Synthesis and biological evaluation of deoxypreussomerin A and palmarumycin CP1 and related naphthoquinone spiroketals

Article abstract of DOI:10.1016/S0040-4020(00)00936-4

Oxidative cyclization of bis-hydroxynaphthyl ethers allows concise total syntheses of palmarumycin CP₁ and deoxypreussomerin A in 8-9 steps and 15-35% overall yield from 5-hydroxy-8-methoxy-1-tetralone (8). Polymer-bound triphenyl phosphine was found to be a superior reagent for the rapid preparation of a small library of palmarumycin analogs. Preliminary biological evaluation of naphthoquinone spiroketals against MCF-7 and MDA-MB-231 human breast cancer cells revealed several low-micromolar growth inhibitors.

Full text of DOI:10.1016/S0040-4020(00)00936-4

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 283±296
Synthesis and biological evaluation of deoxypreussomerin A and
palmarumycin CP1 and related naphthoquinone spiroketals
*
Peter Wipf, Jae-Kyu Jung, Sonia Rodrõguez and John S. Lazo
Â
Departments of Chemistry and Pharmacology, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 24 April 2000; revised 30 May 2000; accepted 10 July 2000
AbstractÐOxidative cyclization of bis-hydroxynaphthyl ethers allows concise total syntheses of palmarumycin CP1 and deoxypreusso-
merin A in 8-9 steps and 15±35% overall yield from 5-hydroxy-8-methoxy-1-tetralone (8). Polymer-bound triphenyl phosphine was found to
be a superior reagent for the rapid preparation of a small library of palmarumycin analogs. Preliminary biological evaluation of naphtho-
quinone spiroketals against MCF-7 and MDA-MB-231 human breast cancer cells revealed several low-micromolar growth inhibitors.
q 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
dematioides by Polishook and coworkers.2 Another report
of an epoxy naphthalenediol spiroketal compound, bipen-
densin, was published in 1990 by Connolly.3 The latter
natural product was isolated in very small amounts from
wood samples of the African tree Afzelia bipendensis. A
compound having the same gross structure as bipendensin
was isolated in 1994 from an unidenti®ed Coniothyium
fungus collected from forest soil on West Borneo, and
was named palmarumycin C11 by Krohn and coworkers.4
The novel antifungal metabolites preussomerins A±F were
identi®ed in 1990 by Gloer and coworkers during the course
of an investigation of chemical agents involved in inter-
species competition among coprophilous (dung-colonizing)
fungi (Fig. 1).1 In addition to these early reports from
Preussia isomera Cain samples, preussomerins were later
also discovered in the endophytic fungus Harmonerna
Figure 1. Preussomerins isolated from Preussia isomera.
Keywords: spirocyclization; naphthoquinone; palmarumycin; deoxypreussomerin; total synthesis; polymer-bound reagent; iodobenzenediacetate; phenol
oxidation; cytotoxicity; breast cancer cell line.
* Corresponding author. Tel.: 1412-624-8606; fax: 1412-624-0787; e-mail: pwipf@pitt.edu
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00936-4

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P. Wipf et al. / Tetrahedron 57 (2001) 283±296
Figure 2. Acidic degradation of preussomerin A.
Figure 3. Preussomerins and deoxypreussomerins isolated from a coelomycetes fungus.
The absolute stereochemistry of preussomerins was
assigned as shown in Fig. 1 on the basis of the isolation of
known (2)-regiolone as a degradation product.1b Although
the ketal linkages were resistant to acid hydrolysis at room
temperature, vigorous cleavage conditions (6 M HCl/
acetone, 1:1, 1008C, 12 h) afforded (2)-regiolone5 as the
major product. Conservation of the stereochemistry at the
C-10 position could be rationalized by a mechanism
involving protonation at the C-20 position during the
decomposition process followed by loss of the 9-OH proton
and formation of an enol ether (Fig. 2). Hydrolysis of the
remaining ketal linkage would then account for the
formation of regiolone without loss of stereochemical
integrity at the hydroxylated benzylic carbon.
Even though preussomerin A exhibited only low-micromo-
lar cytotoxicity toward a mammalian cell line,1b a Merck
group reported that preussomerins and deoxypreussomerins
showed promising effects as novel ras farnesyl-protein
transferase (FTPase) inhibitors.6 Preussomerin G±I and
deoxypreussomerin A and B, accompanied by preussome-
rin D, were isolated from the fermentation broth of an
unidenti®ed coelomycetes fungus collected in Bajo
Verde, Argentina (Fig. 3). IC50's of FTPase inhibitory
activities of preussomerins, deoxypreussomerins and
derivatives of preussomerin G range between 1±20 mM.
Preussomerin G and preussomerin D were the most active.
Interestingly, deoxypreussomerins, which possibly are
biosynthetic precursors of preussomerins,6 had equal or
Scheme 1.

P. Wipf et al. / Tetrahedron 57 (2001) 283±296
285
Figure 4. Palmarumycins from Coniothyrium palmarium.
Figure 5. Palmarumycins from an unidenti®ed Coniothyrium species (relative con®gurations are shown).
better activities than preussomerins H and I. Deoxypreus-
somerin A and B were also reported independently as anti-
fungal agents and named palmarumycin C2 and CP2,
respectively.4,7
palmarumycin C9, isolated as an isomeric mixture of
epoxides, completely inhibited germination and growth of
garden cress. In most palmarumycins, only the relative
con®guration was elucidated, except for palmarumycin
CP4a and CP5. The absolute con®gurations of the latter
compounds were elucidated by CD calculations. After
computation of the CD spectra of six low energy con-
formers, Boltzmann-weighted addition and comparison of
the resulting averaged spectrum with the experimental data
allowed the assignment of the absolute con®guration of
palmarumycin CP4a and CP5 as shown in Fig. 4.8
Preussomerin G reacted with strong nucleophiles in a highly
stereospeci®c Michael fashion to give a quantitative yield of
the C-30 adduct (Scheme 1). Presumably, steric hindrance
makes the top face of preussomerin G inaccessible to
nucleophiles, and thus Michael addition takes place exclu-
sively from the more accessible a-face.
Additional naphthalenediol spiroketals of the palmarumycin
family have been reported by Krohn and coworkers.4,7,8
These metabolites were produced by two strains of the
endophytic fungi Coniothyrium palmarium and an uniden-
ti®ed Coniothyrium species (Figs. 4 and 5).
Krohn and coworkers proposed a biosynthesis of palmaru-
mycin CP1 based on a 1,8-dihydroxynaphthalene or a suita-
ble phenolic derivative precursor.4,9 According to their
hypothesis, coupling could occur via a phenol oxidation as
often encountered in polyketide biosynthesis,10 and the
chlorinated palmarumycins could be derived from addition
of chloride ions to epoxides. In order to probe this mech-
anism, palmarumycin CP2 and palmarumycin C9 were trea-
ted with methanolic hydrochloric acid (Scheme 2). As
expected, formation of chlorinated palmarumycin C4 from
Palmarumycin CP3, CP4, C3, C10 and C12 show high anti-
fungal activity. Apparently, the introduction of an oxygen
function into the 8-position signi®cantly increases the anti-
fungal effect. The chloroepoxide palmarumycin C4 and

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P. Wipf et al. / Tetrahedron 57 (2001) 283±296
Scheme 2.
palmarumycin C9 could be detected by TLC. For the reac-
tion of palmarumycin C2, an intermediate chlorohydrin was
identi®ed as the major isomer. This chlorohydrin slowly
decomposed to palmarumycin C1 upon standing in chloro-
form solution. Palmarumycin C2 was recovered upon treat-
ment with base. These experiments established a possible
pathway to the chlorinated palmarumycins. They also high-
lighted the unexpected stability of the naphthalenediol
spiroketal that was not even affected by heating in acetic
acid at 1008C.4
Interestingly, Krohn and coworkers isolated the open chain
compound 1 from Coniothyrium palmarum.11 This isolation
offered the chance to probe the biosynthetic hypothesis
involving phenol oxidation. Upon exposure to silver(II)
oxide, the binaphthyl ether 1 cyclized to give quinone
ketal 2 (Scheme 3). However, 2 could not be detected in
the fermentation broth of Coniothyrium palmarum. It is
possible that a total synthesis of palmarumycins based on
the phenolic oxidation of binaphthyl ethers could be
Scheme 3.
Figure 6. Representative structurally related fungal metabolites.

P. Wipf et al. / Tetrahedron 57 (2001) 283±296
287
Scheme 4.
Scheme 5.
achieved as shown for 3; however, no further studies along
these lines have been reported. Taylor and coworkers also
investigated a biomimetic cyclization approach with little
success.12
In the course of our approaches toward the total synthesis
of diepoxin s,20,22 we also devised a potential synthetic
strategy toward palmarumycin CP1 and deoxypreussomerin
A (Scheme 4).17 In a preliminary retrosynthetic analysis,
naphthalenediol spiroketal 4 was derived from binaphthyl
ether 5, and dehydrogenation at C(5) and C(6) in 4 should be
facilitated by the presence of the enone moiety. Compound
5 would be easily prepared by an Ullmann ether coupling
reaction with 1-iodo-8-methoxynaphthalene (7)23 and the
tetraline derivative 6. In the present work, we report our
investigations along these lines and the realization of
concise synthetic routes toward the natural products as
well as a series of analogs for biological testing.
Deoxypreussomerins and palmarumycins are structurally
closely related to the more recently isolated diepoxins,13
CJ-12,371 and CJ-12,372,14 and spiroxins15 (Fig. 6).16 Anti-
microbial, antifungal, and some anticancer activities were
identi®ed for diepoxins and spiroxins. A P®zer research
group isolated the novel fungal metabolites CJ-12,371 and
CJ-12,372 from a fermentation broth of an unidenti®ed
fungus N983-46. These compounds showed DNA gyrase
inhibitory activity. The phospholipase D inhibitor Sch
53823 has the same gross structure as palmarumycin C11,
however, the melting point and optical rotation are different,
suggesting that palmarumycin C11 and Sch 53823 are stereo-
isomers.16b
2. Results and discussion
5-Hydroxy-8-methoxy-1-tetralone (8, Scheme 5) was
prepared by a modi®ed literature procedure.22,24 Attempts
for an Ullmann ether coupling between 8 and 8-iodo-1-
methoxynaphthalene (7) failed, quite likely due to the deac-
tivating effect of the tetralone carbonyl group. Coupling
with ketal 6 was more successful and resulted in a 78%
yield of naphthyl ether 9 which was further converted to
ketone 10. While we failed to demethylate ketal 9 with
NaSEt in DMF or with BBr3, demethylation of ketone 10
using BBr3 smoothly afforded compound 11 in 95% yield.
The presence of a ketone function in 11 was likely to retard
The combination of attractive biological activities and novel
structural features in the spirobisnaphthalene family of
natural products has attracted considerable interest from
the synthetic organic community. In addition to pioneering
total syntheses of palmarumycin CP1 and deoxypreusso-
merin A,12,17±19 innovative approaches toward diepoxin
s,20 preussomerins G and I,21 palmarumycin CP2,18,19
palmarumycin C11,18 and CJ-12,37118,19 have been reported
since 1997.

288
P. Wipf et al. / Tetrahedron 57 (2001) 283±296
Scheme 6.
the subsequent oxidative cyclization which involves a very
electron de®cient transition state. Since the ketone function
in 11 was unreactive to acetalization conditions, the pheno-
lic hydroxyl groups were ®rst acetylated, and ketal 13 was
subsequently saponi®ed to afford the oxidative cyclization
precursor 5 in good overall yield (Scheme 6).
Oxidative cyclization of ketal 5 with Phl(OAc)2 in tri¯uoro-
ethanol afforded bisketal 14 in 75% yield (Scheme 7).
Scheme 7.
Scheme 8.
Scheme 9.

P. Wipf et al. / Tetrahedron 57 (2001) 283±296
289
Scheme 10.
Unfortunately, deprotection of 14 under acidic conditions
led to complex mixtures.
conversion of 16 to palmarumycin CP1, a large excess (more
than 50 equiv.) of MnO2 was required, and a considerable
amount of product remained adsorbed on MnO2 and could
not be recovered. When the reaction was performed in dry
benzene at re¯ux, the amount of MnO2 required for the
complete conversion of 16 was decreased to ,10 equiv.,
but the resulting palmarumycin CP1 was contaminated
with a inseparable byproduct. We therefore resorted to a
two-step protocol. Oxidation of 16 with Dess±Martin peri-
odinane, puri®cation of the intermediate ketone by column
chromatography on SiO2, and treatment with 10 equiv. of
MnO2 in dry methylene chloride for 2 d at room temperature
Diol 11 was quantitatively reduced to triol 15, which was
oxidatively cyclized using Phl(OAc)2 in tri¯uoroethanol to
afford naphthalenediol spiroketal 16 in 87% yield (Scheme
8). Further oxidation of the alcohol function of 16 was
attempted with PCC and BaMnO4 under buffered conditions
but failed to provide the desired ketone in acceptable yields.
In contrast, when 16 was treated with activated MnO2 at
room temperature, a clean conversion to the natural product
palmarumycin CP1 was effected (Scheme 9). For complete
Scheme 11.
Scheme 12.

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P. Wipf et al. / Tetrahedron 57 (2001) 283±296
Scheme 13.
Scheme 14.
Figure 7. Deoxypreussomerin A and diepoxin s analogs.
afford the target molecule in 60% yield. Palmarumycin CP1
was thus obtained in 35% overall yield in 8 steps from the
known tetralone 8.
In contrast, treatment of allylic alcohol 16 with hydrogen
peroxide anion resulted in the isolation of the desired mono-
epoxide 20 in 25% yield (Scheme 12). The relative con®g-
uration of the epoxide and the hydroxyl group was not
In consideration of the close structural similarity between
palmarumycin CP1 and the farnesyl-protein transferase
inhibitor deoxypreussomerin A, an epoxidation reaction of
palmarumycin CP1 was attempted. However, treatment with
hydrogen peroxide anion led to decomposition instead of
epoxidation, and a mild epoxidizing agent, dimethyldioxi-
rane also provided only decomposed products. Even after
protection of the phenol function of palmarumycin CP1
as the TBDMS ether, no synthetically useful epoxidation
could be realized (Scheme 10). Therefore, we had to
resort to earlier, more extensively protected synthetic
intermediates.
Table 1. IC50 values [mM] in 2 cancer cell lines
Compound
MCF-7
MDA-MB-231
21
22
23
24
25
26
27
28
7.6
5.5
13.4
43.4
2.3
3.9
1.1
2
3.6
1.4
13.6
9.2
2.7
4.6
2.5
6.5
2
29
30
4.6
2
2
When compound 14 was treated with excess hydrogen
peroxide anion, monitoring of the reaction progress was
dif®cult due to the overlap of products with the starting
material 14 on TLC. The reaction mixture was thus
31
32
33
34
2
1.5
8
2.8
1.4
7.3
2.7
2
2.4
2.1
6.4
23
2
1
Diepoxin s
Palmarumycin CP1
1.5
0.9
1.3
3.8
4.6
1.3
4.6
2.8
quenched before complete consumption of 14. H NMR
analysis of the crude product showed that mono- and diep-
oxides were formed in a ratio of about 1:1 with ,10%
remaining starting material (Scheme 11). This result demon-
strated that a regioselective epoxidation of the disubstituted
double bond of 14 in the presence of the internal tetrasub-
stituted double bond was unlikely to succeed.
35
36
37
38
39
40
3.4
8.2
2.9

P. Wipf et al. / Tetrahedron 57 (2001) 283±296
291
determined. Peroxides and bases were screened to optimize
3. Conclusions
the epoxidation reaction. When cumene hydroperoxide and
NaH were used at 2208C, the epoxidation yield increased to
47%. The two step oxidation protocol developed for the
synthesis of palmarumycin CP1 converted epoxy alcohol
20 to the desired natural product in 55% yield. (^)-Deoxy-
preussomerin A was thus synthesized in 15% overall yield
and 9 steps from the known 8.
Oxidative cyclization of bis-hydroxynaphthyl ethers with
hypervalent iodine reagents allows a ready access to struc-
turally novel naphthoquinone spiroketal natural products.
We have achieved concise total syntheses of palmarumycin
CP1 and deoxypreussomerin A in 8-9 steps and 15±35%
overall yield from 5-hydroxy-8-methoxy-1-tetralone (8).
Polymer-bound triphenylphosphine was found to be a super-
ior reagent for the rapid preparation of a small library of
palmarumycin analogs. Preliminary biological evaluation of
22 naphthoquinone spiroketals against two human breast
cancer cell lines revealed several potent and selective
growth inhibitors. In view of this favorable pro®le, further
biological studies of this series are continuing.
The successful development of ef®cient synthetic strategies
for the preparation of palmarumycin CP1 and deoxypreus-
somerin A allowed us to prepare analogs and investigate the
biological SAR of this class of compounds in more detail. A
small library of palmarumycin analogs was obtained by
Mitsunobu reaction of the natural product using poly-
styrene-bound triphenylphosphine (Scheme 13). A total of
13 alcohols were used for the coupling reaction, and yields
and ease of puri®cation were greatly improved by the use of
the polymer-bound reagent. In the treatment of palmarumy-
cin CP1 with 2-furyl methanol, the ether product 27 was
accompanied by the C-alkylated phenol 28 (Scheme 14).
All other reactions produced a single isomer. In addition
to these palmarumycin analogs, several diepoxin s
derivatives20,22 were subjected to biological testing
(Fig. 7).
4. Experimental
4.1. General
All moisture-sensitive reactions were performed under an
atmosphere of N2 or Ar and all glassware was dried in an
oven at 1408C prior to use. THF and Et2O were dried by
distillation over Na/benzophenone under a nitrogen atmos-
phere. Dry CH2Cl2 was obtained by distillation from CaH2.
Dry DMF was obtained by distillation from alumina under
reduced pressure. Dry CF3CH2OH was obtained by distil-
lation from CaSO4. Unless otherwise noted, solvents or
reagents were used without further puri®cation. NMR spec-
tra were recorded at either 300 MHz/75 MHz (1H/13C NMR)
or 500 MHz/125 MHz (1H/13C NMR) in CDCl3 unless
stated otherwise.
Two widely used human breast cancer cell lines were evalu-
ated for their sensitivity to the cytotoxic effects of the
naphthoquinone spiroketals. MCF-7 cells were originally
derived from an adenocarcinoma of the breast and retain
several characteristics of differentiated mammary epithe-
lium including the ability to process estradiol via cytoplas-
mic estrogen receptors. MCF-7 cells express the tumor
suppressor gene product p53, which is required for the
programmed cell death or apoptosis caused by many
agents.25 MDA-MB-231 cells, which were also derived
from an adenocarcinoma of the breast, are less differentiated
than the MCF-7 cells and fail to express functional p53 or
estrogen receptors. This class of tumor cells are important
targets for new therapies, because loss of estrogen receptor
expression is associated with poor patient prognosis.26 All
cells were tested for 72 h with six concentrations of
compounds ranging from 0.1 to 30 mM to determine the
concentration required for 50% growth inhibition (IC50).
We extrapolated to determine the IC50 for compounds
with little cytotoxicity at 30 mM, the highest concentration
tested. As indicated in Table 1, 45% of the compounds
(10/22) had an IC50,3 mM in both cell types. Half of the
compounds showed no selectivity to either human tumor
cell type, while 32% of the compounds were more cytotoxic
to MCF-7 compared with MDA-MB-231 cells. This
included 37, which was 5-fold more cytotoxic to MCF-7
cells (IC50 4.6 vs 23 mM). The enhanced sensitivity of
MCF-7 to these compounds may be due to the expression
of p53 in these cells. The assay used in our studies, however,
did not speci®cally measure apoptosis and this could be
examined in the future. Studies to be published elsewhere
indicate that at least one compound, 27, can arrest mamma-
lian cells in the G2/M phase of the cell cycle. The ®ve
fold enhanced sensitivity of MDA-MB-231 cells to 24
compared to MCF-7 cells is of interest, because the MDA-
MB-231 cells lack both functional estrogen receptors and
p53.
4.2. Antiproliferative Assay
The antiproliferative actions of our compounds were
examined using a colorimetric assay described previously27
with two human breast cancer cell lines: the p53 replete,
estrogen-receptor positive MCF-7 and the p53 de®cient,
estrogen-receptor negative MDA-MB-231 cells (American
Type Culture Collection, Manassas, VA). Brie¯y, cells were
seeded (6000/well) in 96-well plates that contained Eagle's
minimum essential medium (MCF-7) or RPMI-1640
medium (MDA-MB-231) and 10% fetal bovine serum and
placed in a humidi®ed 378C incubator maintained at 5%
CO2. Cells were allowed to attach overnight and treated
with vehicle or compounds (0.1±30 mM) for 72 h. The
medium was then replaced with serum free medium contain-
ing 0.1% of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetra-
zolium bromide. Plates were incubated for 3 h in the dark
and the total cell number was calculated by colorimetric
determination at 540 nm of the formazane metabolic
product as previously described.27
4.2.1. 5-Hydroxy-8-methoxy-1,2,3,4-tetrahydronaphtha-
lene-1-spiro-20-dioxolane (6). To a solution of 8 (4.8 g,
25 mmol) and ethylene glycol (3.1 g, 50 mmol) in benzene
(700 mL) was added pyridinium p-toluenesulfonate (PPTs)
(0.3 g). The reaction mixture was heated at re¯ux for 30 h in
a ¯ask equipped with a Dean±Stark apparatus, washed with
5% NaHCO3 solution (2£200 mL) and brine (300 mL), dried
(Na2SO4), and concentrated in vacuo. Chromatography on

292
P. Wipf et al. / Tetrahedron 57 (2001) 283±296
SiO2 (hexanes/EtOAc, 2:1) gave 5.32 g (90%) of 6 as a
solid: mp 139±1408C; IR (heat) 3359, 2928, 1583, 1468,
1327, 1244, 1159, 1118, 1064, 1008, 945, 924, 864, 794,
716 cm21; 1H NMR d 6.55 (d, 1H, Jˆ8.8 Hz), 6.54 (d, 1H,
Jˆ8.8 Hz), 5.42 (s, 1H, OH), 4.25 (t, 2H, Jˆ6.6 Hz), 4.07 (t,
2H, Jˆ6.6 Hz), 3.75 (s, 3H), 2.57 (t, 2H, Jˆ6.0 Hz), 1.93±
1.80 (m, 4H); 13C NMR d 152.6, 146.9, 128.3, 125.8, 115.2,
110.7, 108.1, 65.5, 56.6, 35.9, 24.0, 20.1; MS (EI) m/z (rel
intensity) 236 (M1, 94), 208 (100), 193 (19), 175 (11), 164
(19), 149 (11), 134 (20), 121 (10), 106 (10), 99 (20), 77 (10),
65 (9), 55 (13); HRMS (EI) calcd for C13H16O4 236.1049,
found 236.1052.
2.85 (t, 2H, Jˆ6.0 Hz), 2.70 (t, 2H, Jˆ6.3 Hz), 2.06 (p, 2H,
Jˆ6.4 Hz); 13C NMR d 204.7, 161.1, 155.4, 154.0, 141.8,
137.2, 137.1, 131.1, 128.1, 125.5, 123.1, 119.3, 117.4,
117.1, 114.9, 111.0, 107.4, 38.7, 23.6, 22.1; MS (EI) m/z
(rel intensity) 320 (M1, 100), 287 (6), 263 (10), 247 (7), 177
(9), 159 (25), 144 (38), 131 (29), 115 (34), 103 (15), 89 (10),
77 (23), 65 (14); HRMS (EI) calcd for C20H16O4 320.1049,
found 320.1044.
4.2.4. Acetic acid 8-(40-acetoxy-50-oxo-50,60,70,80-tetra-
hydronaphthalen-10-yloxy)-naphthalen-1-yl ester (12).
To a solution of 11 (487 mg, 1.52 mmol) in acetic anhydride
(2 mL) was added sodium acetate (100 mg). The reaction
mixture was heated to 958C, stirred for 4 h and cooled to
room temperature. The mixture was poured into ice water
(100 g), stirred for 1 h and extracted with ethyl acetate
(100 mL). The ethyl acetate layer was washed with brine
(50 mL), dried (Na2SO4) and concentrated in vacuo.
Chromatography on SiO2 (hexanes/EtOAc, 2:1) gave
607 mg (99%) of 12 as an oil: IR (neat) 3059, 2951, 1765,
1686, 1601, 1573, 1460, 1367, 1258, 1202, 1115, 1025, 898,
4.2.2. 8-Methoxy-5-(80-methoxynaphthalene-10-yloxy)-
3,4-dihydro-2H-naphthalen-1-one (10). To a solution of
6 (4.72 g, 0.02 mol) and 7 (8.52 g, 0.03 mol) in degassed
pyridine (150 mL) were added K2CO3 (2.76 g, 0.02 mol)
and Cu2O (286 mg, 0.002 mol). This reaction mixture was
heated at re¯ux for 12 h under a nitrogen atmosphere. After
addition of additional Cu2O (286 mg, 0.002 mol) to
the solution, heating was continued for 12 h. Pyridine
was removed under reduced pressure and the residue was
redissolved in EtOAc (300 mL). It was washed with water
(100 mL) and brine (100 mL), dried (Na2SO4), and concen-
trated in vacuo. Chromatography on SiO2 (hexanes/EtOAc,
2:1) gave 6.14 g (78%) of 9 as an oil. This oil was treated
with TsOH (100 mg) in a mixture of acetone/water (7:1,
50 mL) for 7 h at room temperature. The reaction mixture
was concentrated in vacuo and the residue was diluted with
EtOAc (300 mL), washed with water (2£100 mL) and brine
(100 mL), dried (Na2SO4), and concentrated in vacuo.
Chromatography on SiO2 (hexanes/EtOAc, 1:1) gave
5.44 g (100%) of 10 as a colorless solid: mp 152±1538C;
IR(neat) 2952, 1696, 1581, 1484, 1387, 1272, 1245, 1183,
1
825, 760, 735 cm21; H NMR d 7.77 (d, 1H, Jˆ7.9 Hz),
7.58 (d, 1H, Jˆ8.0 Hz), 7.50 (t, 1H, Jˆ8.0 Hz), 7.29 (t, 1H,
Jˆ7.7 Hz), 7.18 (t, 1H, Jˆ7.4 Hz), 7.16 (d, 1H, Jˆ 7.6 Hz),
6.97 (d, 1H, Jˆ8.7 Hz), 6.58 (dd, 1H, Jˆ7.7, 0.7 Hz), 2.91
(t, 2H, Jˆ5.7 Hz), 2.62 (t, 2H, Jˆ6.2 Hz), 2.40 (s, 3H), 2.19
(s, 3H), 2.07 (p, 2H, Jˆ6.4 Hz); 13C NMR d 196.3, 170.3,
170.0, 153.1, 150.8, 146.8, 146.0, 138.3, 137.1, 126.6,
126.4, 126.3, 126.2, 125.8, 123.3, 123.1, 120.0, 119.4,
111.8, 40.1, 23.8, 22.0, 21.2, 21.1; MS (EI) m/z (rel inten-
sity) 404 (M1, 23), 362 (30), 320 (100), 202 (10), 149 (21),
115 (12), 91 (33), 69 (18), 57 (28); HRMS (EI) calcd for
C24H20O6 404.1260, found 404.1266.
1
1095, 980, 838, 821, 759 cm21; H NMR d 7.59 (dd, 1H,
4.2.5. 8-Hydroxy-5-(80-hydroxynaphthalene-10-yloxy)-
1,2,3,4-tetrahydronaphthalene-1-spiro-200-dioxolane (5).
To a solution of 12 (240 mg, 0.593 mmol) and ethylene
glycol (1.10 g, 17.79 mmol) in benzene (20 mL) was
added PPTS (75 mg, 0.297 mmol). The reaction mixture
was heated at re¯ux for 62 h in a ¯ask equipped with a
Dean±Stark apparatus, cooled to room temperature, diluted
with benzene (100 mL), washed with 5% NaHCO3 solution
(2£50 mL) and brine (50 mL), dried (Na2SO4), and concen-
trated in vacuo. Chromatography on SiO2 (hexanes/EtOAc,
1:1) gave 205 mg (77%) of 13 as on oil. To a solution of 13
(175 mg, 0.39 mmol) in degassed THF/MeOH (15 mL, 2/1)
was added lithium hydroxide monohydrate (41 mg,
0.98 mmol) at 08C. The reaction mixture was stirred for
2 h in an ice bath, neutralized with saturated ammonium
chloride solution and extracted with ethyl acetate
(2£100 mL). The combined organic layers were washed
with brine (100 mL), dried (Na2SO4), and concentrated in
vacuo. Chromatography on SiO2 (hexanes/EtOAc, 2:1) gave
137 mg (96%) of 5 as a solid: mp 174±1758C; IR (neat)
3405, 3318, 3057, 2959, 2904, 1608, 1581, 1469, 1402,
1365, 1301, 1253, 1220, 1182, 1157, 1121, 1035, 944,
Jˆ8.2, 0.8 Hz), 7.45 (dd, 1H, Jˆ8.2, 1.0 Hz), 7.37 (q, 2H,
Jˆ7.9 Hz), 6.87 (dd, 1H, Jˆ7.6, 0.8 Hz), 6.81 (dd, 1H,
Jˆ7.6, 0.8 Hz), 6.72 (d, 1H, Jˆ8.9 Hz), 6.67 (d, 1H,
Jˆ9.1 Hz), 3.84 (s, 3H), 3.74 (s, 3H), 3.05 (t, 2H,
Jˆ6.2 Hz), 2.67 (t, 2H, Jˆ6.3 Hz), 2.11 (p, 2H,
Jˆ6.4 Hz); 13C NMR d 197.9, 156.2, 155.4, 152.7, 149.3,
137.6, 136.4, 126.7, 126.4, 124.1, 123.1, 121.7, 120.7,
118.8, 115.9, 110.1, 106.1, 56.3, 56.0, 40.9, 24.1, 22.5;
MS (EI) m/z (rel intensity) 348 (M1, 100), 319 (7), 305
(10), 291 (14), 261 (8), 218 (7), 189 (12), 174 (24) 158
(45), 127 (34), 115 (29), 101 (10), 77 (15), 63 (8); HRMS
(EI) calcd for C22H20O4 348.1361, found 348.1361.
4.2.3.
8-Hydroxy-5-(80-hydroxynaphthalen-10-yloxy)-
3,4-dihydro-2H-naphthalen-1-one (11). To a solution of
10 (3.92 g, 11.3 mmol) in CH2Cl2 (120 mL) was added a
1 M solution of BBr3 in CH2Cl2 (40 mL, 40 mmol) at
2788C. The reaction mixture was warmed to room tempera-
ture, stirred for 12 h, poured into ice water (200 g) and
extracted with CH2Cl2 (2£300 mL). The combined organic
layers were washed with brine (200 mL), dried (Na2SO4)
and concentrated in vacuo. Chromatography on SiO2
(hexanes/EtOAc, 8:1) gave 3.44 g (95%) of 11 as a colorless
solid: mp 165±1668C; IR (neat) 3403, 2947, 1624, 1449,
1
928, 878, 818, 759 cm21; H NMR d 9.18 (s, 1H, OH),
8.13 (s, 1H, OH), 7.46±7.34 (m, 3H), 7.17 (t, 1H,
Jˆ8.0 Hz), 7.10 (d, 1H, Jˆ8.8 Hz), 6.96 (dd, 1H, Jˆ7.2,
1.1 Hz), 6.85 (d, 1H, Jˆ8.8 Hz), 6.45 (d, 1H, Jˆ7.6 Hz),
4.34±4.17 (m, 4H), 2.68 (t, 2H, Jˆ6.3 Hz), 1.99±1.95
(m, 2H), 1.91±1.83 (m, 2H); 13C NMR d 155.5, 154.8,
154.2, 143.3, 137.0, 133.5, 127.8, 125.7, 124.4, 122.6,
1
1387, 1343, 1289, 1213, 1167, 1024, 808, 749 cm21; H
NMR d 12.46 (s, 1H, OH), 9.02 (s, 1H, OH), 7.50±7.32
(m, 4H), 7.18 (t, 1H, Jˆ8.0 Hz), 6.98 (dd, 1H, Jˆ7.2,
1.1 Hz), 6.93 (d, 1H, Jˆ8.9 Hz), 6.40 (d, 1H, Jˆ7.7 Hz),

P. Wipf et al. / Tetrahedron 57 (2001) 283±296
293
120.6, 119.1, 116.1, 114.9, 110.6, 109.8, 107.3, 63.9, 31.3,
23.5, 19.2; MS (EI) m/z (rel intensity) 364 (M1, 100), 320
(55), 159 (11), 144 (24), 131 (14), 115 (22), 77 (7), 55 (8);
HRMS (EI) calcd for C22H20O5 364.1311, found 364.1311.
4.2.8. 8-Hydroxy-1-oxo-1,4-dihydronaphthalene-4-spiro-
20-naphtho[100,800-de][10,30]dioxin (palmarumycin CP1).
To a solution of 16 (32 mg, 0.1 mmol) in CH2Cl2 (5 mL)
was added Dess±Martin periodinane (64 mg, 0.15 mmol) at
room temperature. The reaction mixture was stirred for 2 h
and diluted with EtOAc (30 mL). It was washed with 5%
NaHCO3 solution (10 mL) and brine (15 mL), dried
(Na2SO4), and concentrated in vacuo. Chromatography on
SiO2 (hexanes/EtOAc, 2:1) gave 32 mg of a yellow residue
which was treated with MnO2 (Aldrich, 85% activated,
102 mg, 1 mmol, dried over P2O5 just before use) in dry
CH2Cl2 (5 mL) for 2 d at room temperature. The reaction
mixture was ®ltered through celite and washed with CH2Cl2
(10 mL). The combined solutions were concentrated in
vacuo. Chromatography on SiO2 (hexanes/EtOAc, 4:1)
gave 19 mg (60%) of palmarumycin CP1 as a yellow
solid: mp 1708C (dec.); IR (neat) 3053, 1659, 1602, 1449,
1409, 1372, 1341, 1269, 1237, 1110, 1073, 942, 822,
4.2.6. 1-Oxo-1,4,5,6,7,8,-hexahydronaphthalene-4-spiro-
20-naphtho[100,800-de][10,30]dioxin-8-spiro-20 00-dioxolane
(14). To a suspension of 5 (58 mg, 0.159 mmol) in tri¯uoro-
ethanol (20 mL) was added Phl(OAc)2 (62 mg,
0.191 mmol). The reaction mixture was stirred for 2 h at
room temperature and NaHCO3 (32 mg, 0.382 mmol) was
added. The resulting mixture was concentrated in vacuo and
the residue was diluted with EtOAc (50 mL), washed with
water (30 mL) and brine (30 mL), dried (Na2SO4), and
concentrated in vacuo. Chromatography on SiO2 (hexanes/
EtOAc, 4:1) gave 43 mg (75%) of 14 as an oily solid: IR
(neat) 3059, 2949, 2897, 1680, 1651, 1608, 1584, 1412,
1396, 1302, 1271, 1144, 1096, 1052, 1031, 949, 825, 814,
757 cm21; 1H NMR d 7.52 (d, 2H, Jˆ8.1 Hz), 7.43 (t, 2H,
Jˆ7.9 Hz), 6.93 (d, 2H, Jˆ7.1 Hz), 6.76 (d, 1H, Jˆ
10.3 Hz), 6.08 (d, 1H, Jˆ10.4 Hz), 4.41±4.36 (m, 2H),
4.08±4.04 (m, 2H), 2.75±2.65 (m, 2H), 1.95±1.85 (m,
4H); 13C NMR d 182.4, 154.1, 146.8, 136.4, 134.1, 134.0,
130.6, 127.6, 121.2, 112.9, 109.7, 105.9, 92.8, 66.1, 35.6,
24.5, 19.5; MS (EI) m/z (rel intensity) 362 (M1, 100), 319
(39), 306 (16), 262 (15), 234 (9), 204 (10), 178 (16), 131
(13), 115 (17), 99 (13), 84 (22), 55 (13); HRMS (EI) calcd
for C22H18O5 362.1154, found 362.1160.
1
746 cm21; H NMR d 12.17 (s, 1H, OH), 7.67 (t, 1H,
Jˆ8.0 Hz), 7.58 (d, 2H, Jˆ8.5 Hz), 7.47 (t, 2H, Jˆ
7.9 Hz), 7.46 (d, 1H, Jˆ7.8 Hz), 7.14 (dd, 1H, Jˆ8.2,
1.1 Hz), 7.02 (d, 1H, Jˆ10.9 Hz), 6.98 (d, 2H, Jˆ7.7 Hz),
6.37 (d, 1H, Jˆ10.9 Hz); 13C NMR d 188.8, 161.9, 147.2,
139.7, 138.8, 136.7, 134.2, 129.8, 127.7, 121.4, 119.7,
119.4, 113.8, 113.0, 109.9, 92.9; MS (EI) m/z (rel intensity)
316 (M1, 100), 288 (12), 287 (19), 259 (8), 175 (11), 114
(45), 88 (11), 63 (9); HRMS (EI) calcd for C20H12O4
316.0736, found 316.0730.
4.2.7. (^)-8-Hydroxy-1-oxo-1,4,5,6,7,8-hexahydronaph-
thalene-4-spiro-20-naphtho[100,800-de][10,30]dioxin (16).
To a solution of 11 (1.51 g, 4.72 mmol) in Et2O (70 mL)
was added in portions solid LiAlH4 (358 mg, 9.44 mmol) at
08C. The solution was stirred for 2 h at 08C, warmed to room
temperature and stirred for an additional 2 h. The reaction
mixture was carefully quenched with 5% sodium bisulfate
solution in an ice bath. After adding 40 mL of 5% sodium
bisulfate solution, the product was extracted with Et2O
(2£150 mL). The combined ether layers washed with
brine (100 mL), dried (Na2SO4) and concentrated in
vacuo. The resulting solid was added to dry tri¯uoroethanol
(150 mL) and stirred until a ®ne suspension was obtained.
After addition of PhI(OAc)2 (1.67 g, 5.19 mmol), the
mixture was stirred for 30 min at room temperature,
NaHCO3 (1.0 g, 12 mmol) was added. The solution was
concentrated in vacuo and the resulting residue was diluted
with EtOAc (300 mL), washed with water (100 mL) and
brine (100 mL), dried (Na2SO4), and concentrated in
vacuo. Chromatography on SiO2 (hexanes/EtOAc, 2:1)
gave 1.32 g (87%) of 16 as a yellow solid: mp 199±
2008C; IR (neat) 3434, 2945, 1673, 1642, 1630, 1600,
4.2.9. (^)-2,3-Epoxy-8-hydroxy-1-oxo-1,2,3,4-tetrahydro-
naphthalene-4-spiro-20-naphtho[100,800-de][10,30]dioxin
[(^)-deoxypreussomerin A]. To a solution of 16 (54.5 mg,
0.17 mmol) in THF (5 mL) was added cumene hydro-
peroxide (157 mL, 0.85 mmol) and NaH (60%, 6.5 mg,
0.17 mmol) at 2208C. The reaction mixture was stirred
for 4 h at 2208C, and diluted with EtOAc (40 mL) and
brine (5 mL). The separated organic layer was washed
with an additional brine(20 mL), dried(Na2SO4), and
concentrated in vacuo. Chromatography on SiO2 (hexanes/
EtOAc, 3:1) gave 27 mg (47%) of monoepoxide 20. To a
solution of this epoxide in CH2Cl2 (4 mL) was added Dess±
Martin periodinane (51 mg, 0.12 mmol) at room tempera-
ture. The reaction mixture was stirred for 2 h, diluted with
EtOAc (30 mL), washed with 5% NaHCO3 solution
(10 mL) and brine (15 mL), dried (Na2SO4), and concen-
trated in vacuo. Chromatography on SiO2 (hexanes/
EtOAc, 2:1) gave 27 mg of a yellow residue which was
treated with MnO2 (Aldrich, 85% activated, 82 mg,
0.8 mmol, dried over P2O5 just before use) in dry CH2Cl2
(5 mL) for 37 h at room temperature. The mixture was
®ltered through celite and washed with CH2Cl2 (10 mL).
The combined solutions were concentrated in vacuo.
Chromatography on SiO2 (hexanes/EtOAc, 3:1) gave
14.5 mg (26% from 16) of (^)-deoxypreussomerin A as a
colorless solid: mp 200±2018C; IR (neat) 3050, 1651, 1605,
1455, 1409, 1380, 1330, 1266, 1239, 1173, 1110, 1061, 963,
920, 878, 820, 809, 759, 720 cm21; 1H NMR d 11.37 (s, 1H,
OH), 7.65 (t, 1H, Jˆ8.0 Hz), 7.60 (d, 1H, Jˆ8.6 Hz), 7.57
(d, 1H, Jˆ8.0 Hz), 7.53 (t, 1H, Jˆ8.3 Hz), 7.45 (t, 1H,
Jˆ7.4 Hz), 7.44 (d, 1H, Jˆ7.9 Hz), 7.19 (dd, 1H, Jˆ7.6,
0.8 Hz), 7.14 (dd, 1H, Jˆ8.6, 0.8 Hz), 6.92 (dd, 1H, Jˆ7.6,
0.7 Hz), 4.09 (d, 1H, Jˆ4.1 Hz), 3.68 (d, 1H, Jˆ3.9 Hz);
13C NMR d 196.6, 161.9, 146.9, 146.7, 137.8, 136.9, 134.2,
1
1409, 1374, 1263, 1080, 944, 757 cm21; H NMR d 7.54
(d, 2H, Jˆ8.0 Hz), 7.45 (td, 2H, Jˆ7.4, 2.2 Hz), 6.95 (td,
2H, Jˆ7.6, 0.7 Hz), 6.90 (d, 1H, Jˆ10.4 Hz), 6.19 (d, 1H,
Jˆ10.4 Hz), 4.82 (t, 1H, Jˆ4.9 Hz), 3.31 (bs, 1H, OH),
2.78±2.51 (m, 2H), 1.98±1.90 (m, 3H), 1.82±1.72
(m, 1H); 13C NMR d 185.8, 151.6, 146.8, 139.3, 135.6,
134.1, 129.1, 127.7, 127.6, 121.3, 112.9, 109.8, 109.7,
92.6, 62.7, 29.6, 24.2, 17.7; MS (EI) m/z (rel intensity)
320 (M1, 100), 304 (30), 265 (35), 247 (21), 235 (10),
219 (11), 197 (18), 169 (24), 160 (32), 144 (35), 133 (35),
115 (50), 103 (16), 88 (13), 77 (28), 63 (17); HRMS (EI)
calcd for C20H16O4 320.1049, found 320.1039.

294
P. Wipf et al. / Tetrahedron 57 (2001) 283±296
127.9, 127.7, 121.5, 121.4, 120.1, 119.1, 112.8, 112.3,
110.2, 109.4, 96.0, 53.3; MS (EI) m/z (rel intensity) 332
(M1, 100), 316 (28), 303 (11), 287 (19), 173 (15), 145
(23), 132 (12), 114 (27), 89 (13), 74 (14), 63 (12), 57 (7);
HRMS(EI) calcd for C20H12O5 332.0685, found 332.0688.
dry CH2Cl2 (0.1 mL) provided after 67 h 1.3 mg (43%) of
1
24 as a colorless oil: H NMR d 7.68 (t, 1H, Jˆ8.3 Hz),
7.60±7.45 (m, 5H), 7.16 (d, 1H, Jˆ8.4 Hz), 6.97 (d, 2H,
Jˆ7.5 Hz), 6.85 (d, 1H, Jˆ10.5 Hz), 6.28 (d, 1H, Jˆ
10.4 Hz), 5.66±5.60 (m, 1H), 5.45±5.30 (m, 1H), 4.15 (t,
2H, Jˆ6.9 Hz), 2.7±2.6 (m, 2H), 2.4±2.3 (m, 2H), 1.00 (t,
3H, Jˆ6.4 Hz).
4.3. General procedure for Mitsunobu reactions
4.3.5. 8-(3-Methoxy-benzyloxy)-1-oxo-1,4-dihydronaph-
thalene-4-spiro-20-naphtho[100,800-de][10,30]dioxin (25).
According to the general procedure, palmarumycin CP1
(2.0 mg, 0.006 mmol), diphenylphosphino-polystyrene
(22.8 mg, 1.41 mmol/g, 0.032 mmol), 3-methoxybenzyl
alcohol (4.0 mL, 0.032 mmol) and DEAD (5.0 mL,
0.032 mmol) in dry CH2Cl2 (0.1 mL) provided after 45 h
4.3.1. (E)-8-(3-Phenyl-allyloxy)-1-oxo-1,4-dihydronaph-
thalene-4-spiro-20-naphtho[100,800-de][10,30]dioxin (21).
A solution of palmarumycin CP1 (7.4 mg, 0.023 mmol),
diphenylphosphino-polystyrene (82.1 mg, 1.41 mmol/g,
0.116 mmol) and cinnamyl alcohol (15.5 mL, 0.118 mmol)
in dry CH2Cl2 (0.4 mL) was stirred for 30 min at room
temperature and cooled to 08C. Diethyl azodicarboxylate
(DEAD) (18.0 mL, 0.114 mmol) was added to the reaction
mixture at 08C and stirring was continued for 24 h at room
temperature. The reaction mixture was washed with 5%
aqueous KOH solution (0.5 mL), followed by 5% HCl
(0.5 mL). The methylene chloride extract was ®ltered, the
resin was washed further with CH2Cl2 (2£0.5 mL) and the
solvent was concentrated. Chromatography on SiO2
(hexanes/EtOAc, 9:1) gave 1.8 mg (24%) of palmarumycin
1
1.6 mg (67%) of 25 as a colorless oil: H NMR d 7.68±
7.54 (m, 4H), 7.45 (t, 2H, Jˆ7.7 Hz), 7.24±7.10 (m, 4H),
6.97 (d, 2H, Jˆ7.5 Hz), 6.9±6.8 (m, 2H), 6.30 (d, 1H,
Jˆ10.4 Hz), 5.29 (s, 2H), 3.86 (s, 3H).
4.3.6. 8-(2-Phenyl-ethoxy)-1-oxo-1,4-dihydronaphthalene-
4-spiro-20-naphtho[100,800-de][10,30]dioxin (26). According
to the general procedure, palmarumycin CP1 (2.0 mg,
0.006 mmol), diphenylphosphino-polystyrene (23.4 mg,
1.41 mmol/g, 0.033 mmol), phenethyl alcohol (3.8 mL,
0.032 mmol) and DEAD (5.0 mL, 0.032 mmol) in dry
CH2Cl2 (0.2 mL) provided after 24 h 1.0 mg (33%) of
26 as a colorless oil: 1H NMR d 7.67±7.1 (m, 12H),
6.98 (d, 2H, Jˆ7.5 Hz), 6.86 (d, 1H, Jˆ10.5 Hz), 6.30
(d, 1H, Jˆ 10.6 Hz), 4.33 (t, 2H, Jˆ7.0 Hz), 3.27 (t,
2H, Jˆ7.0 Hz).
1
CP1 and 5.0 mg (52%) of 21 as a colorless oil: H NMR d
7.70 (t, 1H, Jˆ8.0 Hz), 7.60±7.56 (m, 3H), 7.50±7.45 (m,
4H), 7.37±7.20 (m, 4H), 6.99 (d, 2H, Jˆ7.3 Hz), 6.93 (bs,
1H), 6.87 (d, 1H, Jˆ10.5 Hz), 6.49 (dt, 1H, Jˆ5.2, 16.0 Hz),
6.31 (d, 1H, Jˆ10.5 Hz), 4.93 (d, 2H, Jˆ5.2 Hz);
HRMS(EI) calcd for C29H20O4 432.1362, found 432.1362.
4.3.2. (E)-8-(But-2-enyloxy)-1-oxo-1,4-dihydronaphtha-
lene-4-spiro-20-natphtho[100,800-de][10,30]dioxin
(22).
4.3.7. 8-(Furan-2-ylmethoxy)-1-oxo-1,4-dihydronaphtha-
lene-4-spiro-20-naphtho[100,800-de][10,30]dioxin (27) and
7-(furan-2-ylmethyl)-8-hydroxy-1-oxo-1,4-dihydronaph-
thalene-4-spiro-20-naphtho[100,800-de][10,30]dioxin (28).
According to the general procedure, palmarumycin CP1
(2.1 mg, 0.007 mmol), diphenylphosphino-polystyrene
(22.5 mg, 1.41 mmol/g, 0.032 mmol), furfuryl alcohol
(2.8 mL, 0.032 mmol) and DEAD (5.0 mL, 0.032 mmol) in
dry CH2Cl2 (0.2 mL) provided after 5 d 2.0 mg (71%) of 27
According to the general procedure, palmarumycin CP1
(2.4 mg, 0.008 mmol), diphenylphosphino-polystyrene
(28.2 mg, 1.41 mmol/g, 0.040 mmol), 2-buten-1-ol
(3.3 mL, 0.038 mmol) and DEAD (6.0 mL, 0.038 mmol) in
dry CH2Cl2 (0.2 mL) provided after 24 h 2.5 mg (88%) of
1
22 as a colorless oil: H NMR d 7.68 (t, 1H, Jˆ8.0 Hz),
7.60±7.55 (m, 3H), 7.49 (d, 1H, Jˆ7.7 Hz), 7.46 (d, 1H,
Jˆ8.2 Hz), 7.17 (d, 1H, Jˆ8.6 Hz), 6.98 (d, 2H, Jˆ7.4 Hz),
6.85 (d, 1H, Jˆ10.5 Hz), 6.29 (d, 1H, Jˆ10.5 Hz), 6.03 (dq,
1H, Jˆ15.3, 6.5 Hz), 5.85±5.75 (m, 1H), 4.69 (d, 2H,
Jˆ5.4 Hz), 1.80 (d, 3H, Jˆ6.2 Hz); HRMS(EI) calcd for
C24H18O4 370.1205, found 370.1214.
1
and 1.0 mg (29%) of 28 as colorless oils. 27: H NMR d
7.70±7.45 (m, 6H), 7.29±7.26 (m, 2H), 7.05±6.95 (m, 2H),
6.86 (d, 1H, Jˆ10.5 Hz), 6.55 (bs, 1H), 6.41 (bs, 1H), 6.28
1
(d, 1H, Jˆ10.5 Hz), 5.23 (s, 2H). 28: H NMR d 12.67
(s, 1H), 7.61 (d, 2H, Jˆ8.2 Hz), 7.62±7.44 (m, 4H), 7.11
(d, 1H, Jˆ8.8 Hz), 7.00±6.92 (m, 3H), 6.35 (d, 1H, Jˆ
10.4 Hz), 6.26 (t, 1H, Jˆ2.4 Hz), 5.91 (d, 1H, Jˆ3.2 Hz),
4.26 (s, 2H).
4.3.3. 8-Hexyloxy-1-oxo-1,4-dihydronaphthalene-4-spiro-
20-naphtho[100,800-de][10,30]dioxin (23). According to the
general procedure, palmarumycin CP1 (2.0 mg, 0.006
mmol), diphenylphosphino-polystyrene (31.3 mg, 1.41 mmol/
g, 0.044 mmol), hexyl alcohol (4.0 mL, 0.031 mmol) and
DEAD (5.0 mL, 0.032 mmol) in dry CH2Cl2 (0.1 mL)
provided after 43 h 1.3 mg (50%) of 23 as a colorless oil:
1H NMR d 7.66 (t, 1H, Jˆ8.3 Hz), 7.57±7.50 (m, 3H),
7.48±7.42 (m, 2H), 7.14 (d, 1H, Jˆ8.3 Hz), 6.96 (d, 2H,
Jˆ7.5 Hz), 6.82 (d, 1H, Jˆ10.4 Hz), 6.26 (d, 1H, Jˆ
10.4 Hz), 4.10 (t, 2H, Jˆ5.9 Hz), 2.30±1.20 (m, 11H).
4.3.8. (E,E)-8-(3,7-Dimethyl-octa-2,6-dienyloxy)-1-oxo-
1,4-dihydronaphthalene-4-spiro-20-naphtho[100,800-de]-
[10,30]dioxin (29). According to the general procedure,
palmarumycin CP1 (2.0 mg, 0.006 mmol), diphenylphos-
phino-polystyrene (23.1 mg, 1.41 mmol/g, 0.033 mmol),
geraniol (5.6 mL, 0.032 mmol) and DEAD (5.0 mL,
0.032 mmol) in dry CH2Cl2 (0.2 mL) provided after 29 h
1
2.1 mg (83%) of 29 as a colorless oil: H NMR d 7.67 (t,
4.3.4. (E)-8-(Hex-3-enyloxy)-1-oxo-1,4-dihydronaphtha-
lene-4-spiro-20-naphtho[100,800-de][10,30]dioxin
1H, Jˆ8.2 Hz), 7.59±7.55 (m, 3H), 7.50±7.44 (m, 2H), 7.16
(d, 1H, Jˆ8.2 Hz), 6.98 (d, 2H, Jˆ7.4 Hz), 6.85 (d, 1H,
Jˆ10.5 Hz), 6.28 (d, 1H, Jˆ10.5 Hz), 5.56 (t, 1H,
Jˆ6.0 Hz), 5.10 (bs, 1H), 4.79 (d, 2H, Jˆ6.2 Hz), 2.11
(bs, 4H), 1.78 (s, 3H), 1.69 (s, 3H), 1.62 (s, 3H).
(24).
According to the general procedure, palmarumycin CP1
(2.1 mg, 0.007 mmol), diphenylphosphino-polystyrene
(23.9 mg, 1.41 mmol/g, 0.034 mmol), trans-3-hexen-1-ol
(4.2 mL, 0.034 mmol) and DEAD (5.2 mL, 0.033 mmol) in

P. Wipf et al. / Tetrahedron 57 (2001) 283±296
295
4.3.9. 8-(Furan-3-ylmethoxy)-1-oxo-1,4-dihydronaph-
thalene-4-spiro-20-naphtho[100,800-de][10,30]dioxin (30).
According to the general procedure, palmarumycin CP1
(2.0 mg, 0.006 mmol), diphenylphosphino-polystyrene
(23.4 mg, 1.41 mmol/g, 0.033 mmol), 3-furanmethanol
(2.8 mL, 0.032 mmol) and DEAD (5.0 mL, 0.032 mmol) in
dry CH2Cl2 (0.2 mL) provided after 3 d 1.2 mg (50%) of 30
as a colorless oil: 1H NMR d 7.63±7.45 (m, 5H), 7.42±7.35
(m, 3H), 7.16 (d, 1H, Jˆ8.2 Hz), 6.89 (d, 2H, Jˆ7.4 Hz),
6.77 (dd, 1H, Jˆ10.5, 1.3 Hz), 6.51 (bs, 1H), 6.20 (dd, 1H,
Jˆ10.5, 1.3 Hz), 5.08 (s, 2H); HRMS(EI) calcd for
C25H16O5 396.0998, found 396.0997.
Jˆ8.3 Hz), 6.98 (d, 2H, Jˆ7.0 Hz), 6.86 (d, 1H, Jˆ10.5 Hz),
6.29 (d, 1H, Jˆ10.7 Hz), 6.20±6.06 (m, 1H), 5.68 (dd, 1H,
Jˆ17.2, 1.5 Hz), 5.38 (dd, 1H, Jˆ10.8, 1.5 Hz), 4.77±4.74
(m, 2H); HRMS(EI) calcd for C23H16O4 356.1049, found
356.1064.
Acknowledgements
This work was supported in part by grants from the National
Science Foundation, the National Institutes of Health (CA
78039), Merck & Co. and the Fiske Drug Discovery Fund.
Polymer-supported triphenylphosphine was a gift from
Argonaut Technologies, Inc. We gratefully acknowledge
use of the resources of the Combinatorial Chemistry Center
(CCC) at the University of Pittsburgh and the technical
assistance of Ms Angela Wang. S. R. thanks the Camille
4.3.10. 8-(Pyridin-2-ylmethoxy)-1-oxo-1,4-dihydronaph-
thalene-4-spiro-20-naphtho[100,800-de][10,30]dioxin (31).
According to the general procedure, palmarumycin CP1
(2.2 mg, 0.007 mmol), diphenylphosphino-polystyrene
(29.7 mg, 1.41 mmol/g, 0.042 mmol), 2-pyridylcarbinol
(3.4 mL, 0.035 mmol) and DEAD (5.5 mL, 0.035 mmol) in
dry CH2Cl2 (0.2 mL) provided after 4 d 0.2 mg (9%) of
palmarumycin CP1 and 1.2 mg (43%) of 31 as a colourless
Á
Dreyfus Foundation and the Universitat Autonoma de
Barcelona for support.
1
oil: H NMR d 8.50 (bs, 1H), 8.16 (bs, 1H), 7.88 (bs, 1H),
7.77±7.50 (m, 4H), 7.51±7.45 (m, 3H), 7.4±7.3 (m, 1H);
6.99 (d, 2H, Jˆ7.7 Hz), 6.92 (bd, 1H, Jˆ10.5 Hz), 6.33
(d, 1H, Jˆ10.5 Hz), 5.42 (bs, 2H); HRMS(EI) calcd for
C26H17NO4 407.1158, found 407.1139.
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oil: H NMR d 8.8±8.5 (m, 2H), 8.29 (d, 1H, Jˆ7.9 Hz),
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