 2 H, CHnaphth), 7.26Ϫ7.66 (m, 11 tracted with EtOAc (3 ϫ 10 mL). The organic extracts were washed
H, CHar), 8.63 (d, J ϭ 1.9 Hz, 1 H, CHnaphth) ppm. 13C NMR with brine (15 mL) and dried with Na2SO4, the solvents were evap-
(62.9 MHz, CDCl3, 25 °C): δ ϭ 14.4, 55.7, 57.2, 61.0, 71.2, 104.9, orated under reduced pressure, and the crude product was purified
107.5, 109.4, 118.0, 127.0, 127.5, 127.9, 128.2, 137.2, 150.3, 150.7,
155.9, 166.8 ppm.
by flash column chromatography (silica gel, hexanes/EtOAc, 7:3)
to afford [5,8-bis(benzyloxy)-4-(tert-butyldimethylsilyloxy)naph-
thalen-2-yl]methanol as a white solid (161.9 mg, 98%). Rf ϭ 0.35
(hexanes/EtOAc, 9:1); m.p. 137Ϫ139 °C. IR (KBr): ν˜ ϭ 3414, 2934,
A stirred solution of the above ester (35.2 mg, 0.096 mmol) in an-
hydrous Et2O (6 mL) was treated at 0 °C with excess freshly pre-
pared allylmagnesium bromide (1  in Et2O, 0.22 mL, 0.22 mmol).
The reaction mixture was stirred at the same temperature for
10 min (monitored by TLC) and then quenched with a saturated
aqueous solution of NH4Cl (3 mL). The organic layer was separ-
ated and washed with brine (7 mL) whereas the aqueous layer was
extracted with EtOAc (2 ϫ 7 mL). The combined organic extracts
were dried with Na2SO4 and the solvents were evaporated under
reduced pressure. The crude mixture was purified by flash column
chromatography (silica gel, hexanes/EtOAc, 8:2) to afford 13 as a
white solid (36.5 mg, 94% yield). Rf ϭ 0.65 (hexanes/EtOAc, 8:2);
1606, 1461, 1372, 1283, 1061, 836 cmϪ1 1H NMR (250 MHz,
.
CDCl3, 25 °C): δ ϭ 0.17 (s, 6 H, Me2Si), 0.97 (s, 9 H, tBuSi), 1.73
(s, 1 H, OH), 4.74 (s, 2 H, CH2OH), 5.11 (s, 2 H, OCH2Ph), 5.18
(s, 2 H, OCH2Ph), 6.62 (ABq, J ϭ 8.6 Hz, ∆v ϭ 14.1 Hz, 2 H,
CHnaphth), 6.95 (d, J ϭ 1.9 Hz, 1 H, CHnaphth), 7.26Ϫ7.51 (m, 10
H, CHar), 7.88 (d, J ϭ 1.9 Hz, 1 H, CHnaphth) ppm. 13C NMR
(62.9 MHz, CDCl3, 25 °C): δ ϭ 2.3, 18.7, 26.1, 65.5, 70.4, 71.3,
105.7, 107.9, 112.8, 115.6, 120.3, 127.3, 127.4, 127.5, 127.8, 128.4,
128.5, 129.2, 137.3, 137.9, 138.6, 148.6, 149.9, 152.8 ppm.
A solution of the above alcohol (150.0 mg, 0.30 mmol) in anhyd-
m.p. 91Ϫ93 °C. IR (KBr): ν˜ ϭ 3554, 2940, 1606, 1470, 1363, 1277, rous CH2Cl2 (15 mL) was treated with 4-methylmorpholine N-ox-
1070, 922, cmϪ1 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ ide (86.4 mg, 0.74 mmol) and TPAP (20.7 mg, 0.06 mmol) at 25 °C
2.46Ϫ2.80 (m, 4 H, CH2CHϭ), 3.87 (s, 3 H, OMe), 3.93 (s, 3 H, for 2 h (monitored by TLC). The reaction mixture was then filtered
.
OMe), 4.96Ϫ5.14 (m, 4 H, ϭCH2), 5.20 (s, 2 H, OCH2Ph), through a pad of silica gel (CH2Cl2) and the organic solvent was
5.46Ϫ5.68 (m, 2 H, CHϭCH2), 6.73 (ABq, J ϭ 8.6 Hz, ∆v ϭ concentrated under reduced pressure to afford 15 as a yellow oil
11.2 Hz, 2 H, CHnaphth), 7.02 (d, J ϭ 1.9 Hz, 1 H, CHnaphth), (146.6 mg, 98% yield). Rf ϭ 0.60 (hexanes/EtOAc, 9:1). IR (film):
7.25Ϫ7.61 (m, 10 H, CHar), 7.88 (d, J ϭ 1.9 Hz, 1 H, CHnaphth
)
ν˜ ϭ 3068, 2928, 1694, 1601, 1512, 1453, 1376, 1252, 1050, 836
ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 46.7, 55.7, 57.2, cmϪ1
.
1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 0.22 (s, 6 H,
72.0, 75.4, 104.3, 106.4, 108.4, 111.5, 119.2, 127.2, 127.5, 128.4,
133.5, 137.6, 143.6, 149.6, 150.8, 155.6 ppm.
Me2Si), 0.99 (s, 9 H, tBuSi), 5.16 (s, 2 H, OCH2Ph), 5.20 (s, 2 H,
OCH2Ph), 6.77 (ABq, J ϭ 8.6 Hz, ∆v ϭ 17.9 Hz, 2 H, CHnaphth),
7.26Ϫ7.53 (m, 11 H, CHar), 8.44 (d, J ϭ 1.5 Hz, 1 H, CHnaphth),
10.04 (s, 1 H, CHO) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C):
δ ϭ 2.3, 18.6, 26.0, 70.6, 71.5, 106.6, 111.1, 111.9, 122.7, 123.8,
127.3, 127.4, 127.6, 128.1, 128.5, 128.6, 134.0, 136.8, 137.5, 149.5,
149.9, 153.6, 192.2 ppm.
Preparation of Aldehyde 15: Imidazole (62.3 mg, 0.91 mmol),
TBSCl (110.3 mg, 0.73 mmol), and a catalytic amount of DMAP
were added successively at 0 °C to a stirred solution of 20b
(156.8 mg, 0.37 mmol, detailed procedure for the preparation of
20b is given later in this section) in anhydrous DMF (1 mL). The
ice bath was removed and the reaction mixture was stirred for 2 h
Preparation of Compound 16: A solution of freshly prepared allyl-
at 25 °C (monitored by TLC). The reaction mixture was then magnesium bromide (1  in Et2O, 0.35 mL, 0.35 mmol) was added
3346 Eur. J. Org. Chem. 2002, 3341Ϫ3350

Synthesis of Hydroxylated Naphthoquinone Derivatives
dropwise at 0 °C to a stirred solution of aldehyde 15 (131.4 mg, separated and the aqueous layer was extracted with EtOAc (10
FULL PAPER
0.26 mmol) in anhydrous Et2O (6 mL). The reaction mixture was
stirred at the same temperature for 15 min (monitored by TLC)
and then quenched with a saturated aqueous solution of NH4Cl (6
mL). The organic layer was separated and washed with brine (8
mL) whereas the aqueous layer was extracted with EtOAc (2 ϫ 8
mL). The combined organic extracts were washed with brine (15
mL) and dried with Na2SO4, the solvents were evaporated under
reduced pressure, and the crude product was purified by flash col-
umn chromatography (silica gel, hexanes/EtOAc, 95:5 to 9:1) to
afford 19 as a orange oil (32.3 mg, 30% yield). Rf ϭ 0.75 (hexanes/
mL). The combined organic extracts were dried with Na2SO4 and EtOAc, 9:1). IR (film): ν˜ ϭ 2925, 1648, 1591, 1257, 1088, 829 cmϪ1
.
the solvents were evaporated under reduced pressure. The crude
product was dissolved in anhydrous DMF (1 mL) and cooled at 0
°C, followed by addition of imidazole (35.9 mg, 0.53 mmol), TBSCl
1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ Ϫ0.01 (s, 3 H, MeSi),
0.03 (s, 3 H, MeSi), 0.87 (s, 9 H, tBuSi), 2.39 (t, J ϭ 6.3 Hz, 2 H,
CH2CHϭ), 4.72 (t, J ϭ 5.6 Hz, 1 H, CHOSi), 4.89Ϫ5.07 (m, 2
(66.6 mg, 0.44 mmol), and a catalytic amount of DMAP. The ice H, ϭCH2), 5.60Ϫ5.82 (m, 1 H, CHϭCH2), 6.90 (s, 2 H, CHquin),
bath was removed and the reaction mixture was stirred at 25 °C
for 1.5 h (monitored by TLC). The reaction was then quenched
with methanol (0.15 mL) and a saturated aqueous solution of
NH4Cl was added (7 mL), followed by EtOAc (10 mL). The or-
ganic layer was separated and washed with brine (10 mL), and the
solvent was evaporated under reduced pressure. The crude product
was purified by flash column chromatography (silica gel, hexanes/
EtOAc, 95:5) to afford 16 as a colorless oil (151.6 mg, 89% yield,
based on 15). Rf ϭ 0.85 (hexanes/EtOAc, 9:1). IR (film): ν˜ ϭ 2930,
7.23 (1 H, CHar), 7.52 (d, J ϭ 1.5 Hz, 1 H, CHar), 11.87 (s, 1
H, OH).
General Procedure for the Preparation of Naphthols 20a and 20b: A
catalytic amount of sodium ethoxide was added to a stirred solu-
tion of either 3a or 3b (4.25 mmol) in absolute ethanol (40 mL).
The mixture was heated under reflux for 1 h (monitored by TLC).
Upon completion of the reaction, half of the solvent was evapor-
ated under reduced pressure, and saturated aqueous NH4Cl solu-
tion (20 mL) and EtOAc (35 mL) were added. The organic layer
was separated, washed with brine (30 mL), and dried with Na2SO4.
Evaporation of the organic solvents under reduced pressure af-
forded crude naphthols, which were recrystallized from EtOAc and
Et2O to afford 20a and 20b, respectively, as pale yellow, crystalline
solids. 20a: yield 89%, all spectroscopic data were in accordance
with those reported; 20b: yield 93%; Rf ϭ 0.60 (hexanes/EtOAc,
8:2); m.p. 154Ϫ156 °C. IR (KBr): ν˜ ϭ 3384, 2980, 1715, 1619, 1377,
2855, 1603, 1457, 1375, 1255, 1083, 1057, 833 cmϪ1 1H NMR
.
(250 MHz, CDCl3, 25 °C): δ ϭ Ϫ0.03 (s, 3 H, MeSi), 0.13 (s, 3 H,
MeSi), 0.23 (s, 3 H, MeSi), 0.25 (s, 3 H, MeSi), 0.97 (s, 9 H, tBuSi),
1.04 (s, 9 H, tBuSi), 2.42Ϫ2.64 (m, 2 H, CH2CHϭ), 4.86 (t, J ϭ
6.0 Hz, 1 H, CHOSi), 5.02Ϫ5.14 (m, 2 H, ϭCH2), 5.18 (s, 2 H,
OCH2Ph), 5.23 (s, 2 H, OCH2Ph), 5.77Ϫ5.98 (m, 1 H, CHϭCH2),
6.67 (ABq, J ϭ 8.6 Hz, ∆v ϭ 16.0 Hz, 2 H, CHnaphth), 7.02 (s, 1 H,
CHnaphth), 7.30Ϫ7.59 (m, 10 H, CHar), 7.91 (s, 1 H, CHnaphth) ppm.
13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 2.1, 2.2, 2.6, 3.1, 18.2,
18.7, 25.9, 26.1, 45.4, 70.5, 71.3, 74.9, 105.5, 107.2, 111.9, 114.8,
116.8, 120.0, 127.3, 127.4, 127.7, 128.3, 128.4, 128.5, 129.1, 135.2,
137.5, 138.0, 142.9, 148.7, 150.1, 152.3 ppm.
1
1293, 1226, 1034, 741 cmϪ1. H NMR (250 MHz, CDCl3, 25 °C):
δ ϭ 1.40 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 4.39 (q, J ϭ 7.1 Hz, 2 H,
CH2CH3), 5.16 (s, 2 H, OCH2Ph), 5.19 (s, 2 H, OCH2Ph), 6.73
(ABq, J ϭ 8.6 Hz, ∆v ϭ 25.7 Hz, 2 H, CHnaphth), 7.26Ϫ7.56 (m, 11
H, CHar), 8.57 (d, J ϭ 1.5 Hz, 1 H, CHnaphth), 9.52 (s, 1 H, OH)
ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 14.3, 61.0, 70.4,
72.1, 105.5, 107.3, 110.6, 116.0, 127.1, 127.9, 128.3, 128.6, 128.8,
129.0, 129.1, 135.2, 136.9, 149.0, 150.2, 154.6, 166.6 ppm. HRMS
(MALDI) calcd. for C27H24O5 ([M ϩ Na]ϩ): 451.1516; found
451.1501.
Treatment of Compound 16 with CAN: A solution of CAN
(0.30Ϫ0.90 mmol) in water (4 mL) was added dropwise at 25 °C to
a stirred solution of 16 (100 mg, 0.15 mmol) in CH3CN (10 mL).
The mixture was stirred at the same temperature for 10Ϫ40 min
(monitored by TLC) and then diluted with water (8 mL) and
EtOAc (10 mL). The organic layer was separated, and the aqueous
layer was extracted with EtOAc (2 ϫ 8 mL). The combined organic
extracts were washed with brine (10 mL) and dried with Na2SO4,
the solvents were evaporated under reduced pressure, and the res-
idue was purified by flash column chromatography (silica gel, hex-
anes/EtOAc, 9:1 to 7:3) to afford 17 as a colorless oil and 18 as an
orange oil (yields of 17 and 18 vary from 20 to 40%). 17: Rf ϭ 0.80
(hexanes/EtOAc, 9:1); 18: Rf ϭ 0.50 (hexanes/EtOAc, 8:2). IR
Preparation of Naphthol 21: A solution of DIBAL in CH2Cl2 (1 ,
6.43 mL, 6.43 mmol) was added dropwise at Ϫ78 °C to a stirred
solution of 3a (512.0 mg, 1.61 mmol) in anhydrous CH2Cl2 (20
mL). The mixture was stirred at the same temperature for 2 h and
then quenched with methanol (1 mL). The dry ice/acetone bath
was removed, allowing the mixture to reach 25 °C, and a saturated
aqueous solution of sodium potassium tartrate (20 mL) was then
added. Stirring was continued until the cloudy solution became
clear (about 3 h) and the mixture was extracted with EtOAc (3 ϫ
20 mL). The organic extracts were washed with brine (30 mL) and
dried with Na2SO4, the solvents were evaporated under reduced
pressure, and the crude product was purified by flash column chro-
matography (silica gel, hexanes/EtOAc, 3:7) to afford 3-hydroxyme-
thyl-5,8-dimethoxynaphthalen-1-ol as a white solid (358.3 mg, 95%
yield). Rf ϭ 0.25 (hexanes/EtOAc, 7:3); m.p. 140Ϫ142 °C. IR
(KBr): ν˜ ϭ 3334, 2846, 1619, 1446, 1387, 1280, 1248, 1095, 1044,
(film): ν˜ ϭ 2925, 1659, 1577, 1279, 1093, 836 cmϪ1 1H NMR
.
(250 MHz, CDCl3, 25 °C): δ ϭ Ϫ0.02 (s, 3 H, MeSi), 0.07 (s, 3 H,
MeSi), 0.89 (s, 9 H, tBuSi), 2.24Ϫ2.61 (m, 2 H, CH2CHϭ),
4.89Ϫ5.09 (m, 3 H, ϭCH2 and CHOSi), 5.17 (s, 2 H, OCH2Ph),
5.19 (s, 2 H, OCH2Ph), 5.68Ϫ5.91 (m, 1 H, CHϭCH2), 6.85 (d,
J ϭ 1.5 Hz, 1 H, CHquin), 7.22 (s, 2 H, CHnaphth), 7.27Ϫ7.59 (m,
10 H, CHar).
Preparation of Juglone Derivative 19: A solution of lithium naph-
thalenide or lithium 4,4Ј-di-tert-butylbiphenylide (4.5 mmol) in
THF was added dropwise at Ϫ20 °C to a stirred solution of 16
(200 mg, 0.30 mmol) in anhydrous THF (15 mL). Lithium naph-
thalenide and lithium 4,4Ј-di-tert-butylbiphenylide were prepared
according to literature procedures (see refs.[36Ϫ38]). Upon comple-
tion of the addition, the temperature was allowed to rise to 0 °C
and the mixture was stirred for about 2 h (monitored by TLC). The
reaction was quenched with a saturated aqueous solution of NH4Cl
(6 mL) and diluted with EtOAc (10 mL). The organic layer was
1
974 cmϪ1. H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 1.87 (s, 1 H,
CH2OH), 3.90 (s, 3 H, OMe), 3.97 (s, 3 H, OMe), 4.73 (s, 2 H,
CH2), 6.62 (s, 2 H, CHar), 6.89 (s, 1 H, CHar), 7.65 (s, 1 H, CHar),
9.42 (s,1 H, ArOH) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C):
δ ϭ 55.7, 56.2, 65.5, 103.3, 103.4, 110.0, 110.6, 115.0, 128.3, 140.3,
150.0, 150.2, 154.7. HRMS (MALDI) calcd. for C13H14O4 [Mϩ]:
234.0887; found 234.0883.
This alcohol (300.0 mg, 1.28 mmol) was dissolved in anhydrous
DMF (0.5 mL) and cooled to 0 °C, followed by addition of imida-
Eur. J. Org. Chem. 2002, 3341Ϫ3350
3347

E. A. Couladouros, A. T. Strongilos
zole (113.0 mg, 1.66 mmol) and TBSCl (212.5 mg, 1.41 mmol). The molar amount of K2CO3 was added before the addition of PIFA).
FULL PAPER
ice bath was removed and the reaction mixture was stirred over-
night at 25 °C. Upon consumption of the starting material (mon-
itored by TLC), the reaction mixture was quenched with methanol
(0.15 mL) and a saturated aqueous solution of NH4Cl was added
(10 mL), followed by EtOAc (15 mL). The organic layer was separ-
ated and washed with brine (15 mL), and the solvent was evapor-
ated under reduced pressure. The crude product was purified by
flash column chromatography (silica gel, hexanes/EtOAc, 9:1) to
afford 21 as a white solid of low melting point (379.2 mg, 85%
yield). Rf ϭ 0.70 (hexanes/EtOAc, 8:2). IR (KBr): ν˜ ϭ 3380, 2929,
2854, 1645, 1620, 1516, 1463, 1386, 1251, 1093, 842, 780 cmϪ1. 1H
NMR (250 MHz, CDCl3, 25 °C): δ ϭ 0.09 (s, 6 H, Me2Si), 0.95 (s,
9 H, tBuSi), 3.90 (s, 3 H, OMe), 3.97 (s, 3 H, OMe), 4.82 (s, 2 H,
CH2), 6.61 (s, 2 H, CHar), 6.89 (s, 1 H, CHar), 7.64 (s, 1 H, CHar),
9.40 (s, 1 H, OH) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ
3.8, 18.8, 26.0, 55.8, 56.2, 65.2, 102.7, 102.9, 109.9, 110.0, 114.5,
128.4, 140.9, 150.0, 150.2, 154.2 ppm. HRMS (MALDI) calcd. for
C19H28O4Si ([M ϩ Na]ϩ): 371.1649; found 371.1651.
The ice bath was then removed and the mixture was stirred for 1 h
at 25 °C. The reaction mixture was quenched with a saturated
aqueous solution of NaHCO3 (15 mL), followed by extraction with
EtOAc (2 ϫ 15 mL). The organic layer was washed with brine (20
mL) and dried with Na2SO4, the solvents were evaporated under
reduced pressure, and the crude product was purified by flash col-
umn chromatography (silica gel, hexanes/EtOAc) to afford 25a,
25b, or 22c, respectively.
Compound 25a: Orange solid, yield 55%; Rf ϭ 0.45 (hexanes/
EtOAc, 7:3); m.p. 132Ϫ134 °C. IR (KBr): ν˜ ϭ 3425, 2916, 1715,
1669, 1640, 1583, 1289, 998, 818 cmϪ1 1H NMR (250 MHz,
.
CDCl3, 25 °C): δ ϭ 1.35 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 3.52 (d,
J ϭ 4.5 Hz, 1 H, OH), 3.88 (s, 3 H, OMe), 3.92 (s, 3 H, OMe),
4.34 (q, J ϭ 7.1 Hz, 2 H, CH2CH3), 5.85 (d, J ϭ 4.5 Hz, 1 H,
CHOH), 6.99 (s, 1 H, COCHϭ), 7.06 (ABq, J ϭ 9.1 Hz, ∆v ϭ
43.4 Hz, 2 H, CHar) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C):
δ ϭ 14.1, 56.3, 56.6, 60.1, 61.9, 112.8, 116.9, 120.0, 132.1, 135.4,
142.2, 150.8, 154.3, 165.7, 184.8 ppm. HRMS (MALDI) calcd. for
C15H16O6 [Mϩ]: 292.0941; found 292.0942.
General Procedure for Salcomine-Catalyzed Oxidation: Salcomine
(32.0 mg, 0.09 mmol) was added to a stirred solution of 20a, 20b,
or 21 (0.47 mmol) in CH3CN (35 mL), and the mixture was stirred
under air at 25 °C for 20Ϫ24 h (until no starting material was ob-
served by TLC analysis). The dark red solution was then filtered
through a pad of Celite and the solvent was evaporated under re-
duced pressure to afford 23a, 23b, or 23c, respectively, as shiny dark
red crystals.
Compound 25b: Orange solid, yield 75%; Rf ϭ 0.45 (hexanes/
EtOAc, 7:3); m.p. 101Ϫ103 °C. IR (KBr): ν˜ ϭ 3461, 2932, 1724,
1672, 1590, 1456, 1248, 1105, 1018, 806, 741 cmϪ1 1H NMR
.
(250 MHz, CDCl3, 25 °C): δ ϭ 1.31 (t, J ϭ 7.1 Hz, 3 H, CH2CH3),
3.54 (s, 1 H, OH), 4.30 (q, J ϭ 7.1 Hz, 2 H, CH2CH3), 5.08 (s, 2
H, OCH2Ph), 5.00Ϫ5.20 (m, 4 H, OCH2Ph), 5.86 (s, 1 H, CHOH),
6.96 (s, 1 H, COCHϭ), 6.98 (ABq, J ϭ 9.1 Hz, ∆v ϭ 44.1 Hz, 2 H,
CHar), 7.24Ϫ7.54 (m, 10 H, CHar) ppm. 13C NMR (62.9 MHz,
CDCl3, 25 °C): δ ϭ 14.0, 60.1, 61.8, 71.2, 71.4, 115.4, 118.4, 126.8,
Compound 23a: Yield 90%; Rf ϭ 0.60 (CHCl3/MeOH, 95:5); m.p.
172Ϫ174 °C. 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ 1.37 (t, J ϭ
7.1 Hz, 3 H, CH2CH3), 3.92 (s, 3 H, OMe), 3.94 (s, 3 H, OMe), 127.3, 127.6, 128.3, 128.5, 128.8, 132.4, 135.2, 136.7, 142.3, 150.4,
4.36 (q, J ϭ 7.1 Hz, 2 H, CH2CH3), 7.19 (ABq, J ϭ 9.5 Hz, ∆v ϭ
153.2, 165.7, 184.4 ppm. HRMS (MALDI) calcd. for C27H24O6
9.7 Hz, 2 H, CHar), 8.66 (s, 1 H, CHquin) ppm. 13C NMR ([M ϩ Na]ϩ): 467.1465; found 467.1449.
(62.9 MHz, CDCl3, 25 °C): δ ϭ 14.8, 56.6, 62.1, 119.5, 121.4, 122.2,
Compound 22c: Orange-brown oil, yield 53%; Rf ϭ 0.50 (hexanes/
126.1, 143.9, 152.5, 157.3, 163.2, 177.1, 177.2 ppm. HRMS
(MALDI) calcd. for C15H14O6 ([M ϩ Na]ϩ): 313.0683; found
313.0682.
EtOAc, 7:3). IR (thin film): ν˜ ϭ 2956, 2861, 1653, 1569, 1474, 1281,
1108, 1057, 970, 845, 776 cmϪ1 1H NMR (250 MHz, CDCl3, 25
.
°C): δ ϭ 0.05 (s, 6 H, Me2Si), 0.87 (s, 9 H, tBuSi), 3.87 (s, 3 H,
OMe), 3.88 (s, 3 H, OMe), 4.58 (d, J ϭ 2.2 Hz, 2 H, CH2), 6.79 (t,
J ϭ 2.2 Hz, 1 H, CHquin), 7.23 (ABq, J ϭ 9.7 Hz, ∆v ϭ 10.8 Hz, 2
Compound 23b: Yield 90%; Rf ϭ 0.60 (CHCl3/MeOH, 95:5); m.p.
179Ϫ181 °C. IR (KBr): ν˜ ϭ 2926, 1730, 1663, 1604, 1452, 1383,
1194, 1006, 726 cmϪ1 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ H, CHar) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ 3.8,
.
1.30 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 4.26 (q, J ϭ 7.1 Hz, 2 H,
18.3, 28.8, 56.7, 56.8, 59.3, 119.9, 120.5, 121.1, 121.2, 132.8, 149.4,
CH2CH3), 5.08 (s, 2 H, OCH2Ph), 5.10 (s, 2 H, OCH2Ph), 7.11 153.5, 153.7, 184.8, 184.9 ppm. HRMS (MALDI) calcd. for
(ABq, J ϭ 9.5 Hz, ∆v ϭ 18.8 Hz, 2 H, CHar), 7.20Ϫ7.57 (m, 10 H,
CHar), 8.66 (s, 1 H, CHquin) ppm. 13C NMR (62.9 MHz, CDCl3,
25 °C): δ ϭ 14.0, 61.4, 70.6, 71.5, 120.6, 122.2, 126.4, 127.2, 127.7,
128.4, 128.5, 128.7, 135.4, 135.7, 143.8, 151.6, 155.9, 163.2, 177.1,
177.2 ppm. HRMS (MALDI) calcd. for C27H22O6 ([M ϩ Na]ϩ):
465.1309; found 465.1322.
C19H26O5Si ([M ϩ H]ϩ): 363.1622; found 363.1624.
General Procedure for the Oxidation with PIFA/H؉/FeCl3: A stirred
solution of either 20a or 20b (0.35 mmol) in a 2:1 mixture of
CH3CN/H2O (17 mL) was cooled to 0 °C, and PIFA (227.9 mg,
0.53 mmol) was added. The ice bath was then removed, the mixture
was stirred for 1 h at 25 °C, and a solution of FeCl3·6H2O
(270.3 mg, 1.0 mmol) in HCl (1 , 2.5 mL) was then added. The
reaction mixture was stirred for 6 h at 25 °C and then diluted with
Compound 23c: Yield 93%; Rf ϭ 0.30 (hexanes/EtOAc, 7:3); m.p.
137Ϫ139 °C. IR (KBr): ν˜ ϭ 2938, 2858, 1653, 1632, 1485, 1276,
1196, 1079, 845, 782 cmϪ1 1H NMR (250 MHz, CDCl3, 25 °C): water (10 mL) and EtOAc (18 mL). The organic layer was separ-
.
δ ϭ 0.06 (s, 6 H, Me2Si), 0.91 (s, 9 H, tBuSi), 3.81 (s, 3 H, OMe),
3.84 (s, 3 H, OMe), 4.48 (s, 2 H, CH2), 7.01 (ABq, J ϭ 9.3 Hz,
ated and the aqueous layer was extracted with EtOAc (12 mL). The
combined organic extracts were washed with brine (20 mL) and
∆v ϭ 42.4 Hz, 2 H, CHar), 7.96 (s, 1 H, CHquin) ppm. 13C NMR dried with Na2SO4, the solvents were evaporated under reduced
(62.9 MHz, CDCl3, 25 °C): δ ϭ 3.7, 18.3, 28.8, 56.4, 56.7, 59.4, pressure, and the crude product was purified by flash column chro-
115.8, 118.6, 120.8, 124.2, 133.8, 137.5, 150.7, 157.0, 178.8, 180.1 matography (silica gel, hexanes/EtOAc, 7:3) to afford 22a or 22b,
ppm. HRMS (MALDI) calcd. for C19H26O5Si ([M ϩ H]ϩ):
respectively, as orange solids.
363.1622; found 363.1624.
Compound 22a: Yield ϭ 48%; Rf ϭ 0.65 (CHCl3/MeOH, 95:5); m.p.
110Ϫ112 °C. IR (KBr): ν˜ ϭ 2923, 2858, 1729, 1659, 1482, 1288,
General Procedure for the Oxidation with PIFA: A stirred solution
of 20a, 20b, or 21 (0.29 mmol) in a 2:1 mixture of CH3CN/H2O
(15 mL) was cooled to 0 °C and [bis (trifluoroacetoxy)iodo]benzene
(PIFA, 311.8 mg, 0.72 mmol) was added (in the case of 21 an equi-
1115, 1016, 831 cmϪ1 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ
.
1.34 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 3.92 (s, 3 H, OMe), 3.93 (s, 3
H, OMe), 4.34 (q, J ϭ 7.1 Hz, 2 H, CH2CH3), 7.02 (s, 1 H, CHquin),
3348
Eur. J. Org. Chem. 2002, 3341Ϫ3350

Synthesis of Hydroxylated Naphthoquinone Derivatives
FULL PAPER
7.30 (ABq, J ϭ 9.7 Hz, ∆v ϭ 10.4 Hz, 2 H, CHar) ppm. 13C NMR 2856, 1602, 1373, 1258, 1062, 926, 839 cmϪ1. 1H NMR (500 MHz,
(62.9 MHz, CDCl3, 25 °C): δ ϭ 14.1, 56.8, 56.9, 62.2, 120.2, 121.1, CDCl3, 25 °C): δ ϭ 0.00 (s, 6 H, Me2Si), 0.18 (s, 6 H, Me2Si), 1.03
137.4, 139.8, 153.5, 153.8, 163.6, 181.0, 184.2 ppm. HRMS
(s, 9 H, tBuSi), 1.05 (s, 9 H, tBuSi), 3.79 (s, 3 H, OMe), 3.83 (s, 3
(MALDI) calcd. for C15H14O6 ([M ϩ Na]ϩ): 313.0683; found H, OMe), 4.76 (d, J ϭ 3.5 Hz, 2 H, CH2OH), 6.63 (s, 2 H, CHar),
313.0681.
6.95 (s, 1 H, CHar) ppm. 13C NMR (125.7 MHz, CDCl3, 25 °C):
δ ϭ Ϫ4.4, Ϫ4.5, 18.3, 18.5, 25.8, 25.9, 55.2, 55.5, 60.8, 104.7, 105.0,
116.8, 121.5, 122.5, 128.7, 141.9, 146.5, 150.3, 150.6 ppm. HRMS
(FAB) calcd. for C25H42O5Si2 ([M ϩ H]ϩ): 479.2649; found
479.2662.
Compound 22b: Yield ϭ 67%; Rf ϭ 0.65 (CHCl3/MeOH, 95:5); m.p.
117Ϫ119 °C. IR (KBr): ν˜ ϭ 2924, 1740, 1664, 1567, 1448, 1284,
1118, 1021, 742 cmϪ1 1H NMR (250 MHz, CDCl3, 25 °C): δ ϭ
.
1.35 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 4.36 (q, J ϭ 7.1 Hz, 2 H,
CH2CH3), 5.17 (s, 4 H, OCH2Ph), 7.02 (s, 1 H, CHquin), 7.20Ϫ7.57
(m, 12 H, CHar) ppm. 13C NMR (62.9 MHz, CDCl3, 25 °C): δ ϭ
14.1, 62.2, 71.6, 71.7, 122.3, 123.1, 126.8, 127.0, 127.9, 128.0, 128.6,
136.1, 136.2, 137.3, 139.8, 152.6, 152.9, 163.6, 180.6, 183.9 ppm.
HRMS (MALDI) calcd. for C27H22O6 ([M ϩ Na]ϩ): 465.1309;
found 465.1310.
A solution of the above alcohol (160.4 mg, 0.34 mmol) in anhyd-
rous CH2Cl2 (15 mL) was treated with 4-methylmorpholine N-ox-
ide (98.1 mg, 0.84 mmol) and TPAP (23.5 mg, 0.07 mmol) at 25 °C
for 3 h (the reaction progress was monitored by TLC). The reaction
mixture was then filtered through a pad of silica gel (CH2Cl2) and
the organic solvent was concentrated under reduced pressure to
afford 29 as a yellow oil (154.9 mg, 97% yield). Rf ϭ 0.70 (hexanes/
Et2O, 7:3). IR (thin film): ν˜ ϭ 2955, 2858, 1678, 1605, 1574, 1516,
Preparation of Aldehyde 29: A saturated aqueous solution of
Na2S2O4 (1 mL) was added at 25 °C to a stirred solution of 22a
(72.6 mg, 0.25 mmol) in CHCl3 (5 mL) and the mixture was vigor-
ous stirred for 15 min (disappearance of the orange color of the
quinone moiety). It was then diluted with water (5 mL) and the
organic layer was separated. The aqueous layer was extracted with
CHCl3 (2 ϫ 5 mL), and the combined organic extracts were washed
with brine (10 mL), dried with Na2SO4, and concentrated under
reduced pressure to afford the crude hydroquinone, which was used
in the next step without further purification.
1392, 1372, 1259, 1074, 1059, 925 cmϪ1 1H NMR (400 MHz,
.
CDCl3, 25 °C): δ ϭ 0.00 (s, 6 H, Me2Si), 0.20 (s, 6 H, Me2Si), 1.01
(s, 9 H, tBuSi), 1.07 (s, 9 H, tBuSi), 3.83 (s, 3 H, OMe), 3.84 (s, 3
H, OMe), 6.78 (ABq, J ϭ 8.7 Hz, ∆v ϭ 44.4 Hz, 2 H, CHar), 7.15
(s, 1 H, CHar), 10.40 (s, 1 H, CHO) ppm. 13C NMR (100.5 MHz,
CDCl3, 25 °C): δ ϭ Ϫ4.8, Ϫ4.4, 18.5, 25.8, 25.9, 55.4, 55.9, 106.3,
109.2, 111.4, 124.6, 128.8, 130.9, 146.9, 150.8, 151.8, 152.2, 189.6
ppm. HRMS (FAB) calcd. for C25H40O5Si2 ([M ϩ H]ϩ): 477.2493;
found 477.2478.
A solution of the crude product in anhydrous DMF (0.5 mL) was
treated at 0 °C with imidazole (51.1 mg, 0.75 mmol), TBSCl
(95.0 mg, 0.63 mmol), and a catalytic amount of DMAP. The ice
bath was removed and the reaction mixture was stirred overnight.
The reaction mixture was then quenched with MeOH (0.3 mL) and
a saturated aqueous solution of NH4Cl (5 mL) was added, followed
by extraction with EtOAc (2 ϫ 7 mL). The organic layer was
washed with brine (10 mL), dried with Na2SO4, and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography (silica gel, hexanes/Et2O, 9:1) to afford 27
as a white solid of low melting point (115.9 mg, 89% yield based
on 22a). Rf ϭ 0.75 (hexanes/Et2O, 8:2). IR (thin film): ν˜ ϭ 2951,
2857, 1739, 1608, 1576, 1384, 1366, 1264 1138, 1061, 930 cmϪ1. 1H
NMR (500 MHz, CDCl3, 25 °C): δ ϭ 0.00 (s, 6 H, Me2Si), 0.20 (s,
6 H, Me2Si), 1.03 (s, 9 H, tBuSi), 1.07 (s, 9 H, tBuSi), 1.39 (t, J ϭ
7.1 Hz, 3 H, CH2CH3), 3.82 (s, 3 H, OMe), 3.84 (s, 3 H, OMe),
4.39 (q, J ϭ 7.1 Hz, 2 H, CH2CH3), 6.73 (ABq, J ϭ 8.5 Hz, ∆v ϭ
39.0 Hz, 2 H, CHar), 7.18 (s, 1 H, CHar) ppm. 13C NMR
(125.7 MHz, CDCl3, 25 °C): δ ϭ Ϫ5.1, Ϫ4.5, 14.3, 18.0, 18.2, 20.2,
25.9, 26.0, 55.3, 55.7, 61.2, 105.7, 107.5, 116.8, 119.9, 123.2, 123.9,
146.0, 146.8, 150.2, 152.0, 167.7 ppm.
Acknowledgments
The authors would like to thank P. N. Gerolymatos S.A. and the
General Secretariat of the Ministry of Development of Greece for
financially supporting this work. A. T. S. would also like to thank
the Institute of National Scholarships (IKY) for financial support.
[1]
K. Kroh, Tetrahedron Lett. 1980, 21, 9Ϫ13.
[2]
H. Hiranuma, S. I. Miller, J. Org. Chem. 1982, 47, 5083Ϫ5088.
[3]
K. Kim, G. A. Sulikowski, Angew. Chem. 1995, 107,
2587Ϫ2589; Angew. Chem. Int. Ed. Engl. 1995, 34, 2396Ϫ2398.
[4]
J. G. Allen, M. F. Hentemann, S. J. Danishefsky, J. Am. Chem.
Soc. 2000, 122, 571Ϫ575.
[5]
K. H. Dötz, Angew. Chem. 1975, 87, 672Ϫ673; Angew. Chem.
Int. Ed. Engl. 1975, 14, 644Ϫ645.
D. L. Boger, O. Huter, K. Mbiya, M. Zhang, J. Am. Chem.
[6]
Soc. 1995, 117, 11839Ϫ11849.
Y.-C. Xu, D. T. Kohlman, S. X. Liang, C. Erikkson, Org. Lett.
[7]
1999, 1, 1599Ϫ1602.
[8]
W. D. Wulff, J. Su, P.-C. Tang, Y.-C. Xu, Synthesis 1999,
415Ϫ422.
[9]
F. M. Hauser, R. P. Rhee, J. Org. Chem. 1980, 45, 3061Ϫ3068.
[10]
F. M. Hauser, S. Prasanna, J. Org. Chem. 1982, 47, 383Ϫ384.
A solution of DIBAL in CH2Cl2 (1.0 , 0.44 mL, 0.44 mmol) was
added dropwise at Ϫ78 °C to a stirred solution of 27 (104.2 mg,
0.20 mmol) in CH2Cl2 (7 mL). The reaction mixture was stirred at
the same temperature for 1 h (monitored by TLC) and then
quenched with MeOH (0.4 mL), followed by addition of a satur-
ated aqueous solution of sodium potassium tartrate (8 mL) and
EtOAc (5 mL). The resulting mixture was vigorously stirred for
2 h, whereupon the organic layer was separated and the aqueous
layer was extracted with EtOAc (2 ϫ 8 mL). The combined organic
extracts were washed with brine (10 mL), dried with Na2SO4, and
concentrated under reduced pressure, and the crude product was
purified by flash column chromatography (silica gel, hexanes/
EtOAc, 8:2) to afford [1,4-bis(tert-butyldimethylsilyloxy)-5,8-dime-
thoxynaphthalen-2-yl]methanol as a colorless oil (89.0 mg, 93%
yield). Rf ϭ 0.35 (hexanes/Et2O, 7:3). IR (neat): ν˜ ϭ 3445, 2929,
[11]
F. M. Hauser, D. Mal, J. Am. Chem. Soc. 1983, 105,
5688Ϫ5690.
[12]
M. P. Sibi, J. W. Dankwardt, V. Snieckus, J. Org. Chem. 1986,
51, 273Ϫ275.
[13]
V. Snieckus, Chem. Rev. 1990, 90, 879Ϫ933.
[14]
L. S. Liebeskind, S. Iyer, C. F. Jewell Jr., J. Org. Chem. 1986,
51, 3065Ϫ3067.
[15]
L. S. Liebeskind, S. L. Baysdon, M. S. South, S. Iyer, J. P.
Leeds, Tetrahedron 1985, 41, 5839Ϫ5853.
[16]
H. Stobbe, Ber. 1893, 26, 2312Ϫ2319.
[17]
M. Watanabe, S. Hisamatsu, H. Hotokezaka, S. Furukawa,
Chem. Pharm. Bull. 1986, 34, 2810Ϫ2820.
[18]
H. Laatsch, Liebigs Ann. Chem. 1985, 1847Ϫ1865.
[19]
J. L. Bloomer, K. W. Stagliano, J. A. Gazzillo, J. Org. Chem.
1993, 58, 7906Ϫ7912.
A. Ricci, A. DeglЈ Innocenti, Synthesis 1989, 647Ϫ660.
[20]
Eur. J. Org. Chem. 2002, 3341Ϫ3350
3349

E. A. Couladouros, A. T. Strongilos
FULL PAPER
[21]
[34]
J.-P. Picard, R. Calas, J. Dunogues, N. Duffaut, J. Gerval, P.
J. M. Williams, R. B. Jobson, N. Yasuda, G. Marchesini, U.-
H. Dolling, E. J. J. Grabowski, Tetrahedron Lett. 1995, 36,
5461Ϫ5464.
Lapouyade, J. Org. Chem. 1979, 44, 420Ϫ424.
A. DeglЈ Innocenti, S. Pike, D. R. M. Walton, J. Chem. Soc.,
[22]
[35]
[36]
[37]
[38]
[39]
[40]
Chem. Commun. 1980, 1201Ϫ1202.
R. L. Snowden, B. L. Muller, K. H. Schulte-Elte, Tetrahedron
Lett. 1982, 23, 335Ϫ338.
P. K. Freeman, L. L. Hutchinson, J. Org. Chem. 1980, 45,
1924Ϫ1930.
S. J. Shimshock, R. E. Waltermire, P. DeShong, J. Am. Chem.
Soc. 1991, 113, 8791Ϫ8796.
H.-J. Liu, J. Yip, K.-S. Shia, Tetrahedron Lett. 1997, 38,
2253Ϫ2256.
J. L. Bloomer, K. W. Stagliano, Tetrahedron Lett. 1993, 34,
757Ϫ760.
E. A. Couladouros, A. T. Strongilos, Tetrahedron Lett. 2000,
41, 535Ϫ538.
A. Varvoglis, Tetrahedron 1997, 53, 1179Ϫ1255.
R. Barret, M. Daudon, Tetrahedron Lett. 1990, 31, 4871Ϫ4872.
It should be mentioned that the structures of compounds 25a
and 25b were wrongly assigned as 22a and 22b, respectively,
in a previous communication by our group (see ref.[40]). That
confusing report is clarified here.
V. P. Papageorgiou, A. N. Assimopoulou, E. A. Couladouros,
D. Hepworth, K. C. Nicolaou, Angew. Chem. 1999, 111,
280Ϫ311; Angew. Chem. Int. Ed. 1999, 38, 270Ϫ300.
Received March 22, 2002
[23]
A. Capperucci, A. DeglЈ Innocenti, C. Faggi, A. Ricci, J. Org.
Chem. 1988, 53, 3612Ϫ3614.
[24]
A. Yanagisawa, S. Habaue, H. Yamamoto, J. Org. Chem. 1989,
54, 5198Ϫ5200.
[25]
A. Yanagisawa, S. Habaue, H. Yamamoto, Tetrahedron 1992,
48, 1969Ϫ1980.
C. Fehr, J. Galindo, R. Perret, Helv. Chim. Acta 1987, 70,
1745Ϫ1752.
A. Yanagisawa, S. Habaue, H. Yamamoto, J. Am. Chem. Soc.
1991, 113, 8955Ϫ8956.
E. A. Couladouros, A. T. Strongilos, V. P. Papageorgiou, Z. F.
[26]
[27]
[28]
[41]
[42]
[43]
Plyta, Chem. Eur. Journal 2002, 8, 1795Ϫ1803.
M. Araki, S. Sakata, H. Takei, T. Mukaiyama, Bull. Chem.
[29]
Soc. Jpn. 1974, 47, 1777Ϫ1780.
[30]
T. Mukayiama, M. Araki, H. Takei, J. Am. Chem. Soc. 1973,
95, 4763Ϫ4765.
[31]
H. A. Staab, Angew. Chem. 1962, 74, 407Ϫ423; Angew. Chem.
[44]
Int. Ed. Engl. 1962, 1, 351Ϫ367.
[32]
H. A. Staab, E. Jost, Justus Liebigs Ann. Chem. 1962, 655,
90Ϫ94.
[33]
S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22,
3815Ϫ3818.
[O02160]
3350
Eur. J. Org. Chem. 2002, 3341Ϫ3350