Natural product based inhibitors of the thioredoxin-thioredoxin reductase system

Article abstract of DOI:10.1039/b402431a

Spiroketal naphthodecalins are readily assembled by Barton's base mediated Ullmann binaphthyl ether coupling, Dakin reactions and hypervalent iodine spirocyclization. The core structures can be further diversified by enone addition and Stille coupling reactions. Nanomolar inhibitors for the Trx/TrxR redox control system were prepared by this approach and compared to series of natural product isolates. Cytotoxicity in MCF-7 cell assays ranged from an IC₅₀ of 1.6 to > 100 μM.

Full text of DOI:10.1039/b402431a

View Article Online / Journal Homepage / Table of Contents for this issue
Natural product based inhibitors of the thioredoxin–thioredoxin
reductase system†
Peter Wipf,*a Stephen M. Lynch,a Anne Birmingham,b Giselle Tamayo,c,d Allan Jiménez,c
Nefertiti Camposc and Garth Powisb
a Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
E-mail: pwipf@pitt.edu; Fax: ϩ1-412-624-0787; Tel: ϩ1-412-624-8606
b Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson,
AZ 85724, USA
c Instituto Nacional de Biodiversidad (INBio), Apdo. Postal 22-3100,
Santo Domingo de Heredia, Costa Rica, América Central
d Escuela de Química, Universidad de Costa Rica, 2060 San José, Costa Rica,
América Central
Received 18th February 2004, Accepted 25th March 2004
First published as an Advance Article on the web 11th May 2004
Spiroketal naphthodecalins are readily assembled by Barton’s base mediated Ullmann binaphthyl ether coupling,
Dakin reactions and hypervalent iodine spirocyclization. The core structures can be further diversified by enone
addition and Stille coupling reactions. Nanomolar inhibitors for the Trx/TrxR redox control system were prepared
by this approach and compared to series of natural product isolates. Cytotoxicity in MCF-7 cell assays ranged
from an IC50 of 1.6 to >100 µM.
highly significant correlations between increased Trx levels,
Introduction
tumor proliferation and inhibited apoptosis.4,5 Recent
reports indicate that increased Trx expression is an independent
prognostic factor for decreased patient survival in patients with
colon cancer and non small cell lung cancer.6,7 Redox activity is
essential for the biological effects of Trx.8 Mechanisms by
which Trx-1 produces its effects (Fig. 1) include increased levels
of the hypoxia inducible factor-1α transcription factor subunit
that mediates the growing tumor’s response to hypoxia and its
constant need for increased oxygen and nutrient supply through
increased angiogenesis;9 decreased binding of the NF-E2-
related factor 2 and polyamine modulated factor-1 (Nrf-2/
PMF-1) transcription factor leading to decreased expression of
spermidine/spermine N 1-acetyltransferase (SSAT), a regulator
of polyamine induced apoptosis;10 and inhibition of the tumor
suppressor protein PTEN, a phosphatidylinositol (PtdIns)-3-
phosphatase that attenuates the activity of the PtdIns-3-kinase/
Natural products continue to provide structurally complex but
highly original lead structures for drug discovery programs.1 We
have recently discovered that the naphthoquinone spiroketal
pharmacophore of the palmarumycin family of fungal
metabolites produces potent inhibitors of the thioredoxin–
thioredoxin reductase cellular redox system.2,3 Thioredoxin
(Trx) is the major cellular protein disulfide reductase in a broad
range of organisms, including humans. Trx itself is reduced
by electrons originating from NADPH via the enzymatic assist-
ance of thioredoxin reductase (TrxR). Trx protein levels are
significantly elevated in several human primary cancers with
† Electronic supplementary information (ESI) available: experimental
procedures for S1–S10. Copies of 1H and 13C NMR spectra for all new
compounds. See http://www.rsc.org/suppdata/ob/b4/b402431a/
Fig. 1 Some mechanisms by which Trx stimulates tumor growth. Trx is reduced by thioredoxin reductase (TrxR). Reduced Trx is a cofactor for
thioredoxin peroxidases and ribonucleotide reductase; it increases the HIF-1 transcription factor, thus increasing tumor angiogenesis. It also
decreases the DNA binding of the Nrf-2/PMF-1 transcription factor leading to decreased levels of apoptosis and inducing acetylated polyamines;
and it binds and inhibits PTEN, thus de-repressing the Akt cell survival signaling pathway.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 5 1 – 1 6 5 8
1651

View Article Online
Fig. 2 Chemotherapeutic inhibitors of the Trx/TrxR system.
Akt (protein kinase B) cell survival signaling pathway.11 Trx
Results and discussion
is also implicated in defence against damage caused by H2O2-
based oxidative stress acting through thioredoxin peroxidases,
members of the peroxiredoxin family that use Trx as a source of
reducing equivalents to scavenge H2O2.12
Synthesis
Previous work in our laboratories had identified a rapid
synthetic access toward palmarumycin analogs such as S1.18
Interestingly, although this compound lacks the hydroxyl
substituent on one of the arenes, it was found to be a
moderately potent inhibitor of Trx-1/TrxR. In order to further
investigate the pharmacology of this new structural motif, we
envisioned introducing structural diversity into the S1 scaffold
at several key sites in close proximity to the naphthoquinone
spiroketal. α-Substitution at the ketone was achieved in 97%
yield by a bromination/elimination sequence using PhMe3NBr3
and Et3N (Scheme 1). The bromide S2 was further functional-
ized through a palladium-mediated coupling with organo-
stannanes to afford the heteroaryl derivatives S3 and S4 in good
yield. In order to introduce enone β-functionalization, a 3 step
protocol was devised. Methylaluminium bis(2,6-di-tert-butyl-
4-methylphenoxide) (MAD) promoted Michael addition of
phenyllithium into the naphthoquinone monoketal was con-
ducted according to the procedure of Swenton.19 The resulting
diastereomeric mixture of products was reoxidized in a
bromination/dehydrohalogenation sequence using PhMe3NBr3
and Li2CO3 and resulted in the formation of S5 in good yield.
The carbonyl group of S1 was also converted to either the
oxime (S7) or the oxime ether (S6) by treatment with hydroxyl-
amine or methoxylamine, respectively, in pyridine at ambient
temperature. Repeated attempts to obtain the hydrazone from
S1 under a variety of conditions resulted exclusively in conju-
gate addition to afford the hydrazine S8 as the sole product.
The more highly oxygenated S9 was synthesized analogous
to S1 as outlined in Scheme 2. The known benzyl bromide 120
was substituted by allylmagnesium Grignard reagent to afford
an intermediate butene which was subjected to hydroboration/
oxidation, followed by Jones oxidation to give the acid 2 in
55% yield for the 3 step sequence. The acid underwent cationic
ring closure in the presence of PPA to afford the substituted
tetralone which was oxidized in good yield to the naphthol
3 through a bromination/dehydrohalogenation protocol. The
bromonaphthol was protected as its MOM ether and then
converted to the fluoronaphthaldehyde 4 by treatment with
t-BuLi and quenching with DMF. This key intermediate
4 underwent nucleophilic aromatic substitution (SNAr) by
5-hydroxy-1-methoxynaphthalenecarboxaldehyde21 in the
presence of Barton’s base18 to afford the dinaphthyl ether 5a
in 71% yield. Exposure of the bis-formylated 5a to excess
m-CPBA followed by NaBH4-mediated reduction of the
resulting bisformate ester gave an electron-rich bisnaphthol
which smoothly participated in the intramolecular oxidative
spirocyclization22 initiated by PhI(OCOCF3)2 to provide the
palmarumycin analogue S9 in 74% yield. Apparently, the
slightly acidic environment in the spirocyclization step resulted
in the concomitant loss of the MOM ether. An additional
derivative (S10) bearing a benzyl ether in place of the methyl
ether was prepared from fluoronaphthaldehyde 4 via dinaphthyl
ether 5b using analogous methodology.
The Trx/TrxR system is of medicinal interest due to its
inherent role as a broad based indicator of diseases such as
AIDS, rheumatoid arthritis, and certain forms of cancer and
represents an attractive target for further pharmacological
examination. Over the past decade, biological screening has
identified a number of diverse small organic and organo-
metallic molecules as chemotherapeutic inhibitors of Trx and
TrxR (Fig. 2).13 Nitrosoureas such as BCNU were found early
on to be effective irreversible inhibitors of TrxR.14 However,
these compounds are quite toxic, relatively non-selective, and
known to alkylate DNA. Alkyl 2-imidazolyl disulfides such as
PX-12 and the symmetrical cyclopentanone NSC 131233 were
revealed as inhibitors through screening by a COMPARE
analysis from over 50000 compounds tested by the National
Cancer Institute. PX-12 is currently in Phase I clinical trials and
demonstrated antitumor activity in immunodeficient mice
xenograft models.15 Auranofin, commonly used for the
treatment of rheumatoid arthritis, was also discovered to be a
selective tight-binding inhibitor of Trx/TrxR.16
Our biological assays revealed that palmarumycin CP1
inhibited the Trx/TrxR system with an IC50 of 350 nM, a
level of activity that compared well with that reported for
the structurally more complex para-quinone pleurotin
(Fig. 3).2,17
Fig. 3 Small molecule inhibitors of the Trx/TrxR system.
Moreover, palmarumycin CP1 was found to affect growth
inhibition at 4–20 times lower concentrations than pleurotin,
and several members of a small library of analogs possessing a
naphthoquinone spiroketal moiety were found to be potent and
selective inhibitors of Trx-1/TrxR.2 Both the phenol group
and the enone functionality present in palmarumycin CP1
appeared to be important for maximizing enzymatic activity.
Additionally, it was determined that the presence of the
naphthalenediol ketal enhances Trx-1 over TrxR selectivity
compared to aliphatic ketals. It should be noted that many
of these derivatives also demonstrated potent cytotoxicity as
evidenced through low micromolar activities for growth
inhibition against two breast cancer cell lines.2 We now report
a new SAR study of naphthoquinone spiroketal analogs of
the palmarumycin family of fungal metabolites; many of
these derivatives were again found to be potent inhibitors
of the thioredoxin–thioredoxin reductase cellular redox
system.
O-Demethylation of S1 and S9 under a variety of conditions
led to extensive decomposition, and therefore we had to
devise an alternative route to access the desired free phenols
(Scheme 3). MOM-protection of 623 was followed by
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 5 1 – 1 6 5 8
1652

View Article Online
Scheme 1 Reagents and conditions: (a) PhMe3NBr3, THF, rt, 3 h. (b) Et3N, CH2Cl2, 0 ЊC, 1 h. (c) Bu3SnR, Pd(PPh3)4 (5 mol%), CuI (40 mol%),
DMF, 80 ЊC, 2 h. (d) RONH2ؒHCl, pyridine, rt, 24 h. (e) Me2NNH2, EtOH, 80 ЊC, 1 h. (f ) Methylaluminium bis(2,6-di-tert-butyl-4-
methylphenoxide), toluene/CH2Cl2, Ϫ78 ЊC; PhLi, Ϫ78 ЊC to rt, 1 h. (g) PhMe3NBr3, THF, rt, 30 min. (h) Li2CO3, LiBr, DMF, 130 ЊC, 1 h.
Scheme 2 Reagents and conditions: (a) Allyl-MgBr, THF. (b) BH3ؒDMS, THF; NaOH, H2O2. (c) Jones reagent, acetone. (d) PPA, 120 ЊC. (e)
PhMe3NBr3, THF. (f ) Li2CO3, LiBr, DMF, 130 ЊC. (g) NaH, MOMCl, DMF. (h) t-BuLi, Et2O, Ϫ78 ЊC; DMF. (i) Barton’s base, 5-hydroxy-1-meth-
oxy-4-naphthalenecarboxaldehyde or 5-hydroxy-1-benzyloxy-4-naphthalenecarboxaldehyde, CH3CN, 70 ЊC. (j) m-CPBA, CH2Cl2. (k) NaBH4,
MeOH/THF (1 : 1), 0 ЊC. (l) PhI(OCOCF3)2, CH3CN, 0 ЊC.
substitution with 4-fluoro-1-naphthalenecarboxaldehyde24 or
the fluoride 4 in the presence of Barton’s base18 to give the
diaryl ethers 8a and 8b, respectively. Dakin reactions, reductive
deformylations, and oxidative spirocyclizations provided
the MOM ethers 10a and 10b, which were subsequently
deprotected with TMS-Br25 in good yields to give the desired
S11 and S12. The crude reaction mixture contained significant
amounts of silyl enol ether derived from conjugate addition of
bromide ion to the enone, and therefore a treatment with TBAF
was used as part of the workup protocol.
We were able to augment this synthetic library of palmaru-
mycin and S1 analogs by several natural product naphthalene-
diol ketals.26 As part of INBio’s current initiatives for identifying
trypanothione reductase (TR) inhibitors, natural products
derived from fermentation broths of microfungi have been eval-
uated. The anamorph of an unidentified Ascomycete fungi27
produced several naphthalenediol ketals in culture. The original
teleomorph was collected in 1996 in the Guanacaste Conserv-
ation Area, Costa Rica, from decaying trunk material and
identified originally to belong to the Rhytidhysteron genus.28
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 5 1 – 1 6 5 8
1653

View Article Online
Scheme 3 Reagents and conditions: (a) K2CO3, MOMCl, acetone, rt. (b) 4-Fluoro-1-naphthalenecarboxaldehyde or 4, Barton’s base, CH3CN, 80 ЊC.
(c) m-CPBA, CH2Cl2. (d) NaBH4, MeOH/THF (1 : 1), 0 ЊC. (e) PhI(OCOCF3)2, CH3CN, 0 ЊC. (f ) TMSBr, 4 Å molecular sieves, CH2Cl2. (g) TBAF,
THF.
Fig. 4 Natural products screened for Trx/TrxR inhibition.
Three agar plugs containing the preserved material were
Trx-1/TrxR inhibition and cell growth inhibition assays
activated for 15 days, and the resulting inocula were further
cultured for an additional 15 days at 25 ЊC in 100 mL of Czapek
Dox broth media (100 mL × 60 flasks) in an orbital shaker
at 150 rpm for a final volume of 6 L. Approximately 100 mL
of 95% ethanol were added to each culture media and left
overnight. Cell disruption was further assisted with a biomixer
on the following day. Filtration to separate mycelia and evap-
oration to 10% of its original volume was achieved under
vacuum. The resulting hydroalcoholic solution was added to
water and extracted with three portions of methylene chloride
and three portions of ethyl acetate, and all organic extractions
were combined and evaporated. The resulting 1.97 g of extract
were separated on MPLC using RP-18 to yield five main
fractions. The fraction with the correct NMR profile was
collected, yielding 565 mg. The final step of separation was
achieved using a BioXplore© HPLC system whereby 98 mg of
MK-3018,29 87 mg of the new compound palmarumycin CR1,30
For all compounds, Trx/TrxR activities were measured in
microtiter plate colorimetric assays using purified human
placenta TrxR and recombinant human Trx.33 TrxR activity
was measured as the increase in absorbance at 405 nm which
occurs as dithionitrobenzoic acid (DTNB) is reduced by the
enzyme-mediated transfer of reducing equivalents from
NADPH. Trx activity was measured as the Trx dependent
reduction of insulin in the presence of TrxR and NADPH,
detected by the reduction of DTNB at the end of the
incubation. Antiproliferative activity was measured using an
estrogen receptor positive, p53 positive MCF-7 human
breast cancer cell line. The cells were seeded at 4000 cells/well in
96-well microtiter plates and allowed to attach overnight. After
exposure to the compounds for 72 h, viable cells were stained
with
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium
bromide. Plates were incubated for 3 h in the dark and
measured spectrophotometrically at 540 nm.34 Results are
summarized in Table 1.
In contrast to palmarumycin CP1 and MK 3018, the
naturally occurring naphthalenediol spiroketals palmarumycin
CP2, CJ-12,372, and palmarumycin CR1 showed no cytotox-
icity and only insignificant inhibition of the Trx-1/TrxR redox
system. This demonstrates that the presence of an enone func-
tion is necessary for biological activity in this class of fungal
32
54 mg of CJ-12,37231 and 5 mg of palmarumycin CP2 were
obtained (Fig. 4). All structures were elucidated by means of
1H-/13C-NMR, COSY, HSQC, DEPT and HMBC experiments
and the molecular weight was corroborated with HR-MS.
These natural products are currently under evaluation for their
TR and hGR inhibitory activity at INBio’s laboratories, and we
were also interested in determining their specificity by assays in
the mammalian Trx/TrxR system.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 5 1 – 1 6 5 8
1654

View Article Online
Table 1 IC50 values [µM] for Trx-1/TrxR inhibition and cell growth
exceed the Trx-1/TrxR activities of the potent natural products
inhibition35
palmarumycin CP1 and pleurotin. Further biological studies, in
particular in vivo assays of suitable derivatives, will be reported
in due course.
Entry
Compound
Trx-1/TrxR
MCF-7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Pleurotin
Palmarumycin CP1
Palmarumycin CP2
CJ-12,372
MK 3018
Palmarumycin CR1
S9
0.17
0.35
>100
14.4
8.4
>50
1.0
5.2
3.2
>50
23.6
3.1
6.4
5.0
>50
16.6
0.34
0.20
4.1
1.0
Experimental
>50
>50
10.0
>100
14.0
14.2
9.2
80.0
10.2
2.6
6.0
1.6
>100
10.4
2.8
General
All reactions were performed in flame-dried or oven-dried
glassware under a dry nitrogen atmosphere. THF and ether
were distilled over Na/benzophenone, and CH2Cl2 was purified
by passage through a column of activated alumina. All other
reagents and solvents were used as received unless otherwise
noted. NMR spectra were recorded in CDCl3 (unless otherwise
noted) at either 300 MHz (1H NMR) or 75 MHz (13C NMR)
using a Bruker Avance 300 with XWIN-NMR software.
Melting points were determined on a Mel-Temp II and are
uncorrected.
S10
S1
S6
S7
S2
S3
S4
S5
S8
S11
S12
2.6
8-Hydroxy-4-methoxymethoxynaphthalene-1-carbaldehyde (7)
To a solution of 4,8-dihydroxynaphthalene-1-carbaldehyde
(6, 1.00 g, 5.31 mmol) in acetone (25 mL) was added K2CO3
(1.47 g, 10.6 mmol) followed by chloromethyl methyl ether
(80%; 0.46 mL, 4.8 mmol). The reaction mixture was stirred at
room temperature for 1.5 h, quenched with H2O and extracted
with CH2Cl2 (3 × 30 mL). The combined organic layers were
washed with H2O, dried (MgSO4), and concentrated under
reduced pressure. The residue was dissolved in CH2Cl2 and
passed through a 1Љ pad of SiO2 (CH2Cl2) to provide 1.06 g
(95%) of 7 as a yellow solid: mp 64–65 ЊC (CH2Cl2); IR (neat)
metabolites. The introduction of an oxime or oxime ether
in place of the carbonyl group present in S1 also led to a signifi-
cant reduction of the Trx-1/TrxR inhibition, although cyto-
toxicity was conserved in the oxime S7. We were particularly
interested in reducing the inherent electrophilicity of the α,β-
unsaturated carbonyl moiety by chemical modifications at the
α- and β-sites in order to reduce the possibility for unselective
alkylations of other cellular thiols. Substitution at the enone
β-position was not tolerated for cytotoxicity. An increase in
biological activity in both the cellular and the enzymatic assays
over the parent S1 was only accomplished with the brominated
derivative S2. However, the cytotoxicity increased several-fold
in S4, the 2-pyridyl derivative. Since the 2-furyl derivative S3
also showed a low-micromolar cytotoxicity, it is possible to
generalize that substitution at the α-position of the enone is
well tolerated by the Trx-1/TrxR complex and can be used to
increase cellular activity. Interestingly, while we expected a
significant boost in the Trx-1/TrxR activity due to the presence
of the phenolic hydroxy group in S9 versus the lead structure
S1, the increase in enzymatic inhibitory activity was only 3-fold,
and the cellular activity dropped off to 14 µM. Conversely, the
O-demethylated analog, bis-phenolic S12, as well as the mono-
phenol S11 demonstrated excellent Trx-1/TrxR activities of
0.20 and 0.34 µM, respectively, while maintaining a high level
of cytotoxicity in the MCF-7 cell line. S12 represents therefore
the first thioredoxin inhibitor equipotent to pleurotin, in spite
of the considerably simpler structure of the newer compound.
S11 is also of considerable interest for this structure–activity
analysis because it demonstrates that the substituents of the
naphthalene moiety of S1 are indeed strongly influencing
biological activity.
2904, 2806, 2704, 1649, 1519, 1273, 1222 cmϪ1 1H NMR
;
δ 12.11 (d, 1H, J = 0.9 Hz), 9.61 (d, 1H, J = 0.9 Hz), 7.91 (d, 1H,
J = 8.2 Hz), 7.87 (dd, 1H, J = 8.3, 1.2 Hz), 7.50 (t, 1H, J = 8.0
Hz), 7.18 (dd, 1H, J = 7.8, 1.2 Hz), 7.12 (d, 1H, J = 8.2 Hz), 5.49
(s, 2H), 3.56 (s, 3H); 13C NMR δ 196.1, 160.9, 156.0, 145.4,
128.9, 128.6, 126.4, 122.9, 116.9, 113.8, 106.2, 95.0, 57.1; MS
(EI) m/z (rel intensity) 232 (Mϩ, 100), 202 (22), 170 (28), 131
(22), 115 (25), 77 (20); HRMS (EI) calcd for C13H12O4 232.0736,
found 232.0735.
4-(5-Methoxymethoxy-8-formylnaphthalen-1-yloxy)-
naphthalene-1-carbaldehyde (8a)
To a solution of naphthol 7 (510 mg, 2.20 mmol) and 4-fluoro-
1-naphthalenecarbaldehyde36 (348 mg, 2.00 mmol) in CH3CN
(8 mL) at room temperature was added 2-tert-butyl-1,1,3,3-
tetramethylguanidine (0.48 mL, 2.4 mmol). The reaction
mixture was heated at 70 ЊC for 1 h, additional Barton’s base
(0.10 mL, 0.50 mmol) was added, and heating was continued
for 2 h. The reaction mixture was then cooled to room temper-
ature, poured into 1.0 M HCl (30 mL), and extracted with
CH2Cl2 (2 × 40 mL). The combined organic layers were washed
with H2O (30 mL), dried (MgSO4), and concentrated under
reduced pressure. Chromatography of the residue on SiO2
(hexanes/EtOAc, 7 : 3) gave 552 mg (72%) of 8a as a pale yellow
solid: mp 100–101 ЊC (hexanes/EtOAc); IR (neat) 2904, 2735,
Conclusion
We have been able to expand the structural diversity and the
SAR of naphthalenediol spiroketal-based low-micromolar
Trx-1/TrxR inhibitors by the preparation of a focused library
of S1 derivatives that takes advantage of selective and high-
yielding chemical modifications of the pharmacophore moiety.
The enone function is critical for biological activity, but a
β-hydrazine adduct (S8) could likely function as a precursor
of this group. Carbon-substitution at the β-position tends
to reduce the activity, in particular in the MCF-7 assay. Cyto-
toxicity can be increased significantly by the presence of
α-substituents at the enone, and several derivatives that lack
the phenolic hydroxy group found in palmarumycin CP1 but
maintain a good overall activity profile could be identified. Two
synthetic derivatives, S11 and S12, were found that match or
1682, 1576, 1507, 1419, 1321, 1219, 1161 cmϪ1 1H NMR
;
δ 10.90 (d, 1H, J = 0.5 Hz), 10.22 (s, 1H), 9.35 (d, 1H, J = 8.5
Hz), 8.47 (dd, 1H, J = 8.4, 0.7 Hz), 8.35 (dd, 1H, J = 8.5, 1.1
Hz), 8.15 (d, 1H, J = 8.3 Hz), 7.79–7.74 (m, 1H), 7.78 (d, 1H,
J = 8.0 Hz), 7.69–7.64 (m, 1H), 7.53 (dd, 1H, J = 8.4, 7.6 Hz),
7.30 (dd, 1H, J = 7.6, 1.1 Hz), 7.24 (d, 1H, J = 8.3 Hz), 6.76 (d,
1H, J = 8.0 Hz), 5.50 (s, 2H), 3.59 (s, 3H); 13C NMR δ 192.2,
192.1, 158.8, 157.7, 152.2, 138.0, 132.6, 131.0, 130.2, 128.3,
127.6, 127.5, 127.4, 126.7, 126.3, 126.2, 125.3, 122.3, 120.5,
119.9, 110.1, 108.0, 95.0, 56.9; MS (EI) m/z (rel intensity)
386 (Mϩ, 57), 359 (54), 331 (26), 159 (87), 130 (27), 105
(100); HRMS (EI) calcd for C24H18O5 386.1154, found
386.1147.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 5 1 – 1 6 5 8
1655

View Article Online
4-(5-Methoxymethoxy-8-hydroxynaphthalen-1-yloxy)-naphth-1-
ol (9a)
mL) containing powdered 4 Å molecular sieves (200 mg) at 0 ЊC
was added bromotrimethylsilane (0.12 mL, 0.88 mmol). The
reaction mixture was stirred at 0 ЊC for 1 h, warmed to room
temperature, stirred for 12 h and filtered over Celite (CH2Cl2).
The filtrate was concentrated under reduced pressure. The
residue was dissolved in THF (3 mL), and TBAF (1.0 M in
THF; 0.22 mL, 0.22 mmol) was slowly added. The reaction
mixture was stirred at room temperature for 15 min, quenched
with H2O and extracted with EtOAc. The combined organic
layers were dried (MgSO4) and concentrated under reduced
pressure. The residue was passed through a short pad of SiO2
(CH2Cl2) to afford 48 mg (68%) of S11 as an orange solid: mp
195 ЊC (acetone, dec); IR (neat) 3344 (br), 1666, 1597, 1415,
To a solution of dialdehyde 8a (464 mg, 1.20 mmol) in CH2Cl2
(25 mL) was added 70% m-CPBA (890 mg, 3.60 mmol). The
reaction mixture was stirred at room temperature for 15 h. A
solution of 10% Na2S2O3 (30 mL) was added and stirring was
continued for 1 h. The organic layer was diluted with CH2Cl2,
washed with saturated aqueous NaHCO3, dried (MgSO4), and
concentrated under reduced pressure. Chromatography of the
residue on SiO2 (hexanes/EtOAc, 3 : 2) afforded 340 mg (68%)
of 4-(5-methoxymethoxy-8-formyloxynaphthalen-1-yloxy)-1-
formyloxynaphthalene as a pale yellow foam: IR (neat) 2945,
1739, 1601, 1508, 1461, 1369, 1254, 1113 cmϪ1; 1H NMR δ 8.50
(s, 1H), 8.33–8.29 (m, 1H), 8.18 (dd, 1H, J = 8.5, 1.0 Hz), 8.08
(s, 1H), 7.99–7.96 (m, 1H), 7.66–7.56 (m, 2H), 7.42 (dd, 1H,
J = 8.4, 7.8 Hz), 7.17 (d, 1H, J = 8.3 Hz), 7.14 (d, 1H, J = 8.1
Hz), 7.08 (d, 1H, J = 8.4 Hz), 7.01 (dd, 1H, J = 7.6, 1.0 Hz), 6.70
(d, 1H, J = 8.3 Hz), 5.42 (s, 2H), 3.58 (s, 3H); 13C NMR δ 160.5,
159.9, 152.3, 151.7, 141.4, 138.7, 129.3, 127.9, 127.8, 127.3,
127.1, 126.5, 122.6, 121.6, 121.1, 120.1, 119.0, 117.7, 117.5,
111.5, 108.2, 95.2, 56.6; MS (EI) m/z (rel intensity) 418 (Mϩ,
74), 390 (72), 345 (100), 317 (41), 299 (37), 159 (42), 144 (86),
115 (67); HRMS (EI) calcd for C24H18O7 418.1053, found
418.1065.
1
1385, 1264, 1044 cmϪ1; H NMR (acetone-d6) δ 8.99 (s, 1H),
8.12 (ddd, 1H, J = 7.8, 1.4, 0.5 Hz), 8.05 (ddd, 1H, J = 7.8, 1.3,
0.5), 7.90 (dd, 1H, J = 8.5, 0.8), 7.88 (td, 1H, J = 7.6, 1.4 Hz),
7.74 (td, 1H, J 7.6, 1.3 Hz), 7.51 (dd, 1H, J = 8.5, 7.6 Hz), 7.14
(d, 1H, J = 10.6 Hz), 7.03 (dd, 1H, J = 7.6, 0.8 Hz), 6.94 (d, 1H,
J = 8.3 Hz), 6.86 (d, 1H, J = 8.3 Hz), 6.42 (d, 1H, J = 10.6 Hz);
13C NMR (acetone-d6) δ 183.0, 148.6, 147.8, 140.2, 139.3, 139.2,
134.0, 130.6, 130.2, 130.0, 128.4, 126.6, 125.9, 125.5, 116.6,
114.0, 110.4, 110.1, 109.5, 93.1; MS (EI) m/z (rel intensity) 316
(Mϩ, 100), 219 (6), 174 (24), 159 (29), 144 (28), 131 (17), 115
(15), 102 (22); HRMS (EI) calcd for C20H12O4 316.0736, found
316.0734.
To a solution of this bisformate ester (248 mg, 0.593 mmol)
in 1 : 1 MeOH/THF (10 mL) at 0 ЊC was slowly added NaBH4
(50.0 mg, 1.30 mmol). The reaction mixture was stirred at 0 ЊC
for 1 h, diluted with EtOAc (25 mL) and washed with H2O. The
organic layer was dried (MgSO4) and concentrated under
reduced pressure. The residue was immediately subjected to
chromatography on SiO2 (hexanes/EtOAc, 3 : 2) to afford 177
mg (83%) of 9a as a white foam: IR (neat) 3433 (br), 1608, 1460,
1395, 1262, 1228, 1152 cmϪ1; 1H NMR δ 9.20 (s, 1H), 8.29–8.26
(m, 1H), 7.96–7.91 (m, 2H), 7.55–7.43 (m, 2H), 7.17 (d, 1H,
J = 8.4 Hz), 7.16 (dd, 1H, J = 8.4, 7.8 Hz), 7.09 (d, 1H, J = 8.1
Hz), 6.97 (d, 1H, J = 8.4 Hz), 6.76 (d, 1H, J = 8.1 Hz), 6.50 (dd,
1-(5-Methoxymethoxy-8-formylnaphthalen-1-yloxy)-5-methoxy-
methoxy-naphthalene-4-carbaldehyde (8b)
To a solution of naphthol 7 (592 mg, 2.55 mmol) and fluoride 4
(400 mg, 1.70 mmol) in CH3CN (6 mL) at room temperature
was added 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.52 mL,
2.6 mmol). The reaction mixture was heated at 80 ЊC for 5 h,
cooled to room temperature, poured into 1.0 M HCl (20 mL),
and extracted with CH2Cl2 (3 × 25 mL). The combined organic
layers were washed with H2O, dried (MgSO4), and concentrated
under reduced pressure. Chromatography on SiO2 (hexanes/
EtOAc, 7 : 3) afforded 100 mg (25%) of fluoride 4 and 410 mg
(54%) of 8b as a pale yellow solid: mp 123–124 ЊC (hexanes/
EtOAc); IR (neat) 1675, 1505, 1417, 1321, 1260, 1220, 1159,
1000 cmϪ1; 1H NMR δ 11.09 (s, 1H), 10.94 (s, 1H), 8.30 (dd, 1H,
J = 8.4, 1.0 Hz), 8.16 (d, 1H, J = 8.3 Hz), 8.10 (dd, 1H, J = 8.3,
0.8 Hz), 7.88 (d, 1H, J = 8.1 Hz), 7.53 (t, 1H, J = 8.4 Hz), 7.50
(t, 1H, J = 8.4 Hz), 7.40 (d, 1H, J = 7.8 Hz), 7.25 (d, 1H, J = 8.3
Hz), 7.21 (dd, 1H, J = 7.7, 1.0 Hz), 6.80 (d, 1H, J = 8.1 Hz), 5.50
(s, 2H), 5.43 (s, 2H), 3.59 (s, 3H), 3.55 (s, 3H); 13C NMR δ 194.2,
192.5, 157.7, 157.2, 154.2, 152.8, 130.9, 130.8, 128.8, 128.2,
127.6, 127.5, 126.6, 126.2, 125.7, 120.0, 119.1, 116.4, 112.1,
111.9, 108.0, 95.4, 95.0, 56.9, 56.8; MS (EI) m/z (rel intensity)
446 (Mϩ, 63), 401 (100), 373 (7), 341 (10), 215 (13), 171 (45), 114
(17); HRMS (EI) calcd for C26H22O7 446.1366, found 446.1370.
1H, J = 7.7, 0.9 Hz), 6.46 (s, 1H), 5.36 (s, 2H), 3.61 (s, 3H); 13
C
NMR δ 156.6, 150.2, 148.8, 146.0, 143.0, 129.1, 128.2, 127.6,
126.3, 125.9, 125.7, 122.7, 121.8, 118.3, 117.1, 115.8, 111.7,
110.0, 109.6, 108.1, 95.9, 56.5; MS (EI) m/z (rel intensity) 362
(Mϩ, 67), 317 (57), 299 (14), 143 (100), 115 (45); HRMS (EI)
calcd for C22H18O5 362.1154, found 362.1153.
1-Oxo-1,4-dihydronaphthalene-4-spiro-2Ј-naphtho[4Љ-methoxy-
methoxy-1Љ,8Љ-de][1Ј,3Ј]dioxin (10a)
To a solution of bisnaphthol 9a (285 mg, 0.786 mmol) in dry
CH3CN (15 mL) at 0 ЊC was added PhI(OCOCF3)2 (370 mg,
0.860 mmol) in one portion. The reaction mixture was stirred at
0 ЊC for 30 min and concentrated under reduced pressure. The
residue was dissolved in EtOAc (40 mL), washed with H2O (20
mL), dried (MgSO4) and concentrated under reduced pressure.
Chromatography on SiO2 (hexanes/EtOAc, 4 : 1) gave 207 mg
(74%) of 10a as a yellow foam: IR (neat) 2955, 1675, 1611,
1-(5-Methoxymethoxy-8-hydroxynaphthalen-1-yloxy)-5-meth-
oxymethoxynaphth-4-ol (9b)
1
1425, 1385, 1299, 1266, 1157, 1047 cmϪ1; H NMR δ 8.16 (dd,
To a solution of dialdehyde 8b (320 mg, 0.717 mmol) in CH2Cl2
(15 mL) was added 70% m-CPBA (525 mg, 2.13 mmol). The
reaction mixture was stirred at room temperature for 15 h,
treated with a solution of 10% Na2S2O3 (15 mL) and stirred for
another 1 h. The organic layer was separated and diluted with
CH2Cl2 then washed with saturated aqueous NaHCO3, dried
(MgSO4), and concentrated under reduced pressure. Chrom-
atography of the residue on SiO2 (hexanes/EtOAc, 3 : 2)
afforded 206 mg (61%) of 1-(5-methoxymethoxy-8-formyloxy-
naphthalen-1-yloxy)-5-methoxymethoxy-4-formyloxynaph-
thalene as a yellow foam: IR (neat) 2950, 1739, 1601, 1506,
1416, 1369, 1254, 1117 cmϪ1; 1H NMR δ 8.38 (s, 1H), 8.17 (dd,
1H, J = 8.5, 1.0 Hz), 8.08 (s, 1H), 7.98 (dd, 1H, J = 8.5, 0.9 Hz),
7.46 (t, 1H, J = 8.1 Hz), 7.42 (dd, 1H, J = 8.4, 7.7 Hz), 7.25 (dd,
1H, J = 7.8, 0.9 Hz), 7.16 (d, 1H, J = 8.4 Hz), 7.07 (d, 1H, J = 8.4
Hz), 7.00 (d, 1H, J = 8.3 Hz), 6.99 (dd, 1H, J = 7.6, 1.0 Hz), 6.68
1H, J = 7.8, 1.1 Hz), 7.97 (dd, 1H, J = 7.8, 0.8 Hz), 7.90 (dd, 1H,
J = 8.5, 0.8 Hz), 7.75 (td, 1H, J = 7.6, 1.4 Hz), 7.62 (td, 1H, 7.6,
1.2 Hz), 7.47 (dd, 1H, J = 8.5 and 7.6 Hz), 7.10 (d, 1H, J = 8.3
Hz), 7.01 (dd, 1H, J = 7.6, 0.7 Hz), 7.00 (d, 1H, J = 10.6 Hz),
6.88 (d, 1H, J = 8.3 Hz), 6.37 (d, 1H, J = 10.6 Hz), 5.37, 5.35
(AB-system, 2H, J = 6.7 Hz), 3.57 (s, 3H); 13C NMR δ 183.5,
148.4, 147.7, 141.9, 138.9, 138.7, 134.0, 130.4, 130.3, 130.2,
128.1, 127.3, 126.7, 126.5, 116.4, 113.9, 110.8, 110.3, 109.8,
95.6, 93.2, 56.4; MS (EI) m/z (rel intensity) 360 (Mϩ, 71), 315
(100), 264 (7), 202 (7), 174 (62), 158 (33); HRMS (EI) calcd for
C22H16O4 360.0998, found 360.0993.
1-Oxo-1,4-dihydronaphthalene-4-spiro-2Ј-naphtho[4Љ-hydroxy-
1Љ,8Љ-de][1Ј,3Ј] dioxin (S11)
To a solution of spirocycle 10a (80 mg, 0.22 mmol) in CH2Cl2 (3
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 5 1 – 1 6 5 8
1656

View Article Online
(d, 1H, J = 8.3 Hz), 5.42 (s, 2H), 5.32 (s, 2H), 3.57 (s, 3H), 3.55
(s, 3H); 13C NMR δ 160.7, 160.5, 152.7, 152.3, 151.7, 151.6,
141.0, 138.7, 129.3, 127.5, 126.5, 121.1, 120.3, 120.1, 119.5,
119.0, 117.5, 116.2, 112.3, 111.6, 108.2, 95.3, 95.2, 56.7, 56.6;
MS (EI) m/z (rel intensity) 478 (Mϩ, 85), 450 (100), 422 (44),
373 (54), 345 (54), 315 (51), 187 (63), 174 (70); HRMS (EI)
calcd for C26H22O9 478.1264, found 478.1241.
(d, 1H, J = 10.5 Hz); 13C NMR (acetone-d6) δ 190.0, 162.6,
149.3, 148.3, 141.6, 140.7, 140.4, 137.6, 130.2, 127.3, 126.2,
120.4, 120.1, 117.3, 114.6, 114.5, 111.1, 110.9, 110.2, 93.6; MS
(EI) m/z (rel intensity) 332 (Mϩ, 100), 303 (6), 275 (6), 174 (28),
118 (34), 102 (35), 92 (26), 63 (41); HRMS (EI) calcd for
C20H12O5 332.0685, found 332.0694.
To a solution of this bisformate ester (200 mg, 0.418 mmol)
in 1 : 1 MeOH/THF (8 mL) at 0 ЊC was slowly added NaBH4
(35 mg, 0.92 mmol). The reaction mixture was stirred at 0 ЊC for
1 h, diluted with EtOAc (20 mL) and washed with H2O. The
organic layer was dried (MgSO4) and concentrated under
reduced pressure. The residue was immediately subjected to
chromatography on SiO2 (hexanes/EtOAc, 3 : 2) to afford 157
mg (89%) of 9b as a white foam: IR (neat) 3432 (br), 1632, 1608,
Acknowledgements
This work was supported by the National Institutes of
Health (U19CA-52995). Costa Rican and ChagasSpaceProject
activities are supported by NASA (NAG 13171).
References and notes
1
1461, 1395, 1264, 1226, 1158, 1010 cmϪ1; H NMR δ 9.36 (s,
1 (a) D. J. Newman, G. M. Cragg and K. M. Snader, J. Nat. Prod.,
2003, 66, 1022–1037; (b) R. Breinbauer, I. R. Vetter and
H. Waldmann, Angew. Chem., Int. Ed., 2002, 41, 2878–2890;
(c) P. Wipf, J. T. Reeves, R. Balachandran and B. W. Day, J. Med.
Chem., 2002, 45, 1901–1917.
2 P. Wipf, T. D. Hopkins, J.-K. Jung, S. Rodriguez, A. Birmingham,
E. C. Southwick, J. S. Lazo and G. Powis, Bioorg. Med. Chem. Lett.,
2001, 11, 2637–2641.
3 For a review on natural products derived from naphthalenoid
precursors, see: K. Krohn, Progr. Chem. Org. Nat. Prod., 2003, 85,
1–49.
4 T. M. Grogan, C. Fenoglio-Prieser, R. Zeheb, W. Bellamy,
Y. Frutiger, E. Vela, G/ Stemmerman, J. MacDonald, L. Richter,
A. Gallegos and G. Powis, Hum. Pathol., 2000, 31, 475–481.
5 M. Berggren, A. Gallegos, J. R. Gasdaska, P. Y. Gasdaska,
J. Warneke and G. Powis, Anticancer Res., 1996, 16, 3459–3466.
6 A. Gallegos, J. Raffel, A. K. Bhattacharyya and G. Powis, Proc. Am.
Assoc. Cancer Res., 2000, 41, 189.
7 S. Kakolyris, A. Giatromanolaki, M. Koukourakis, G. Powis,
J. Souglakos, E. Sivridis, K. C. Gatter and A. L. Harris, Clin. Cancer
Res., 2001, 7, 3087–3091.
8 J. E. Oblong, M. Berggren, P. Y. Gasdaska and G. Powis, J. Biol.
Chem., 1994, 269, 11714–11720.
9 S. J. Welsh, W. T. Bellamy, M. M. Briehl and G. Powis, Cancer Res.,
2002, 62, 5089–5095.
10 B. Husbeck, D. E. Stringer, E. W. Gerner and G. Powis, Biochem.
Biophys. Res. Commun., 2003, 306, 469–475.
1H), 8.99 (s, 1H), 7.89 (dd, 1H, J = 8.5, 0.9 Hz), 7.63 (dd, 1H,
J = 8.5, 0.8 Hz), 7.30 (t, 1H, J = 8.2 Hz), 7.26 (d, 1H, J = 8.3
Hz), 7.17–7.12 (m, 3H), 6.91 (d, 1H, J = 8.3 Hz), 6.90 (d, 1H,
J = 8.4 Hz), 6.46 (dd, 1H, J = 7.7, 0.9 Hz), 5.48 (s, 2H), 5.32 (s,
2H), 3.62 (s, 3H), 3.56 (s, 3H); 13C NMR δ 156.5, 154.1, 152.6,
148.9, 145.9, 141.6, 130.0, 129.0, 127.2, 125.5, 120.5, 117.0,
116.6, 116.3, 115.7, 111.5, 110.0, 109.9, 109.2, 108.9, 95.9, 95.8,
57.1, 56.3; MS (EI) m/z (rel intensity) 422 (Mϩ, 32), 345 (22),
264 (38), 205 (31), 189 (35), 173 (100); HRMS (EI) calcd for
C24H22O7 422.1366, found 422.1361.
4Ј-Methoxymethoxypalmarumycin CP1 (10b)
To a solution of bisnaphthol 9b (230 mg, 0.544 mmol) in dry
CH3CN (8 mL) at 0 ЊC was added PhI(OCOCF3)2 (253 mg,
0.588 mmol) in one portion. The reaction mixture was stirred at
0 ЊC for 30 min and concentrated under reduced pressure. The
residue was dissolved in EtOAc (30 mL), washed with H2O and
saturated aqueous NaHCO3, dried (MgSO4) and concentrated
under reduced pressure. Chromatography on SiO2 (hexanes/
EtOAc, 7 : 3) gave 80 mg (40%) of 10b as a yellow foam: IR
(neat) 2955, 1662, 1610, 1456, 1425, 1266, 1240, 1010 cmϪ1; 1H
NMR δ 12.17 (s, 1H), 7.91 (dd, 1H, J = 8.5, 0.7 Hz), 7.65 (t, 1H,
J = 8.0 Hz), 7.50–7.44 (m, 2H), 7.13 (dd, 1H, J = 8.4, 1,0 Hz),
7.11 (d, 1H, J = 8.3 Hz), 7.02 (dd, 1H, J = 7.5, 0.6 Hz), 7.01
(d, 1H, J = 10.5 Hz), 6.89 (d, 1H, J = 8.3 Hz), 6.35 (d, 1H,
J = 10.5 Hz), 5.38, 5.35 (AB-System, 2H, J = 6.7 Hz), 3.57 (s,
3H); 13C NMR δ 189.0, 162.1, 148.5, 147.5, 141.8, 140.0, 139.2,
136.7, 129.9, 127.3, 126.7, 119.8, 119.5, 116.5, 114.1, 113.8,
110.9, 110.3, 109.9, 95.7, 93.1, 56.5; MS (EI) m/z (rel intensity)
376 (Mϩ, 14), 331 (15), 174 (100), 149 (21), 118 (41); HRMS
(EI) calcd for C22H16O6 376.0947, found 376.0948.
11 E. Meuillet, D. Mahadevan, M. Berggren, A. Coon and G. Powis,
Arch. Biochem. Biophys., 2004, in press.
12 M. I. Berggren, B. Husbeck, B. Samulitis, A. F. Baker, A. Gallegos
and G. Powis, Arch. Biochem. Biophys., 2001, 392, 103–109.
13 S. Gromer, S. Urig and K. Becker, Med. Res. Rev., 2004, 24, 40–89.
14 K. U. Schallreuter, F. K. Gleason and J. M. Wood, Biochim. Biophys.
Acta, 1990, 1054, 14–20.
15 S. J. Welsh, R. R. Williams, A. Birmingham, D. J. Newman,
D. L. Kirkpatrick and G. Powis, Mol. Cancer Ther., 2003, 2,
235–243.
16 S. Gromer, L. D. Arscott, C. H. Williams Jr., R. H. Schirmer and
K. Becker, J. Biol. Chem., 1998, 273, 20096–20101.
17 M. W. Kunkel, D. L. Kirkpatrick, J. I. Johnson and G. Powis, Anti-
Cancer Drug Des., 1997, 12, 659–670.
4Ј-Hydroxypalmarumycin CP1 (S12)
To a solution of spirocycle 10b (45 mg, 0.12 mmol) in CH2Cl2
(2 mL) containing powdered 4 Å molecular sieves (120 mg) at
0 ЊC was added bromotrimethylsilane (65 µL, 0.50 mmol). The
reaction mixture was stirred at 0 ЊC for 1 h, warmed to room
temperature and stirred for 12 h. The reaction mixture was
filtered over Celite (CH2Cl2) and the filtrate was concentrated
under reduced pressure. The residue was dissolved in THF
(3 mL), and TBAF (1.0 M in THF; 0.12 mL, 0.12 mmol) was
slowly added. The reaction mixture was stirred at room temper-
ature for 15 min, quenched with H2O and extracted with
EtOAc. The combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. The residue was passed
through a short pad of SiO2 (CH2Cl2) to afford 28 mg (70%) of
S12 as a yellow–brown solid: mp 280 ЊC (acetone, dec); IR
18 P. Wipf and S. M. Lynch, Org. Lett., 2003, 5, 1155–1158.
19 (a) K. Maruoka, K. Nonoshita and H. Yamamoto, Tetrahedron
Lett., 1987, 28, 5723–5726; (b) A. J. Stern, J. J. Rohde and
J. S. Swenton, J. Org. Chem., 1989, 54, 4413–4419.
20 Y. M. Choi-Sledeski, D. G. McGarry, D. M. Green, H. J. Mason,
M. R. Becker, R. S. Davis, W. R. Ewing, W. P. Dankulich,
V. E. Manetta, R. L. Morris, A. P. Spada, D. L. Cheney,
K. D. Brown, D. J. Colussi, V. Chu, C. L. Heran, S. R. Morgan,
R. G. Bentley, R. J. Leadley, S. Maignan, J.-P. Guilloteau, C. T.
Dunwiddie and H. W. Pauls, J. Med. Chem., 1999, 42, 3572–3587.
21 R. L. Hannan, R. B. Barber and H. Rapoport, J. Org. Chem., 1979,
44, 2153–2158.
22 (a) P. Wipf and J.-K. Jung, J. Org. Chem., 2000, 65, 6319–6337;
(b) P. Wipf, J.-K. Jung, S. Rodriguez and J. S. Lazo, Tetrahedron,
2001, 57, 283–296.
23 N. G. Tregub, A. P. Knyazev and V. V. Mezheritskii, J. Org. Chem.
USSR, 1990, 26, 143–146.
(neat) 3400 (br), 1661, 1609, 1456, 1417, 1347, 1265, 956 cmϪ1
;
1H NMR (acetone-d6) δ 12.18 (s, 1H), 8.99 (s, 1H), 7.90 (dd, 1H,
J = 8.5, 0.8 Hz), 7.77 (dd, 1H, J = 8.2, 7.8 Hz), 7.50 (dd, 1H,
J = 8.5, 7.6 Hz), 7.49 (dd, 1H, J = 7.6, 1.0 Hz), 7.17 (d, 1H, J =
10.5 Hz), 7.15 (dd, 1H, J = 8.4, 1.0 Hz), 7.03 (dd, 1H, J = 7.5,
0.8 Hz), 6.94 (d, 1H, J = 8.1 Hz), 6.86 (d, 1H, J = 8.1 Hz), 6.44
24 G. E. Boswell and J. F. Licause, J. Org. Chem., 1995, 60, 6592–6594.
25 S. Hanessian, D. Delorme and Y. Dufresne, Tetrahedron Lett., 1984,
25, 2515–2518.
26 Natural products transferred with the Material Transfer Agreement
number BP-001-03.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 5 1 – 1 6 5 8
1657

View Article Online
27 Current molecular and morphological studies are being carried out
to assess the taxonomy of both, the anamorph and teleomorph of
the original isolate and will be published shortly. Both anamorph
and teleomorph specimens are preserved at INBio’s laboratories for
future reference, under accession number 3352.
for C20H20O5. Full assignments and further data will be published
shortly.
1
31 Identified by H-/13C-NMR, HSQC and HMBC experiments and
MS data. Compared with spectroscopic data reported in A. G. M.
Barrett, F. Blaney, A. D. Campbell, D. Hemprecht, T. Meyer, A. J. P.
White, D. Witty and D. J. Williams, J. Org. Chem., 2002, 67, 2735–
2750 Originally reported in S. Sakemi, T. Inagaki, K. Kaneda,
H. Hirai, E. Iwata, T. Sakakibara, Y. Yamauchi, M. Norcia, L. M.
Wondrack and J. A. Sutcliffe, J. Antibiot., 1995, 48, 134.
28 Collection permit number 005-96-VUI.
29 Identified by 1H/13C-NMR, HSQC, DEPT, COSY and HMBC
experiments and MS data. MK3018 was originally reported in
H. Ogishi, N. Chiba, T. Mikawa, T. Sasaki, S. Miyagi and M. Sezaki,
JP 01,294,686,1989; Chem. Abstr., 1990, 113, 38906q.
1
32 Identified by H-/13C-NMR, HSQC and HMBC experiments and
30 Palmarumycin CR1 spectroscopic data: 1H-NMR (400 MHz,
CD3OD, δ/ppm): 7.52 (d br, 2H, H-2Ј and 7Ј overlapped),
7.46 (dd br, 2H, H-3Ј and 6Ј overlapped), 6.98 (dd br, H, H-4Ј or 5Ј),
6.95 (dd br, 1H, H-5Ј or 4Ј), 5.92 (m, 2H, H-6 and 7), 4.76 (m,
1H, H-8), 4.54 (m, 1H, H-5), 4.31 (s br, 1H, H-4), 2.38 (m, 2H, H-4a
and 8a), 1.90 (m, 3H, H-2 and 32 overlapped), 1.76 (m, 1H, H-31);
13C NMR (100 MHz, CD3OD, δ ppm): 149.0 s (C-1Ј or C-8Ј), 147.8
s, (C-8Ј or C-1Ј), 135.7 s (C-4Јa), 134.8 d (C-6 or C-7), 129.3 d
(C-7 or C-6), 128.6 d (C-3Ј or C-6Ј), 128.4 d (C-6Ј or C-3Ј), 121.7 d
(C-2Ј or C-7Ј), 121.3 d (C-7Ј or C-2Ј), 115.2 s (C-8Јa), 110.6 d (C-4Ј
or C-5Ј), 110.2 d (C-5Ј or C-4Ј), 105.1 s (C-1), 67.7 d (C-5), 64.2
d (C-4), 63.2 d (C-8), 43.3 d (C4a or C8a), 42.3 d (C8a or C4a), 29.6
t (C-3), 26.7 t (C-2); HR-MS: obs. 340.1301, calc. 340.1311
MS data, and compared with published spectroscopic information
in Barrett et al., ref. 31. Originally reported in K. Krohn, A. Michel,
U. Floerke, H.-J. Aust, S. Draeger and B. Schulz, Annalen, 1994,
1093–1097 and 1099–1108.
33 P. Y. Gasdaska, J. E. Oblong, I. A. Cotgreave and G. Powis, Biochim.
Biophys. Acta, 1994, 1218, 292–296.
34 D. A. Scudiero, A. Monks, M. L. Hursey, M. J. Czerwinski, D. L.
Fine, B. J. Abbott, J. G. Mayo, R. H. Shoemaker and M. R. Boyd,
Cancer Res., 1988, 48, 589–601.
35 All synthetic intermediates and products were fully characterized
spectroscopically. See supplementary material for experimental
details†.
36 G. E. Boswell and J. F. Licause, J. Org. Chem., 1995, 60, 6592–6594.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 5 1 – 1 6 5 8
1658