Synthesis of biologically active nonnatural palmarumycin derivatives

Article abstract of DOI:10.1002/ejoc.201001503

Diels-Alder reaction of benzoquinone monoacetal 1 with 1-methoxy-1,3- butadiene (4) and dimethyl(1-methyl-3-vinylcyclohex-3-enyl)(phenyl)silane (5) gave the expected adducts 2 and 3, whereas with siloxy-dienes such as 3-methyl-1-(trimethylsiloxy)-1,3-buta

Full text of DOI:10.1002/ejoc.201001503

FULL PAPER
DOI: 10.1002/ejoc.201001503
Synthesis of Biologically Active Nonnatural Palmarumycin Derivatives
Abdulselam Aslan,[a] Sultan Altun,[a] Ishtiaq Ahmed,[a] Ulrich Flörke,[a] Barbara Schulz,[b]
and Karsten Krohn*[a]
Dedicated to Professor Horst Kunz on the occasion of his 70th birthday
Keywords: Palmarumycins / Diels–Alder reaction / Epoxidation / Weiz–Scheffer reaction / Dihydroxylation / Cycloaddition
Diels–Alder reaction of benzoquinone monoacetal 1 with 1-
latter conditions. The olefins 1, 2, 10, 11, and 20 were also
methoxy-1,3-butadiene (4) and dimethyl(1-methyl-3-vinylcy- transformed into the respective cis-diols 21a and 23a–26a.
clohex-3-enyl)(phenyl)silane (5) gave the expected adducts
2 and 3, whereas with siloxy-dienes such as 3-methyl-1-(tri-
methylsiloxy)-1,3-butadiene (6) a 1,2-aldol-type adduct 9
was isolated. The Diels–Alder adduct 2 was isomerized under
mild basic conditions to the olefin 10 and eliminated to the
diene 11 under mild acidic or thermal conditions. The olefins
2, 10 and 11 were subjected to epoxidation with m-chloroper-
benzoic acid and tert-butyl hydroperoxide under mild basic
conditions to afford the epoxides 12, 15, and 18 under the
former conditions and 13, 14, 16, 17, 19, and 20 under the
From theses diols the corresponding diacetates (b) and
acetonides (c) were prepared. The compounds were tested
against the Gram-negative bacterium Escherichia coli, the
Gram-positive bacterium Bacillus megaterium, and the fun-
gus Microbotryum violaceum. Whereas compound 25b was
the most active of the diacetates and the epoxide 18 the most
active of all substances, all of the compounds were biolo-
gically active against the three test organisms, equalling and
surpassing those of the natural palmarumycins.
transformed into the naturally occurring palmarumy-
cins CP1, CP2.[2] In this communication, the diolefin 2 was
the starting material for further transformations (see be-
low). However, prior to reporting on these reactions, we
wanted to test some Diels–Alder reactions of the dienophile
1 with the dienes 5, 6, and 7. The first experiment was con-
ducted with dimethyl(1-methyl-3-vinylcyclohex-3-enyl)-
(phenyl)silane (5), previously used in our group for the syn-
thesis of angucyclines.[3,4] Similarly, as reported for the reac-
tion with the 1-methoxy-1,3-butadiene (4), the addition was
performed without solvent (“neat”) with a fourfold excess
of the diene 5 to afford the crystalline adduct 3 in 90%
yield (Scheme 1).
Next, a concentrated solution of the benzoquinone acetal
1 in dichloromethane was treated with 3-methyl-1-(trimeth-
ylsiloxy)-1,3-butadiene (6)[5] to yield the allyl alcohol 8 in
72% yield after acidic hydrolysis of the intermediate silyl
ether. Although compound 8 is structurally very close to
the palmarumycins, there is no naturally occurring
bis(dioxy)spironaphthalene with a methyl group in position
7.
Introduction
Palmarumycins are a relatively new and large class of
fungal metabolites, derived by coupling of two units of 1,8-
dihydroxynaphthalene followed by a multitude of chemical
transformations. Their interesting structure and diverse bio-
activity have aroused the interest of natural-product and
synthetic chemists.[1] In a preceding communication, we de-
scribed the synthesis of palmarumycins CP1, CP2, and CJ-
12.371 methyl ether (see Scheme 1).[2] In this paper, we re-
port on the synthesis of biologically active nonnatural pal-
marumycin derivatives, employing the same strategy of
Diels–Alder reaction of dienes to benzoquinone mono-
acetal
1
and subsequent chemical transformations
(Scheme 1).
Results and Discussion
The addition of 1-methoxy-1,3-butadiene (4) to benzo-
quinone monoacetal 1 afforded the adduct 2, which was
Interestingly, neither (buta-1,3-dien-1-yloxy)trimethylsil-
ane nor the (4-methoxybuta-1,3-dien-2-yloxy)trimethylsil-
ane (Danishefsky diene) gave Diels–Alder adducts under
similarly mild conditions. A probable reaction mode be-
came clearer when the reaction of 1 was tried with 1,4-di-
[a] Department of Chemistry, University of Paderborn,
Warburger Straβe 100, 33098 Paderborn, Germany
Fax: +49-5251-60-3245
E-mail: k.krohn@uni-paderborn.de
[b] Institute of Microbiology, University of Braunschweig,
Spielmannstraße 7, 31806 Braunschweig, Germany
1176
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Biologically Active Nonnatural Palmarumycin Derivatives
Scheme 1. Diels–Alder reaction of dienes 4–7 with the dienophile 1. (a) 4–5 d, r.t, 95%; (b) 2 d, r.t., 90%; (c) 2 d, r.t., 72%; (d) 3 d, r.t.,
14%.
methoxy-1,4-bis(trimethylsilyloxy)buta-1,3-diene (7), again romethane) (Scheme 2). This way, the starting materials 2,
under neat conditions. We hoped that this diene could in- 10, and 11 were available in sufficient amounts for further
troduce the two oxygen functions present in many pal- transformation to potentially biologically active pal-
marumycin derivatives. However, the only product that marumycin derivatives.
could be isolated was the 1,2 adduct 9 in a very low yield
of 14%. This compound showed some instability on silica
gel, perhaps due to β-elimination of the OH group, and
could not be obtained in entirely pure form. However, the
NMR spectra unambiguously confirmed the proposed
structure, in particular the signals of C-1 (δ = 71.09 ppm),
C-2ЈЈ (methine) (δ = 48.02 ppm) and C-3ЈЈ (methylene) (δ =
32.2 ppm) in the 13C NMR spectrum.
The poor dienophilicity with some siloxy-dienes and the
potential to prepare palmarumycin analogues suggested ex-
ploiting the synthetic options of the easily available Diels–
Scheme 2. Base-catalyzed isomerization of diene 2 to 10 and ther-
mal or acid-catalyzed elimination to diene 11. (a) DMAP (0.1 mg),
Alder adduct 2.[2] The idea was to obtain starting materials
2 d, r.t., 70%; (b) xylene, 2 d reflux, 72%, or TMSCl, CH2Cl2, 4 h,
95%.
for further chemical transformation such as epoxidation or
hydroxylation of the double bonds in adduct 2.
The first experiment was treatment of 2 with a mild base
to initiate a β-elimination of the methoxy group to give the
A large number of palmarumycin derivatives carry epox-
diene 11. However, surprisingly, no β-elimination but an ide groups, which are most probably responsible for a vari-
isomerization to the olefin 10 took place. This base-cata- ety of biological activities such as cytotoxicity.[1] Therefore,
lyzed isomerization of 2 to 10 is surprising. However, calcu- the first reactions tried were epoxidations with meta-chloro-
lations of the relative energies of absolute lowest energy mi- perbenzoic acid (MCPBA) of the dienes 2, 10, and 11. As
nima with an MMFF-based (Merck molecular force field) expected, in all cases the most electron-rich double bond
conformational search and reoptimization of all minima was oxidized selectively to afford the corresponding mono-
with DFT showed that compound 10 is slightly more stable epoxides in 70, 63, and 88% yield, respectively. The relative
(ca. 2 kcal/mol) than the olefin 2.[7] By contrast, the conju- configuration of the racemic epoxides 12, 15 and 18 could
1
gated diene 11 was easily obtained by thermal isomerization be deduced from the coupling constants in the H NMR
(heating in xylene) in 72% yield or even almost quantita- spectra. In all cases, the oxygen atom was supposed to be
tively by treatment with dilute acid (TMSCl in moist dichlo- introduced from the less hindered convex side of the bicycle
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1177

A. Aslan, S. Altun, I. Ahmed, U. Flörke, B. Schulz, K. Krohn
FULL PAPER
tetralene molecule, similarly as in 18 and structurally con- deficient double bond (in our case the enone or vinylogous
firmed by X-ray analysis (Figure 1).
double bonds) followed by elimination of tert-butyl alcohol
to form the α,β-epoxy ketone.
The fist reaction performed was the epoxidation of pal-
marumycin CP1 methyl ether (13a) and palmarumycin CP1
(13b) in order to obtain optically enriched compounds for
biological testing and to test the reaction conditions. We
used the procedure of Barrett et al.[8] with dichloromethane
instead of toluene as the solvent (Scheme 3). The products
were isolated in essentially quantitative yield, and the phe-
nol 14b was produced in much higher enantiomeric excess
(Ͻ99% ee) than the methyl ether 14a (48% ee), thus con-
firming the results obtained by Barrett et al.[9] The two aro-
matic sidearms in the enones 13a,b direct the oxidant pref-
erentially to the Si face of the enone. This and the much
higher ee values for the phenol 14b are discussed in detail
by Barret et al.[8]
Figure 1. Molecular structure of epoxy-diene 18. Anisotropic dis-
placement ellipsoids are shown at the 50% probability level.
The epoxidations of other olefins were performed by
The central C-11 atom lies 0.560(2) Å above the aromatic using the same procedure (Scheme 3). The spectrum of the
ring moiety, and the geometry around C-11 is a slightly epoxidation products of the triene 11 strongly depended on
distorted tetrahedron with angles in the range of 104.9(1)– the reaction time. It would be expected that the most elec-
113.2(1)°. The epoxy moiety is almost perpendicular to the tron-deficient double bonds would be epoxidized most
six-membered ring; the corresponding O3–C14–C13 and rapidly. In fact, in one experiment, a 77% yield of the
O3–C15–C16 angles measure 116.35(15)° and 116.01(15)°, monoepoxide 19 and a 15% yield of the diepoxide 20 were
respectively.
isolated. The triepoxide 17 was formed in 92% yield under
The other epoxidations were performed according to prolonged reaction times. Interestingly, also the unexpected
Weiz–Scheffer[6] in basic media (NaOH) with N-benzylcin- diepoxide 16 was isolated in one experiment in 8% yield
chonium chloride as the phase-transfer catalyst and tert- together with 80% of the triepoxide 17 with the Diels–Alder
butyl hydroperoxide (TBHP) as the oxygen source. This adduct 2 as the starting material. We presume that this is
epoxidation has a different mechanism and proceeds by a the result of elimination of the 5-methoxy group from a 5-
Michael-type addition of the TBHP anion to the electron- methoxy-2,3;6,7-diepoxide intermediate. In the diepoxide
Scheme 3. Epoxidation of olefins. (a) 1 equiv. MCPBA in CH2Cl2; (b) N-benzylcinchonium chloride, TBHP in CH2Cl2, NaOH, 24 h, r.t.
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Biologically Active Nonnatural Palmarumycin Derivatives
16, electron deficiency of the isolated 4a,5 double bond is
missing, and further epoxidation under Weiz–Scheffer con-
ditions is probably very slow. Therefore, under careful TLC
monitoring, the yield of the diepoxide 16 could be opti-
mized, and in one case a 75% yield of 16 was obtained. The
formation of the triepoxide starting from the methyl ether
2 is easily explained by elimination of the methoxy group
and further slow epoxidation under prolonged reaction
times. The exact timing of methoxy group elimination and
epoxidations is not known. With the epoxides 15, 17 and
18 in hand, we could optimize the reaction times required
for the optimum yield of these individual epoxides by TLC
monitoring starting from triene 11 (see Experimental Sec-
tion).
The relative and absolute stereochemistry of the epoxides
16–20 could not be elucidated conclusively from their NMR
spectra as shown in the structures in Scheme 3. Relevant
protons for analysis of the coupling constants or Over-
hauser effects were missing in all cases. However, they all
represent compounds with only one relative stereochemistry
as confirmed by analysis of their NMR spectra. Also, the
individual enantiomeric excess is not known due to lack of
compounds for comparison of the specific optical rotations.
In the next section, the olefins 1, 2, 10, 11, and 20 were
subjected to cis-dihydroxylations with catalytic amounts of
osmium tetroxide and N-methylmorpholine N-oxide as the
oxidant in THF (Scheme 4).[10] Again, in all relevant cases
(2, 10, and 11), the least electron-rich double bonds were
dihydroxylized to the corresponding diols 23a–25a in ac-
Scheme 4. cis-Hydroxylation of the olefins 1, 2, 10, 11, and 20 to
the diols 21a (65%), 23a (86%), 24a (88%), 25a (75%), and 26a
ceptable yields. But the osmylation was also possible at pro- (90%) and conversion into the corresponding acetates 22b (60%),
23b (96%), 24b (97%), and 25b (95%), and 26b (98%) and the
longed reaction times with the less reactive enones 1 and
20, which were transformed in good yields to the cis-diols
21a and 26a. All products are racemic, and the relative ste-
acetonides 21c and 23c–25c. (a) Catalytic OsO4 (0.1 equiv.) in
tBuOH, NMO (1 equiv.), H2O/THF, 6–48 h; (b) pyridine, Ac2O;
cat. DMAP, 6–12 h, r.t.; (c) catalytic perchloric acid (60%,
0.01 mL), acetone (10 mL), 2,2-dimethoxypropan (0.14 mmol), 21c
(66%), 24c (98%), 25c (97%), and 26c (98%).
reochemistry could be deduced from the coupling constants
1
in the H NMR spectra.
Next, the cis-diols were transformed into the correspond-
ing acetates (Scheme 4). Not surprisingly, the diol 21a
underwent β-elimination to form the stable benzoquinone
acetal monacetate 22b in 60% yield. The acetylations of all
other diols 23a–26a were uneventful, and the diacetates
23b–26b were isolated in essentially quantitative yields. The
diacetates served as valuable samples for testing for antimi-
crobial activity (see below), and they also provided ad-
ditional NMR spectroscopic data to secure the relative ste-
reochemistry of the diols.
yield. As stated earlier, methyl groups on the palmarumycin
ring system do not occur naturally. Next, we prepared the
oxime 28 starting again from the palmarumycin CP1 methyl
ether 13a (Scheme 5). The (E) or (Z) configuration of the
oxime hydroxy group could not be established unambigu-
ously. The intuitively favored (E) configuration requires a
seven-membered ring for chelation to the neighboring
methoxy group. The chemical shifts in the 13C NMR spec-
The same twofold purpose was expected from the corre-
sponding acetonides 22c–26c. With exception of 21c (66%),
they were prepared in 97–98% yield by reaction of the diols
with 2,2-dimethoxypropan in acetone with perchloric acid
as the catalyst. It was particularly interesting to see the in-
crease in the coupling constants caused by the transition
from the flexible acetates (gauche conformation) to the cor-
responding acetonides (synclinal conformation; 2.8 Hz and
2.6 Hz for 24b and 26b to 4.1 and 7.5 Hz for 24c and 26c).
To conclude the preparation of palmarumycin deriva-
tives, the palmarumycin CP1 methyl ether 13a was treated
with methylmagnesium chloride. As expected, a clean 1,2-
Scheme 5. Formation of the tertiary alcohol 27, the oxime 28 and
the open-chain ethyl ether 29. (a) MeMgCl (1.2 equiv.), THF,
–78 °C to r.t., 80%; (NH2OH)HCl, ethanol, r.t., overnight, 95%;
addition to form the tertiary alcohol 27 occurred in 80% (c) TMSCl, ethanol, 40 °C, 6 h.
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FULL PAPER
tra of the methoxy carbon atoms of 13a and 28 are virtually
After the successful synthesis of the diols 21a, 23a, 24a,
unchanged, and this suggests the (Z) configuration as 25a and 26a, these compounds were also tested for their
shown in Scheme 5. In another reaction, the spiro acetal antibacterial and antifungal activities (Table 2). All of the
was opened. Under strongly acidic conditions, attained by diols had quite promising biological activities, in particular
heating the Diels–Alder adduct 2 in a mixture of TMSCl in the diol 25a with both antifungal and antibacterial inhibi-
ethanol, the acetal was opened, the methoxy group elimin- tions. The tests against the Gram-positive bacterium with
ated, and the resulting cation trapped by the solvent to form some of the diols (23a, 24a, and 26a) and epoxides (9, 14a,
the ethyl ether 29.
19) resulted in only partial inhibitions (p.i.), i.e. there was
some growth within the inhibition zone, suggesting that
some of the B. megaterium individuals were relatively resist-
ant to these compounds.
Biological Activity
Testing of the acetonide derivatives against the same bac-
terial and fungal test organisms again demonstrated excel-
lent biological activities (Table 3). 6,7,8,8a-Pentahydrospi-
ro[naphthalene-1,2Ј-naphtho[1,8-de][1,3]dioxin]-4-one 6,7-
acetonide (25c) had the most pronounced activities, both
against the two bacteria and against the fungus M. vi-
olaceum. It is quite remarkable that the acetonide 24c also
significantly inhibited B. megaterium. 5-Methoxyspiro-
Table 1 summarizes the test results for biological activi-
ties of the synthetic epoxide palmarumycins, which were
tested in an agar diffusion assay at a concentration of
0.05 mg against the Gram-negative bacterium Escherichia
coli, the Gram-positive bacterium Bacillus megaterium, and
the fungus Microbotryum violaceum. Whereas the epoxide
18 was the most active of the substances, all of the com-
pounds were biologically active against the three test organ-
isms, most with quite substantial zones of inhibition. Inter-
esting, and somewhat unusual is the fact that inhibition of
the Gram-negative bacterium E. coli, which is often resist-
[naphthalene-1,2Ј-naphtho[1,8-de][1,3]dioxin]-4-one
2,3-
acetonide (26c) only led to a partial inhibition of B. megat-
erium.
Synthesis of the diacetates 23b–26b resulted in yields
ant to antimicrobial agents, was often more pronounced of Ͼ95% (Scheme 4). The tests for biological activities
than that of the Gram-positive bacterium B. megaterium. again showed that all of the compounds were biologically
In Table 1, the data for inhibition of palmarumycin CP1 very active, both against the bacterial and the fungal test
and CP2 from the literature[11] for E. coli and B. megaterium organisms (Table 4). Compound 25b was the most active of
are also included for comparison; they show much lower the diacetates, with radii of zones of inhibition of up to
activity than the synthetic compounds.
20 mm (!).
Table 1. Biological activities of the palmarumycin epoxide derivatives tested in an agar diffusion assay.[a]
Compound
Escherichia coli
Bacillus megaterium
Microbotryum violacaeum
29
9
14a
18
16
19
14b
9
7
9
10
7
9
10
3–4
0
28
30
12
p.i. 7
p.i. 10
p.i. 15
15
12
p.i. 9
15
2
2
20
25
7
9
10
23
10
10
13
–
–
0
0
0
[11]
Palmarumycin CP1[11]
Palmarumycin CP2
Penicillin
Streptomycin
Acetone
0
[a] 0.05 μg of the test or control compound dissolved in acetone, applied to a filter disc and sprayed with a suspension of the respective
test organism. Radii of the zones of inhibition given in mm. p.i. = partial inhibition.
Table 2. Biological activities of the palmarumycin diol derivatives tested in an agar diffusion assay.[a]
Compound
Escherichia coli
Bacillus megaterium
Microbotryum violacaeum
21a
23a
10
7
9
12
p.i. 9
20
p.i. 7
p.i. 12
20
10
9
18
10
8
0
0
25a
24a
26a
Penicillin
Streptomycin
Acetone
7
10
28
30
12
25
0
0
[a] See Table 1.
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Biologically Active Nonnatural Palmarumycin Derivatives
Table 3. Biological activities of the palmarumycin acetonide derivatives 24c–26c, tested in an agar diffusion assay.[a]
Compound
Escherichia coli
Bacillus megaterium
Microbotryum violacaeum
25c
24c
10
7
7
28
30
12
18
15
PI 9
20
25
0
20
10
10
0
0
0
26c
Penicillin
Streptomycin
Acetone
[a] See Table 1.
Table 4. Biological activities of the palmarumycin diacetate derivatives 23b–26b, tested in an agar diffusion assay.[a]
Compound
Escherichia coli
Bacillus megaterium
Microbotryum violacaeum
23b
25b
9
PI 10
20
PI 9
PI 10
20
25
0
9
16
10
10
0
0
0
10
10
8
28
30
12
24b
26b
Penicillin
Streptomycin
Acetone
[a] See Table 1.
the past proved to be accurate initial test organisms for antibacte-
rial and antifungal activities.
Conclusion
All of the synthetic palmarumycins – epoxides, diols and
diacetates – showed considerable antifungal and antibacte-
rial activities, equaling and slightly surpassing those of the
natural palmarumycins.[11,12] However, these relatively high
activities are not yet sufficient for application in crop pro-
tection, and further studies are warranted. But the results
suggest that the enone system of ring A is a major pharma-
cophore activated by oxygen substituents on ring B that
may modify the lipophilicity of the compounds.
Diels–Alder Product 3: A suspension of ketal 1 (100 mg, 0.4 mmol)
in dimethyl(1-methyl-3-vinylcyclohex-3-enyl)(phenyl)silane (5)
(307 mg, 1.2 mmol) was stirred under argon for 2 d (TLC monitor-
ing). The mixture was separated by column chromatography on
silica gel of afford the Diels–Alder adduct 3 as a yellow solid
1
(182 mg, 90%); m.p. 84–86 °C. H NMR (500 MHz, CDCl3): δ =
0.36 (s, 3 H, SiCH3), 0.39 (s, 3 H, SiCH3), 0.80 (s, 3 H, CCH3),
0.83–0.97 (m, 2 H, 5a-H, 6a-H), 1.56–1.65 (m, 2 H, 5b-H, 6b-H),
1.90–1.94 (m, 1 H, 8-H), 2.13–2.24 (m, 2 H, 10-H), 2.30–2.26 (m,
1 H, 8-H), 2.67–2.76 (m, 1 H, 4b-H), 2.79–2.83 (m, 1 H, 4a-H),
3.32–3.34 (m, 1 H, 10a-H), 5.26 (d, J = 3.2 Hz, 1 H, 9-H), 6.03 (d,
J = 10.2 Hz, 1 H, 3-H), 6.56 (d, J = 10.2 Hz, 1 H, 2-H), 6.95 (m,
2 H, 2Ј-H, 7Ј-H), 7.34 (m, 3 H, Ph-H), 7.42–7.53 (m, 4 H, 3Ј-
H, 4Ј-H, 5Ј-H, 6Ј-H), 7.54–7.59 (m, 2 H, Ph-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = –3.9 [q, Si(CH3)2], –3.4 [q, Si(CH3)2], 22.2
(s, C-7) 24.0 (t, C-10), 26.2 (t, C-5), 28.1 (q, CH3), 36.7 (t, C-6),
40.9 (d, C-10a), 42.9 (t, C-8), 44.2 (d, C-4b), 46.7 (d, C-4a), 100.1
(s, C-1), 109.1 (d, C-7Ј), 109.7 (d, C-2Ј), 113.8 (s, C-8aЈ), 117.2 (d,
C-9), 120.7 (d, C-6Ј), 120.9 (d, C-3Ј), 127.4 (d, C-5Ј), 127.5 (d, C-
4Ј), 128.5, 128.6, 128.8 (d, 3C-Ph), 132.7 (d, C-3), 134.3 (s, C-4aЈ),
134.5, 134.6 (d, 2C-Ph), 138.0 (d, C-2), 138.4 (s, C-8a), 138.6 (s, C-
Experimental Section
General Experimental Procedures: Melting points were determined
with a Gallenkamp melting point apparatus. Optical rotations were
measured with a Perkin–Elmer 241 MC polarimeter. IR spectra
were recorded with a Nicolet-510P spectrometer. NMR spectra
were recorded with a Bruker Avance-500 NMR spectrometer with
TMS as internal standard. Assignments of NMR signals are based
on 2D spectra. 13C notations are: s (quaternary C), d (tertiary C),
t (secondary C), q (primary C). EI mass spectra were obtained with
an MAT 8200 mass spectrometer. CD spectra were recorded with
a J-810 spectropolarimeter. Silica gel (70–230 mesh) was used for
column chromatography.
Ph), 146.6, 147.4 (s, C-1Ј, C-8Ј), 199.2 (s, C-4) ppm. IR (KBr): ν =
˜
2919, 1692, 1607, 1586, 1412, 1381, 1272, 1179, 1109, 1078, 1030,
964, 823, 757, 736, 701 cm–1. UV (CH2Cl2): λmax (lgε) = 327 (3.21),
312 (3.30), 298 (3.54), 231 (4.13) nm. MS (EI, 70 eV): m/z (%) =
506 (20) [M+], 370 (10), 279 (12), 250 (51), 197 (36), 185 (81), 135
(80), 97 (87), 55 (100), 28 (34). HRMS (EI, 70 eV): calcd. for
C33H34O3Si 506.22772; found 447.21680.
Agar Diffusion Test for Biological Activity: Compounds 1–11 were
dissolved in acetone at a concentration of 1 mg/mL; 50 µL of the
solution (0.05 μg of compound) was pipetted onto a sterile filter
disc (Schleicher & Schuell, 9 mm), which was placed onto an appro-
priate agar growth medium for the respective test organism and
subsequently sprayed with a suspension of the test organism. The
test organisms were the Gram-negative bacterium Escherichia coli,
the Gram-positive bacterium Bacillus megaterium (both grown on
Hydroxy-methyl Spiro Ketal 8: A solution of benzoquinone acetal
1, (0.5 g, 1.9 mmol) in CH2Cl2 (2 mL) was treated with 3-methyl-1-
(trimethylsiloxy)-1,3-butadiene (6),[5] (0.4 g, 5.9 mmol) and stirred
under nitrogen at room temp. for 4 d. Excess of diene and solvent
NB medium), and the fungus Microbotryum violaceum (MPY me- were removed under reduced pressure, and methanolic HCl
dium). Commencing in the middle of the filter disc, the radius of
the zone of inhibition was measured in mm. These microorganisms
were chosen because (a) they are non-pathogenic and (b) had in
(1.56 mmol/mL) was added at 0 °C until the color changed to faint
yellow. The acidic solution was extracted with CH2Cl2 (3ϫ2 mL),
the combined organic phases were dried (Na2SO4), filtered, and
Eur. J. Org. Chem. 2011, 1176–1188
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1181

A. Aslan, S. Altun, I. Ahmed, U. Flörke, B. Schulz, K. Krohn
FULL PAPER
the solvent was removed under reduced pressure. The residue was
purified by filtration through a pad of silica gel (CH2Cl2) to afford
the allyl alcohol 8 as a yellow solid (510 mg, 72%); m.p. 57–58 °C.
1HNMR (500 MHz, CDCl3): δ = 1.67 (s, 3 H, CH3), 2.15 (m, 2 H,
8-H), 2.97 (m, 1 H, 8a-H), 3. 59 (m, 1 H, 4a-H), 4.50 (m, 1 H, 5-
H), 5.58 (d, J = 11.0 Hz, 1 H, 6-H), 6.10 (d, J = 10.0 Hz, 1 H, 3-
H), 6.70 (dd, J = 3.0, J = 10.0 Hz, 1 H, 2-H), 6.88 (br. dd, 2 H,
Spiro Ketal 11: A solution of the Diels–Alder adduct 2 (1.0 g,
2.99 mmol) in dry xylene (20 mL) was heated under Ar under re-
flux for 2 d (TLC monitoring, CH2Cl2). The solvent was removed
at 50 °C under reduced pressure and the residue purified by column
chromatography on silica gel (CH2Cl2) to afford 0.65 g of elimi-
nation product 11 as a yellow solid (72%); m.p. 130–132 °C. Alter-
natively, a solution of 2 (668 mg, 2 mmol) in CH2Cl2 (5 mL) was
7Ј-H, 2Ј-H), 7.46 (t, J = 8.1 Hz, 2 H, 3Ј-H, 6Ј-H), 7.53 (dd, J = 8.1, treated with TMSCl (0.1 mL). The solution was kept at room temp.
J = 1.5 Hz, 2 H, 4Ј-H, 5Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ for 10 h (TLC monitoring), the solvent was removed and the resi-
= 22.8 (q, CH3), 28.1 (t, C-8), 41.9 (d, C-8a), 46.3 (d, C-4a), 69.3
(s, C-5), 99.3 (s, C-1), 109.69 (d, C-7Ј), 110.13 (d, C-2Ј), 114.17 (s, 95%). H NMR (500 MHz, CDCl3): δ = 2.73 (m, 1 H, 8-H), 2.95
C-8aЈ), 121.33 (d, C-5Ј), 121.54 (d, C-4Ј), 123.26 (d, C-6), 125.45 (m, 1 H, 8-H), 3.58 (m, 1 H, 8a-H), 6.18 (d, J = 10.4 Hz, 1 H, 3-
(d, C-3), 127.95 (d, C-3Ј, C-6Ј), 134.86 (d, C-7), 134.66 (s, C-4aЈ), H), 6.23 (m, 1 H, 7-H), 6.33 (m, 1 H, 6-H), 6.79 (d, J = 10.4 Hz,
138.78 (d, C-2), 146.76 (s, C-8Ј), 147.55 (s, C-1Ј), 202.32 (s, C-4) 1 H, 2-H), 6.86 (d, J = 7.5 Hz, 1 H, 7Ј-H), 6.98 (d, J = 7.5 Hz, 1
due crystallized from diethyl ether (1 mL) to afford 11 (57 mg,
1
ppm. IR (KBr): ν = 3424, 1670, 1601, 1505, 1413, 1385, 1077, H, 2Ј-H), 7.25 (t, J = 4.6 Hz, 1 H, 5-H), 7.39 (t, J = 8.4 Hz, 1 H,
˜
826 cm–1. UV (CH2Cl2): λmax (lgε) = 329 (1.66), 314 (2.22), 300 6Ј-H), 7.45 (t, J = 7.5 Hz, 1 H, 3Ј-H), 7.51 (d, J = 8.4, Hz, 2 H,
(2.49), 299 (2.49) nm. MS (EI, 70 eV): m/z (%) = 334 (16) [M+], 160
(100), 252 (22), 77 (12). HRMS (EI, 70 eV): calcd. for C21H18O4
334.1205; found 334.1212.
4Ј-H, 5Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 22.6 (t, C-8),
40.7 (d, C-8a), 97.3 (s, C-1), 109.4 (d, C-2Ј,C-7Ј), 113.2 (s, C-8aЈ),
120.7 (d, C-4Ј, C-5Ј), 123.5 (d, C-6), 127.4 (d, C-3Ј, C-6Ј), 127.5 (d,
C-7), 132.4 (d, C-3), 132.9 (d, C-4a), 134.2 (s, C-4aЈ), 134.3 (d, C-
5), 141.9 (d, C-2), 146.4 (s, C-1Ј, C-8Ј), 185.2 (s, C-4) ppm. IR
Spiro Alcohol 9: A mixture of benzoquinone acetal 1 (100 mg,
0.38 mmol) and 1,4-dimethoxy-1,4-bis(trimethylsiloxy)-1,3-butadi-
ene (7)[13] (632 mg, 1.52 mmol) was stirred under Ar at 22 °C for
3 d. Excess of diene was removed under high vacuum, and the resi-
due purified by repeated preparative layer chromatography (1 mm;
n-hexane/AcOEt, 95:5) to afford the crude 1-hydroxybenzoquinone
acetal 9 as a slightly yellow oil (20 mg, 14%). 1H NMR (500 MHz,
(KBr): ν = 3450, 1667, 1634, 1601, 1541, 1406, 1384, 1259, 1134,
˜
1085, 742 cm–1. UV (CH2Cl2): λmax (lgε) = 327 (3.11), 312 (3.24),
296 (3.33), 232 (3.80) nm. MS (EI, 70 eV): m/z (%) = 302 (80) [M+],
115 (100), 149.1 (66), 57 (62), 43 (44), 71 (41). HRMS (EI, 70 eV):
calcd. for C20H14O 302.09429; found 302.09572.
CDCl3): δ = 2.5 (m, 2 H, 2ЈЈ-H), 3.1 (m, 1 H, 3Ј-H), 3.69 (s, 3 H, Methoxy-epoxy Spiro Ketal 12: Olefin 10 (0.020 g, 0.054 mmol) in
OCH3), 3.76 (s, 3 H, OCH3), 6.01 (d, J = 11.3 Hz, 1 H, 2-H), 6.15
(d, J = 11.0 Hz, 2 H, 3-H, 5-H), 6.28 (d, J = 11.0 Hz, 2 H, 6-H),
7.02 (d, J = 8.0, Hz, 2 H, 2Ј-H, 7Ј-H), 7.46 (d, J = 8.0 Hz, 2 H, 4Ј-
dry CH2Cl2 (5 mL) was treated with a stoichiometric amount of
m-CPBA (0.005 g, 0.029 mmol). The mixture was stirred at room
temp. under nitrogen for 1 d, the solution was diluted by addition
H, 5Ј-H) 7.56 (t, J = 8.0 Hz, 2 H, 3Ј-H, 6Ј-H) ppm. 13C NMR of CH2Cl2 (5 mL), shaken with an aqueous Na2S2O4 solution
(125 MHz, CDCl3): δ = 32.2 (t, C-3ЈЈ), 48.02 (d, C-2ЈЈ), 51.5 (q, (0.2 n, 1 mL), and subsequently with a solution of NaHCO3 (0.2 n,
2ϫOCH3), 71.09 (s, C-1), 92.03 (s, C-4), 109.7 (d, C-2Ј, C-7Ј),
113.5 (s, C-8aЈ), 120.6 (d, C-4Ј, C-5Ј), 126.1 (d, C-3Ј, C-6Ј), 127.4
(d, C-2, C-6), 134.1 (s, C-4aЈ), 135.8 (d, C-3, C-5), 147.5 (d, C-1Ј,
C-8Ј), 172.6 (s, 2ϫCO) ppm.
2 mL) and water (2 mL). The organic phase was dried (Na2SO4),
the solvent removed under reduced pressure, and the residue puri-
fied by column chromatography on silica gel to afford epoxide 12 as
a white solid (0.012 g, 63%); m.p. 115–117 °C. 1H NMR (500 MHz,
CDCl3): δ = 2.41 (m, 2 H, 6-H), 2.73 (m, 1 H, 8a-H), 2.88 (m, 1
H, 4a-H), 3.25 (dd, J = 10.0, 4.5 Hz, 1 H, 8-H), 3.45 (dd, J = 10.0,
4.5 Hz, 1 H, 7-H), 3.70 (s, 3 H, OCH3), 4.23 (m, 1 H, 5-H), 6.03
(d, J = 10.0 Hz, 1 H, 2-H), 6.79 (d, J = 10.0 Hz, 1 H, 3-H), 6.87
(dd, J = 10.0, 3.0 Hz, 1 H, 7Ј-H), 6.98 (dd, J = 8.1, 1.5 Hz, 1 H,
2Ј-H), 7.54 (t, J = 8.1 Hz, 2 H, 3Ј-H, 6Ј-H), 7.53 (dd, J = 8.1,
1.5 Hz, 2 H, 4Ј-H, 5Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
22.6 (d, C-8a), 29.6 (t, C-6), 37.8 (d, C-4a), 47.64 (d, C-8), 52.4 (d,
C-7), 57.8 (q, OCH3), 72.7 (s, C-5), 97.4 (s, C-1), 109.2 (d, C-7Ј),
109.8 (d, C-2Ј), 113.3 (s, C-8aЈ), 120.8 (d, C-5Ј), 121.0 (d, C-4Ј),
127.5 (d, C-6Ј), 127.5 (d C-3Ј), 131.6 (d, C-3), 134.2 (s, C-4aЈ),
141.8 (d, C-2), 146.7 (s, C-8Ј), 147.1 (s, C-1Ј), 197.3 (s, C-4) ppm.
Methoxy Spiro Ketal 10: A solution of 2 (0.20 g, 0.06 mmol) in dry
CH2Cl2 (10 mL) as treated under Ar with 4-(dimethylamino)-
pyridine (DMAP) (0.02 g, 0.16 mmol). The solution was stirred at
room temp. for 2 d (TLC monitoring). After completion of the re-
action, the mixture was treated with water (10 mL), extracted twice
with CH2Cl2, and the combined organic phases were dried with
MgSO4, filtered, and the solvent was removed under reduced pres-
sure. Chromatography of the residue on silica gel (CH2Cl2) afforded
the rearranged methyl ether as a white solid (0.14 g, 70%); m.p.
203–204 °C. 1H NMR (500 MHz, CDCl3): δ = 2.46 (m, 1 H, 6-H),
2.68 (m, 1 H, 6-H), 2.80 (m, 1 H, 8a-H), 3.17 (m, 1 H, 4a-H), 3.56
(s, 3 H, OCH3), 4.23 (m, 1 H, 5-H), 5.94 (dd, J = 8.1, 1.5 Hz, 1 H,
8-H), 5.98 (m, 1 H, 7-H), 6.01 (d, J = 10.3 Hz, 1 H, 2-H), 6.77 (d,
J = 10.3 Hz, 1 H, 3-H), 6.89 (dd, J = 7.5, 0.7 Hz, 1 H, 7Ј-H), 6.96
(dd, J = 7.5, 0.7 Hz, 1 H, 2Ј-H), 7.43 (dd, J = 8.4, 7.5 Hz, 2 H, 3Ј-
H, 6Ј-H), 7.53 (dd, J = 8.4, 0.7 Hz, 2 H, 4Ј-H, 5Ј-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 23.02 (t, C-6), 44.4 (d, C-8a), 48.1
(d, C-4a), 56.3 (q, OCH3), 73.7 (s, C-5), 97.5 (s, C-1), 109.2 (d, C-
7Ј), 109.9 (d, C-2Ј), 113.2 (s, C-8aЈ), 120.8 (d, C-5Ј), 121.1 (d, C-
4Ј), 125.5 (d, C-7), 127.5 (d, C-3Ј), 127.54 (d, C-6Ј), 127.6 (d, C-3),
130.9 (d, C-8), 134.2 (s, C-4aЈ), 141.6 (d, C-2), 146.8 (s, C-8Ј), 147.1
IR (KBr): ν = 3467, 2906, 2852, 1656, 1409, 1370, 1274, 1087, 932,
˜
730 cm–1. UV (CH2Cl2): λmax (lgε) = 327 (3.10), 312 (3.23), 297
(3.32), 233 (3.92) nm. MS (EI, 70 eV): m/z (%) = 350 (100) [M+],
332 (60), 77 (20), 27 (10). HRMS (EI, 70 eV): calcd. for C21H18O5
350.1154; found 350.11539.
Methoxy-epoxy Spiro Ketal 15: The Diels–Alder adduct 2 (20.0 mg,
0.06 mmol) in dry CH2Cl2 (10 mL) was treated m-CPBA (10.4 mg,
0.06 mmol) and stirred at room temp. for 2 d. Workup proceeded
as described for 12 to afford epoxide 15 as a white solid (13.2 mg.
(s, C-1Ј), 198.3 (s, C-4) ppm. IR (KBr): ν = 1682, 1600, 1408, 1377, 63%); m.p. 115–117 °C. 1H NMR (500 MHz, CDCl3): δ = 1.88
˜
1274, 1268, 1087, 932, 842, 731 cm–1. UV (CH2Cl2): λmax (lgε) =
(ddd, J = 16.0, 11.4, 2.9 Hz, 1 H, 8-H), 2.41 (m, 1 H, 8-H), 2.62
327 (3.10), 312 (3.25), 298 (3.34), 233 (3.91) nm. MS (EI, 70 eV): (m, 1 H, 8a-H), 3.26 (m, 1 H, 4a-H), 3.33 (d, J = 4.9 Hz, 1 H, 5-
m/z (%) = 334 (100) [M+], 302 (22), 197 (55), 160 (20), 115 (42), 84 H), 3.38 (d, J = 4.0 Hz, 1 H, 6-H), 3.54 (s, 3 H, OCH3), 3.57 (m,
(30), 71 (10). HRMS (EI, 70 eV): calcd. for C21H18O4 334.1205; 1 H, 7-H), 6.12 (d, J = 10.3 Hz, 1 H, 3-H), 6.79 (d, J = 10.3 Hz, 1
found 334.1212.
H, 2-H), 6.94 (d, J = 7.5 Hz, 2 H, 2Ј-H, 7Ј-H), 7.44 (t, J = 8.1 Hz,
1182
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1176–1188

Biologically Active Nonnatural Palmarumycin Derivatives
2 H, 3Ј-H, 6Ј-H), 7.52 (dd, J = 8.1, 1.5 Hz, 2 H, 4Ј-H, 5Ј-H) ppm.
13C NMR (125 MHz, CDCl3): δ = 22.4 (t, C-8), 39.2 (d, C-8a),
45.8 (d, C-7), 52.7 (d, C-4a), 54.5 (d, C-6), 58.4 (q, OCH3), 77.7
(d, C-5), 99.9 (s, C-1), 109.2 (d, C-7Ј), 109.6 (d, C-2Ј), 113.6 (s, C-
8aЈ), 121.1 (d, C-5Ј), 121.3 (d, C-4Ј), 127.9 (d, C-3Ј, C-6Ј), 132.4
(500 MHz, CDCl3): δ = 2.05 (ddd, J = 14.7, 11.9, 0.7 Hz, 1 H, 8-
H), 2.70 (ddd, J = 14.7, 7.0, 3.2 Hz, 1 H, 8-H), 3.44 (d, J = 4.3 Hz,
1 H, 3-H), 3.45 (ddd, J = 15.6, 7.0, 2.7 Hz, 1 H, 8a-H), 3.51 (t, J
= 4.1 Hz, 1 H, 6-H), 3.68 (m, 1 H, 7-H), 3.81 (d, J = 4.3 Hz, 1 H,
2-H), 6.86 (dd, J = 7.6, 0.8 Hz, 1 H, 7Ј-H), 7.07 (dd, J = 7.6, 0.8 Hz,
(d, C-3), 134.3 (s, C-4aЈ), 138.5 (d, C-2), 146.1 (s, C-8Ј), 146.9 (s, 1 H, 2Ј-H), 7.27 (dd, J = 4.1, 3.3 Hz, 1 H, 5-H) 7.40 (t, J = 7.6, Hz,
C-1Ј), 197.2 (s, C-4) ppm. IR (KBr): ν = 3434, 1629, 1411, 1384,
1 H, 6Ј-H), 7.48 (t, J = 7.6, Hz, 1 H, 3Ј-H), 7.52 (dd, J = 8.4,
0.9 Hz, 1 H, 5Ј-H), 7.54 (dd, J = 8.4, 0.9 Hz, 1 H, 4Ј-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 20.1 (t, C-8), 35.1 (d, C-8a), 45.8 (d,
C-6), 53.6 (d, C-7), 55.4 (d, C-3) 55.6 (d, C-2) 99.5 (s, C-1), 109.1
(d, C-7Ј), 110.1 (d, C-2Ј), 112.6 (s, C-8aЈ), 121.1 (d, C-4Ј, C-5Ј),
127.5 (d, C-6Ј), 127.7 (d, C-3Ј), 133.8 (s, C-4aЈ), 134.9 (d, C-5),
˜
1272, 1074, 1123, 821, 794 cm–1. UV (CH2Cl2): λmax (lgε) = 328
(3.10), 312 (3.22), 297 (3.32), 233 (3.92) nm. MS (EI, 70 eV): m/z
(%) = 350 (48) [M+], 322 (42), 256 (20), 162 (100), 134 (52), 84 (85),
43 (28). HRMS (EI, 70 eV): calcd. for C21H18O5 350.11542; found
350.11522.
146.4 (s, C-8Ј), 146.8 (s, C-1Ј), 190.7 (s, C-4) ppm. IR (KBr): ν =
˜
Epoxy Spiro Ketal 18: A solution of the diene 11 (50.0 mg,
0.16 mmol) in dry CH2Cl2 (20 mL) was treated with m-CPBA
(27.6 mg, 0.16 mmol) and stirred at room temp. for 4 h (TLC moni-
toring). Workup was performed as described for 12 to afford the
epoxide 18 as a yellow solid (46.3 mg, 88%); m.p. 85–87 °C. 1H
NMR (500 MHz, CDCl3): δ = 2.44 (ddd, J = 15.0, 11.3, 1.0 Hz, 1
H, 8-H), 2.81 (ddd, J = 15.0, 7.5, 2.5 Hz 1 H, 8-H), 3.50 (m, 1 H,
8a-H), 3.58 (t, J = 4.1 Hz, 1 H, 6-H), 3.79 (m, 1 H, 7-H), 6.18 (d,
J = 10.5 Hz, 1 H, 3-H), 6.83 (dd, J = 7.5, 0.7 Hz, 1 H, 7Ј-H), 6.88
(d, J = 10.5 Hz, 1 H, 2-H), 7.03 (dd, J = 7.5, 0.7 Hz, 1 H, 2Ј-H),
7.42 (d, J = 10.0 Hz, 1 H, 5-H), 7.62 (t, J = 8.1 Hz, 2 H, 3Ј-H, 6Ј-
H), 8.05 (dd, J = 8.1, 1.5 Hz, 2 H, 4Ј-H, 5Ј-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 20.8 (t, C-8), 40.3 (d, C-8a), 46.2 (d, C-6),
55.7 (d, C-7), 96.9 (s, C-1), 109.3 (d, C-2Ј,C-7Ј), 113.5 (s, C-8aЈ),
120.9 (d, C-4Ј, C-5Ј), 127.4 (d, C-3Ј, C-6Ј), 132.1 (d, C-3), 133.7 (d,
C-4a), 134.2 (s, C-4aЈ), 134.3 (d, C-5), 141.9 (d, C-2), 146.4 (s, C-
3446, 3033, 1701, 1629, 1607, 1413, 1380, 1270, 1145, 1121, 1083,
1051, 1023, 984, 971, 888, 819, 770, 758, 644, 625 cm–1. UV
(CH2Cl2): λmax (lgε) = 327 (3.08), 312 (3.20), 297 (3.30), 231 (3.90)
nm. MS (EI, 70 eV): m/z (%) = 334 (100) [M+], 305 (10), 171 (19),
167 (21), 160 (30), 149 (58), 115 (25), 71 (24), 57 (38). HRMS (EI,
70 eV): calcd. for C20H14O5 334.08411; found 334.08418.
Triepoxy Spiro Ketal 17: A solution of the triene 11 (50.0 mg,
0.16 mmol) in dry CH2Cl2 (10 mL) was treated with N-benzylcin-
chonium chloride (10 mg, 0.025 mmol), H2O (2 mL) and TBHP
in CH2Cl2 (3.17 m; 0.75 mL, 2.4 mmol). NaOH (0.10 m, 1.50 mL,
50 mol-%) was added, and the mixture was stirred under Ar at
room temp. for 2 d. Workup was performed as described for 14a
to afford the triepoxide 17 as a colorless solid (51.5 mg, 92%); m.p.
195–197 °C. 1H NMR (500 MHz, CDCl3): δ = 2.26 (ddd, J = 14.7,
11.8, 0.7 Hz, 1 H, 8-H), 2.45 (ddd, J = 14.7, 5.8, 3.8 Hz, 1 H, 8-
H), 3.34 (m, 1 H, 7-H), 3.47 (dd, J = 3.8, 2.5 Hz, 1 H, 6-H), 3.48
(d, J = 4.0 Hz, 1 H, 2-H), 3.54 (dd, J = 11.8, 5.8 Hz, 1 H, 8a-H),
3.83 (d, J = 4.0 Hz, 1 H, 3-H), 3.92 (d, J = 2.5 Hz, 1 H, 5-H), 7.00
(dd, J = 7.0, 0.7 Hz, 1 H, 7Ј-H), 7.06 (d, J = 7.0, 0.7 Hz, 1 H, 2Ј-
H), 7.43 (t, J = 8.2 Hz, 1 H, 6Ј-H), 7.47 (t, J = 8.2 Hz, 1 H, 3Ј-H)
7.53 (br. d, J = 8.2 Hz, 2 H, 4Ј-H, 5Ј-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 19.2 (t, C-8), 33.0 (d, 8a-H), 49.8 (d, C-2), 52.7 (d, C-
7), 54.8 (d, C-3), 54.9 (d, C-5), 55.6 (d, C-6), 57.3 (d, C-4a), 99.2
(s, C-1), 109.5 (d, C-7Ј), 109.9 (d, C-2Ј), 112.6 (s, C-8aЈ), 121.1 (d,
C-5Ј), 121.2 (d, C-4Ј), 127.6 (d, C-6Ј), 127.7 (d, C-3Ј), 134.2 (s, C-
4aЈ), 146.3 (s, C-8Ј), 146.6 (s, C-1Ј), 197.5 (s, C-4) ppm. IR (KBr):
1Ј, C-8Ј), 183.4 (s, C-4) ppm. IR (KBr): ν = 3059, 2977, 1677, 1607,
˜
1411, 1373, 1270, 894, 753, 715 cm–1. UV (CH2Cl2): λmax (lgε) =
327 (3.06), 312 (3.18), 297 (3.28), 233 (3.88) nm. MS (EI, 70 eV):
m/z (%) = 318 (40) [M+], 223 (21), 197 (30), 149 (62), 139 (100),
113 (51), 57 (53), 43 (32). HRMS (EI, 70 eV): calcd. for C20H14O4
318.0892; found 318.0891.
Methoxy-epoxy Spiro Ketal 14a: A solution of diene 2 (100 mg,
0.30 mmol) in dry CH2Cl2 (10 mL) was treated with N-benzylcin-
chonium chloride (10 mg, 0.025 mmol), H2O (2 mL) und TBHP in
CH2Cl2 (3.17 m; 1.40 mL, 4.5 mmol). An aqueous solution of
NaOH (0.10 m, 1.50 mL, 50 mol-%) was then added, and the mix-
ture was stirred under Ar at room temp. for 24 h (TLC monitoring).
The reaction mixture was acidified by addition of HCl (1 m,
0.8 mL), water was added (10 mL), and the mixture was extracted
twice with CH2Cl2 (20 mL). The organic phase was dried
(Na2SO4), the solvent removed under reduced pressure, and the
residue purified by column chromatography on silica gel to afford
the epoxide 14a as a yellow solid (97 mg, 96%); m.p. 188–190 °C.
[α]D = –140.35 (c = 0.28, CH2Cl2) (48% ee); ref.[9] [α]D = –291.3 (c
= 0.28, CH2Cl2). The spectroscopic data are identical with those in
the literature.[8]
ν = 3430, 1726, 1609, 1589, 1415, 1380, 1275, 1204, 1129, 1088,
˜
1054, 1023, 987, 879, 819, 799, 762, 735, 625 cm–1. UV (CH2Cl2):
λmax (lgε) = 327 (3.10), 312 (3.22), 297 (3.32), 232 (3.92) nm. MS
(EI, 70 eV): m/z (%) = 350 (100) [M+], 251 (11), 211 (8), 160 (19),
115 (18), 77 (10). HRMS (EI, 70 eV): calcd. for C20H14O6
350.07904; found 350.07908.
Epoxy Spiro Ketal 19: A Solution of triene 11 (50.0 mg, 0.16 mmol)
was treated as described for 14a and the mixture stirred for 6 h
(TLC monitoring) to yield the monoepoxides 19 as a white solid
(39.2 mg, 77%); m.p. 160–162 °C. From the less polar fraction 15%
of diepoxide 20 (8.0 mg, 0.024 mmol) was obtained. 1H NMR
(500 MHz, CDCl3): δ = 2.49 (m, 1 H, 8-H), 2.61 (m, 1 H, 8-H),
3.36 (d, J = 4.3 Hz, 3-H), 3.71 (m, 1 H, 8a-H), 3.75 (d, J = 4.3 Hz,
2-H), 6.10 (m, 1 H, 7-H), 6.28 (m, 1 H, 6-H), 6.87 (dd, J = 7.5,
0.7 Hz, 7Ј-H), 6.97 (dd, J = 7.5, 0.7 Hz, 2Ј-H), 7.06 (m, 1 H, 5-H),
7.33–7.46 (m, 4 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 21.8 (t, C-8), 37.9 (d, C-8a), 56.0 (d, C-3),
57.3 (d, C-2), 99.3 (s, C-1), 109.2 (d, C-7Ј), 109.8 (d, C-2Ј), 113.4
(s, C-8aЈ), 120.9 (d, C-5Ј), 121.0 (d, C-4Ј), 123.5 (d, C-6), 127.0 (d,
C-4a), 127.5 (d, C-6Ј), 127.6 (d, C-3Ј), 133.2 (d, C-7), 134.2 (s, C-
4aЈ), 135.8 (d, C-5), 146.7 (s, C-8Ј), 147.1 (s, C-1Ј), 191.9 (s, C-4)
Epoxy-hydroxy Spiro Ketal 14b: A solution of 13b (200 mg,
0.63 mmol) in dry CH2Cl2 (25 mL) was epoxidized as described for
14a to afford 14b as a yellow solid (207 mg, 0.62 mmol, 99%; m.p.
219–221 °C. [α]D = –340 (c = 1, CHCl3), (99.7% ee); ref. [α]D[9] –341
(c = 1, CHCl3). The spectroscopic data are identical with those in
the literature).[8]
Diepoxy Spiro Ketal 16: A solution of diene 2 (50.0 mg, 0.16 mmol)
in dry CH2Cl2 (10 mL) was treated with N-benzylcinchonium chlo-
ride (10 mg, 0.025 mmol), H2O (2 mL) und TBHP in CH2Cl2
(3.17 m; 0.30 mL, 0.96 mmol). An aqueous solution of NaOH
(0.10 m, 1.50 mL, 50 mol-%) was then added, and the mixture was
stirred for 12 h (TLC monitoring). Workup proceeded as described
for 14a to afford 16 (40.1 mg, 75%); m.p. 215–217 °C. 1H NMR
ppm. IR (KBr): ν = 3436, 3069, 1684, 1609, 1554, 1412, 1379, 1272,
˜
1212, 1132, 978, 869, 818, 756, 715, 627, 529 cm–1. UV (CH2Cl2):
λmax (lgε) = 327 (3.06), 312 (3.18), 298 (3.28), 233 (3.88) nm. MS
Eur. J. Org. Chem. 2011, 1176–1188
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1183

A. Aslan, S. Altun, I. Ahmed, U. Flörke, B. Schulz, K. Krohn
FULL PAPER
(EI, 70 eV): m/z (%) = 318 (79) [M+], 300 (30), 184 (52), 149 (23),
10.0, J7-ax,6-eq = 3.1 Hz, 1 H, 7-Hax), 6.03 (d, J = 10.3 Hz, 3-H),
131 (42), 86 (62), 84 (93), 49 (100). HRMS (EI, 70 eV): calcd. for 6.62 (dd, J = 10.3, 2.4 Hz, 1 H, 2-H), 6.97 (dd, J = 7.5, 1.0 Hz, 2
C20H14O6 350.07904; found 350.07908.
H, 2Ј-H, 7Ј-H), 7.45 (d, J = 7.5 Hz, 2 H, 4Ј-H, 5Ј-H), 7.53 (t, J =
7.5 Hz, 2 H, 3Ј-H, 6Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
28.5 (t, C-8), 40.7 (d, C-8a), 44.0 (d, C-4a), 57.7 (q, OCH3), 67.6
(d, C-7), 70.6 (d, C-6), 79.9 (d, C-5), 98.8 (s, C-1), 109.2 (d, C-7Ј),
109.9 (d, C-2Ј), 113.5 (s, C-8aЈ), 121.0 (d, C-5Ј), 121.2 (d, C-4Ј),
127.4 (d, C-6Ј), 127.6 (d, C-3Ј), 132.1 (d, C-3), 134.3 (s, C-4aЈ),
139.4 (d, C-2), 146.1 (s, C-8Ј), 147.0 (s, C-1Ј), 197.5 (s, C-4) ppm.
Diepoxy Spiro Ketal 20: A solution of the triene 11 (50.0 mg,
0.16 mmol) in dry CH2Cl2 (20 mL) was treated as described for
14a. Stirring was continued for 24 h, and the diepoxide 20 was iso-
lated as a colorless solid (38.5 mg, 72%); m.p. 206–208 °C. 1H
NMR (500 MHz, CDCl3): δ = 2.34 (m, 1 H, 8-H), 2.74 (ddd, J =
18.7, 6.1, 1.1 Hz, 1 H, 8-H), 3.43 (br. d, J = 9.6 Hz, 1 H, 8a-H),
3.48 (d, J = 3.8 Hz, 1 H, 3-H), 3.56 (m, 1 H, 5-H), 3.79 (d, J =
3.8 Hz, 1 H, 2-H), 5.93–6.00 (m, 2 H, 6-H, 7-H), 6.85 (dd, J = 7.6,
0.6 Hz, 1 H, 7Ј-H), 7.09 (dd, J = 7.6, 0.9 Hz, 1 H, 2Ј-H), 7.41 (t, J
= 7.6 Hz, 6Ј-H), 7.49 (t, J = 7.6 Hz, 3Ј-H), 7.51 (dd, J = 7.6, 0.9 Hz,
1 H, 5Ј-H), 7.53 (dd, J = 7.6, 0.9 Hz, 1 H, 4Ј-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 22.9 (t, C-8), 33.1 (d, C-8a), 53.9 (d, C-2),
55.4 (d, C-3), 56.3 (d, C-5), 59.6 (s, C-4a), 100.8 (s, C-1), 109.1 (d,
C-7Ј), 109.9 (d, C-2Ј), 112.5 (s, C-8aЈ), 120.3 (d, C-7), 121.1 (d, C-
5Ј), 121.2 (d, C-4Ј), 127.4 (d, C-6Ј), 127.8 (d, C-3Ј), 133.2 (d, C-6),
134.2 (s, C-4aЈ), 146.3 (s, C-8Ј), 146.5 (s, C-1Ј), 198.4 (s, C-4) ppm.
IR (KBr): ν = 3454, 1682, 1607, 1412, 1270, 1123, 1105, 1069, 973,
˜
840, 818, 754, 677 cm–1. UV (CH2Cl2): λmax (lgε) = 327 (3.01), 312
(3.24), 298 (3.32), 233 (3.93) nm. MS (EI, 70 eV): m/z (%) = 368
(95) [M]+, 336 (67), 318 (100), 294 (80), 266 (29), 160 (58), 159 (38),
131 (27), 84 (40), 57 (38). HRMS (EI, 70 eV): calcd. for C21H20O6
368.12598; found 368.12589.
Dihydroxy-methoxy Spiro Ketal 24a: Diene 10 (200 mg, 0.60 mmol)
was treated according to General Procedure 1 to afford the diol
24a as a white solid (194 mg, 88%); m.p. 221–223 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.91 (ddd, J6-ax,6-eq = 14.2, J6-ax,5-ax = 12.0,
J6-ax,7-eq = 3.9 Hz, 1 H, 6-Hax), 2.27 (ddd, J6-eq,6-ax = 14.2,
J6-eq,7-eq = 7.8, J6-eq,5-ax = 3.8 Hz, 1 H, 6-Heq), 2.95 (ddd, J5-ax,6-ax
= 12.0, J5-ax,4a-eq = 8.1, J5-ax,6-eq = 3.8 Hz, 1 H, 5-Hax), 2.96 (m, 1
H, 4a-Heq), 3.58 (dd, J8-ax,8a-ax = 9.1, J8-ax,7-eq = 2.8 Hz, 1 H, 8-
Hax), 3.70 (m, 1 H, 8a-Hax), 3.73 (s, 1 H, OCH3), 4.10 (m, 1 H, 7-
Heq), 5.90 (d, J = 10.3 Hz, 1 H, 3-H), 6.63 (d, J = 10.3 Hz, 1 H,
2-H), 6.83 (d, J = 8.2 Hz, 1 H, 7Ј-H), 6.87 (d, J = 8.2 Hz, 1 H, 2Ј-
H), 7.34 (d, J = 8.2 Hz, 2 H, 3Ј-H, 6Ј-H), 7.43 (d, J = 8.2 Hz, 2 H,
4Ј-H, 5Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 28.2 (t, C-6),
41.5 (d, C-5), 50.0 (d, C-4a), 60.6 (q, OCH3), 69.0 (d, C-7), 76.5
(d, C-8), 78.4 (d, C-8a), 97.8 (s, C-1), 109.1 (d, C-7Ј), 109.8 (d, C-
2Ј), 113.2 (d, C-8aЈ), 120.8 (d, C-5Ј), 120.9 (d, C-4Ј), 127.4 (d, C-
6Ј), 127.5 (d, C-3Ј), 130.9 (d, C-3), 134.2 (d, C-4aЈ), 140.8 (d, C-2),
IR (KBr): ν = 3057, 1725, 1607, 1412, 1380, 1271, 1126, 1043, 986,
˜
881, 817, 754, 609 cm–1. UV (CH2Cl2): λmax (lgε) = 326 (3.08), 312
(3.20), 298 (3.30), 231 (3.90) nm. MS (EI, 70 eV): m/z (%) = 334
(30) [M+], 197 (12), 111 (18), 97 (28), 86 (62), 84 (100), 49 (82).
HRMS (EI, 70 eV): calcd. for C20H14O5 334.08411; found
334.08306.
General Procedure 1 for cis-Dihydroxylation:[10] A solution of the
olefin in THF (10 mL) was treated with N-methylmorpholine N-
oxide (24 mg, 0.18 mmol), H2O (2 mL), THF (20 mL) and OsO4
(0.016 mmol, 0.2 mL, 2.5 wt.-% solution in tBuOH). The mixture
was stirred at room temp. for 6–48 h (TLC monitoring), diluted
with CH2Cl2 (50 mL) and washed with aqueous Na2S2O3
(2ϫ50 mL, 10 g/100 mL), water (50 mL) and brine (50 mL). The
organic phase was dried (Na2SO4), the solvent removed under re-
duced pressure, and the residue purified by column chromatog-
raphy on silica gel.
146.7 (s, C-8Ј), 147.1 (s, C-1Ј), 198.3 (s, C-4) ppm. IR (KBr): ν =
˜
3411, 2934, 1678, 1605, 1413, 1381, 1276, 1265, 1133, 1092, 1080,
1067, 954, 820, 758, 626 cm–1. UV (CH2Cl2): λmax (lgε) = 327
(2.92), 313 (3.13), 298 (3.19), 228 (3.80) nm. MS (EI, 70 eV): m/z
(%) = 368 (95) [M]+, 336 (10), 318 (18), 294 (100), 266 (22), 160
(38), 155 (23), 131 (18), 57 (11). HRMS (EI, 70 eV): calcd. for
C21H20O6 368.12598; found 368.12585.
Dihydroxy Spiro Ketal 21a: Ketal 1 (200 mg, 0.8 mmol) was treated
according to General Procedure 1 to afford the faint yellow diol
1
21a (147 mg, 65%); m.p. 73 °C. H NMR (500 MHz, CDCl3): δ =
4.67 (d, J = 2.7 Hz, 1 H, 5-H), 4.82 (d, J = 2.7 Hz, 1 H, 6-H), 6.26
(d, J = 10.3 Hz, 1 H, 3-H), 6.73 (dd, J = 10.3, 2.5 Hz, 1 H, 2-H),
6.92 (d, J = 7.5 Hz, 1 H, 7Ј-H), 7.04 (d, J = 7.5 Hz, 1 H, 2Ј-H),
7.41 (t, J = 7.9 Hz, 1 H, 6Ј-H), 7.46 (t, J = 7.9 Hz, 1 H, 3Ј-H), 7.53
(d, J = 8.5 Hz, 1 H, 5Ј-H), 7.54 (d, J = 8.5 Hz, 1 H, 4Ј-H) ppm.
13C NMR (125 MHz, CDCl3): δ = 73.6 (d, C-6), 74.5 (d, C-5), 97.8
(s, C-1), 109.3 (d, C-7Ј), 110.1 (d, C-2Ј), 113.4 (s, C-8aЈ), 121.4 (d,
C-5Ј), 121.6 (d, C-4Ј), 127.5 (d, C-6Ј), 127.6 (d, C-3Ј), 129.4 (d, C-
3), 134.2 (C-4aЈ), 140.7 (d, C-2), 145.4 (s, C-8Ј), 146.4 (s, C-1Ј),
Dihydroxy Spiro Ketal 25a: Triene 11 (200 mg, 0.66 mmol) was
treated according to General Procedure 1 to afford diol 25a as a
yellow solid (166 mg, 75%); m.p. 193–195 °C. 1H NMR (500 MHz,
CDCl3): δ = 2.25 (ddd, J8-ax,8-eq = 14.3, J8-ax,7-ax = 10.5, J8-ax,8a-eq
= 1.7 Hz, 1 H, 8-Hax), 2.53 (ddd, J8-eq,8-ax = 14.3, J8-eq,8a-eq = 10.0,
J8-eq,7-ax = 5.0 Hz, 1 H, 8-Heq), 3.64 (m, 1 H, 8a-Heq), 4.35 (m, 1
H, 7-Hax), 4.53 (m, 1 H, 6-H), 6.17 (d, J = 10.4 Hz, 1 H, 3-H), 6.81
(dd, J = 7.5, 1.0 Hz, 1 H, 7Ј-H), 6.88 (d, J = 10.4 Hz, 1 H, 2-H),
6.94 (m, 1 H, 5-H), 7.00 (dd, J = 7.5, 1.0 Hz, 1 H, 2Ј-H), 7.38 (t,
J = 7.5 Hz, 1 H, 6Ј-H), 7.46 (t, J = 7.5 Hz, 1 H, 3Ј-H), 7.47 (d, J
= 7.5 Hz, 1 H, 5Ј-H), 7.53 (dd, J = 7.5, 1.0 Hz, 1 H, 4Ј-H) ppm.
13C NMR (125 MHz, CDCl3): δ = 26.8 (t, C-8), 39.7 (d, C-8a),
66.6 (d, C-7), 68.2 (d, C-6), 97.5 (s, C-1), 109.2 (d, C-7Ј), 110.0 (d,
C-2Ј), 113.6 (s, C-8aЈ), 120.9 (d, C-5Ј), 121.1 (d, C-4Ј), 127.4 (d, C-
6Ј), 127.5 (d, C-3Ј), 132.0 (d, C-3), 132.2 (s, C-4a), 134.2 (s, C-4aЈ),
137.2 (d, C-5), 144.0 (s, C-2), 146.7 (s, C-8Ј), 147.2 (s, C-1Ј), 190.0
196.8 (s, C-4) ppm. IR (KBr): ν = 3417, 1702, 1608, 1412, 1380,
˜
1102, 1073, 1033, 985, 823, 757, 621, 493 cm–1. UV (CH2Cl2): λmax
(lgε) = 326 (2.82), 311 (3.14), 296 (3.27), 234 (3.86) nm. MS (EI,
70 eV): m/z (%) = 284 (100) [M]+, 237 (10), 224 (83), 196 (70), 160
(78), 114 (20), 83 (18), 57 (10). HRMS (EI, 70 eV): calcd. for
C16H12O5 284.06848; found 284.06830.
Dihydroxy-methoxy Spiro Ketal 23a: Diene 2 (200 mg, 0.60 mmol)
was treated according to General Procedure 1 to afford 23a as a
(s, C-4) ppm. IR (KBr): ν = 3459, 1670, 1608, 1413, 1381, 1274,
˜
colorless solid (190 mg, 86%); m.p. 202–204 °C. 1H NMR 1245, 1135, 1080, 1063, 987, 833, 820, 756, 734, 642 cm–1. UV
(500 MHz, CDCl3): δ = 1.51 (ddd, J8-ax,8-eq = 15.8, J8-ax,7-ax = 10.0,
(CH2Cl2): λmax (lgε) = 327 (3.11), 312 (3.21), 297 (3.28), 232 (3.89)
J8-ax,8a-eq = 2.7 Hz, 1 H, 8-Hax), 2.44 (m, 1 H, 8-Heq), 3.15 (ddd, nm. MS (EI, 70 eV): m/z (%) = 336 (98) [M]+, 318 (100), 289 (19),
J8a-eq,8-eq = 13.1, J8a-eq,4a-ax = 6.2, J8a-eq,8-ax = 2.7 Hz, 1 H, 8a-Heq), 273 (10), 197 (22), 160 (72), 131 (77), 115 (43), 114 (33), 77 (22)
3.54 (m, 1 H, 5-H), 3.55 (s, 3 H, OCH3), 3.70 (m, 1 H, 4a-Hax), 57 (20). HRMS (EI, 70 eV): calcd. for C20H16O5 336.09976; found
3.91 (br. d, J6-eq,7-ax = 3.1 Hz, 1 H, 6-Heq), 4.18, (dd, J7-ax,8-ax
=
336.09979.
1184
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1176–1188

Biologically Active Nonnatural Palmarumycin Derivatives
Dihydroxy-methoxy Spiro Ketal 26a: Enone 20 (200 mg, 0.6 mmol)
was treated according to General Procedure 1 to yield the diol 26a
42.3 (d, C-8a), 50.5 (d, C-4a), 60.6 (q, OCH3), 68.8 (d, C-7), 75.2
(d, C-5), 76.6 (d, C-6), 97.5 (q, C-1), 109.3 (d, C-7Ј), 109.9 (d, C-
a colorless solid (197 mg, 90%); m.p. 240–242 °C. 1H NMR 2Ј), 113.2 (s, C-8aЈ), 121.0 (d, C-5Ј), 121.2 (d, C-4Ј), 127.5 (d, C-
(500 MHz, CDCl3): δ = 4.00 (s, 3 H, OCH3), 4.63 (m. 1 H, 3-H), 6Ј), 127.6 (d, C-3Ј), 130.9 (d, C-3), 134.2 (s, C-4aЈ), 140.6 (d, C-2),
4.83 (m, 1 H, 2-H), 6.91 (d, J = 7.2 Hz, 1 H, 7Ј-H), 7.11 (d, J = 146.5 (s, C-8Ј), 146.9 (s, C-1Ј), 169.9 (s, CO), 170.3 (s, CO), 197.3
7.2 Hz, 1 H, 2Ј-H), 7.17 (d, J = 8.1 Hz, 1 H, 6-H), 7.43 (t, J = (q, C-4) ppm. IR (KBr): ν = 2924, 1746, 1699, 1606, 1608, 1587,
˜
8.3 Hz, 1 H, 6Ј-H), 7.49 (t, J = 8.3 Hz, 1 H, 3Ј-H), 7.55 (d, J =
8.3 Hz, 1 H, 5Ј-H), 7.57 (d, J = 8.3 Hz, 1 H, 4Ј-H), 7.64 (dd, J =
1413, 1379, 1241, 1093, 1070, 1033, 954, 819, 763, 622 cm–1. UV
(CH2Cl2): λmax (lgε) = 327 (3.21), 312 (3.34), 298 (3.43), 233 (4.03)
8.1, 0.8 Hz, 1 H, 8-H), 7.74 (t, J = 8.1 Hz, 1 H, 7-H) ppm. 13C nm. MS (EI, 70 eV): m/z (%) = 452 (75) [M]+, 414 (12), 400 (14),
NMR (125 MHz, CDCl3): δ = 56.4 (q, OCH3), 71.5 (d, C-3), 74.0 360 (26), 318 (54), 279 (20), 231 (18), 191 (31), 167 (38), 149 (79),
(d, C-2), 109.1 (s, C-1), 109.1, 109.9 (d, C-7Ј, C-1Ј), 113.2 (s, C- 97 (88) 57 (100). HRMS (EI, 70 eV): calcd. for C25H24O8
8aЈ), 113.9 (d, C-6), 118.7 (s, C-4a), 120.4 (d, C-8), 121.2, 121.4 (d,
C-4Ј, C-5Ј), 127.5, 127.7 (d, C-3Ј, C-6Ј), 134.2 (s, C-4aЈ), 136.3 (d,
C-7), 140.2 (s, C-8a), 146.4, 147.4 (s, C-1Ј, C-8Ј), 159.3 (d, C-5),
452.14713; found 452.14756.
Diacetoxy-methoxy Spiro Ketal 24b: A solution of diol 24a (100 mg,
0.271 mmol) was acetylated according to General Procedure 2 to
afford 24b as a white solid (191 mg; 97%); m.p. 197–199 °C. 1H
NMR (500 MHz, CDCl3): δ = 2.10 (s, 3 H, CH3CO2), 2.15 (s, 3 H,
194.5 (s, C-4) ppm. IR (KBr): ν = 3421, 1702, 1610, 1414, 1380,
˜
1278, 1091, 1055, 968, 822, 792, 759 cm–1. UV (CH2Cl2): λmax (lgε)
= 326 (2.94), 312 (3.08), 298 (3.34), 229 (3.92) nm. MS (EI, 70 eV):
m/z (%) = 364 (100) [M]+, 346 (23), 318 (19), 275 (70), 246 (19),
205 (22), 160 (60), 149 (38), 109 (32), 57 (22) 28 (41). HRMS (EI,
70 eV): calcd. for C21H16O6 364.09470; found 364.09433.
CH3CO2), 2.19 (ddd, J6-ax,6-eq = 14.7, J6-ax,5-ax = 12.4, J6-ax,7-eq
=
2.2 Hz, 1 H, 6-Hax), 2.32 (ddd, J6-eq,6-ax = 14.7, J6-eq,7-eq = 8.5,
J6-eq,5-ax = 4.2 Hz, 1 H, 6-Heq), 2.83 (ddd, J5-ax,6-ax = 12.4,
J5-ax,4a-eq = 8.4, J5-ax,6-eq = 4.2 Hz, 1 H, 5-Hax), 3.22 (dd,
J4a-eq,8a-ax = 13.3, J4a-eq,5-ax = 8.4 Hz, 1 H, 4a-Heq), 3.69 (s, 3 H,
OCH3), 3.90 (t, J = 9.7 Hz, 1 H, 8a-Hax), 4.98 (dd, J8-ax,8a-ax = 9.7,
J8-ax,7-eq = 2.8 Hz, 1 H, 8-Hax), 5.52 (m, 1 H, 7-Heq), 6.01 (d, J =
10.3 Hz, 1 H, 3-H), 6.70 (d, J = 10.3 Hz, 1 H, 2-H), 6.91 (d, J =
7.5 Hz, 1 H, 7Ј-H), 6.95 (d, J = 7.5, Hz, 1 H, 2Ј-H), 7.42 (t, J =
7.5 Hz, 1 H, 6Ј-H), 7.44 (t, J = 7.5 Hz, 1 H, 3Ј-H), 7.51 (d, J =
7.5 Hz, 2 H, 5Ј-H, 4Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
21.0 (q, CH3CO2), 21.1 (q, CH3CO2), 26.4 (t, C-6), 42.3 (d, C-5),
50.5 (d, C-4a), 60.6 (q, OCH3), 68.8 (d, C-7), 75.2 (d, C-8a), 76.6
(d, C-8), 97.5 (s, C-1), 109.3 (d, C-7Ј), 109.9 (d, C-2Ј), 113.3 (s, C-
4aЈ), 121.0 (d, C-5Ј), 121.2 (d, C-4Ј), 127.5 (d, C-6Ј), 127.6 (d, C-
3Ј), 130.9 (d, C-3), 134.2 (s, C-8aЈ), 140.6 (d, C-2), 146.5 (s, C-8Ј),
146.9 (s, C-1Ј), 170.0 (s, CO), 170.3 (s, CO), 197.3 (s, C-4) ppm. IR
General Procedure 2 for Acetylation: A solution of the diol in pyr-
idine (5 mL) was treated with acetic anhydride (0.1 mL) and
DMAP (2 mg). The mixture was stirred at room temp. for 6–12 h
(TLC monitoring). The solution was acidified by addition of 2 n
HCl (20 mL) and extracted with diethyl ether (3ϫ20 mL). The or-
ganic phase was dried (Na2SO4), the solvent removed under re-
duced pressure, and the residue purified by column chromatog-
raphy on silica gel.
Acetoxy Spiro Ketal 22b: The diol 21a (100 mg, 0.35 mmol) was
treated as described in General Procedure 2 to afford the
monoacetate 22b as
a
yellow oil (65 mg, 60%). 1H NMR
(500 MHz, CDCl3): δ = 2.25 (s, 3 H, CH3CO2), 6.34 (d, J =
10.3 Hz, 1 H, 3-H), 6.64 (d, J = 3.1 Hz, 1 H, 6-H), 6.96 (dd, J =
10.3, 3.1 Hz, 1 H, 2-H), 6.98 (dd, J = 8.3, 3.1 Hz, 2 H, 7Ј-H, 2Ј-
H), 7.45 (t, J = 8.3 Hz, 2 H, 6Ј-H, 3Ј-H), 7.55 (d, J = 8.3 Hz, 2 H,
5Ј-H, 4Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 20.3 (q,
CH3CO2), 93.8 (s C-1), 109.9 (d, C-7Ј, C-2Ј), 113.2 (s, C-8aЈ), 121.4
(d, C-5Ј,C-4Ј), 126.6 (d, C-6), 127.6 (d, C-6Ј, C-3Ј), 128.6 (d, C-3),
134.2 (s, C-4aЈ), 140.6 (d, C-2), 146.2 (s, C-5), 146.3 (s, C-8Ј, C-1Ј),
(KBr): ν = 2942, 1743, 1697 1607, 1586, 1413, 1380, 1242, 1209,
˜
1138, 1092, 1056, 955, 819, 763 cm–1. UV (CH2Cl2): λmax (lgε) =
327 (3.21), 312 (3.33), 298 (3.43), 233 (4.03) nm. MS (EI, 70 eV):
m/z (%) = 452 (100) [M+], 448 (7), 360 (29), 318 (78), 263 (10), 240
(9), 197 (19), 160 (51), 131 (13), 91 (8), 43 (38). HRMS (EI, 70 eV):
calcd. for C25H20O8 452.14713; found 452.14702.
Diacetoxy Spiro Ketal 25b: A solution of 25a (100 mg, 0.297 mmol)
was acetylated according to General Procedure 2 to afford 25b as a
yellow solid (120 mg, 95%); m.p. 158–160 °C. 1H NMR (500 MHz,
CDCl3): δ = 2.10 (s, 3 H, CH3CO2), 2.11 (s, 3 H, CH3CO2), 2.41
(ddd, J8ax,8eq = 14.6, J8-ax,7-ax = 10.4, J8-ax,8a-eq = 1.9 Hz, 1 H, 8-
Hax), 2.50 (ddd, J8-eq,8-ax = 14.6, J8-eq,8a-ax = 9.3, J8-eq,7-ax = 5.3 Hz,
1 H, 8-Heq), 3.58 (m, 1 H, 8a-Hax), 5.65 (m, 1 H, 7-H), 5.75 (m, 1
H, 6-H), 6.19 (d, J = 10.4 Hz, 1 H, 3-H), 6.84 (d, J = 8.2 Hz, 1 H,
7Ј-H), 6.87 (m, 1 H, 5-H), 6.90 (d, J = 10.4 Hz, 1 H, 2-H), 7.00 (d,
J = 8.2 Hz, 1 H, 2Ј-H), 7.40 (t, J = 8.2 Hz, 1 H, 6Ј-H), 7.46 (t, J
= 8.2 Hz, 1 H, 3Ј-H), 7.49 (d, J = 8.2 Hz, 1 H, 5Ј-H), 7.53 (d, J =
8.2 Hz, 1 H, 4Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 20.7
(q, CH3CO2), 21.0 (q, CH3CO2), 24.8 (t, C-8), 40.7 (d, C-8a), 66.4
(d, C-7), 68.4 (d, C-6), 97.2 (s, C-1), 109.4 (d, C-7Ј), 110.0 (d, C-
168.0 (s, CH CO ), 177 (s, C-4) ppm. IR (KBr): ν = 2923, 1774,
˜
3
2
1696, 1670, 1608, 1585, 1412, 1378, 1269, 1197, 1070, 1013, 951,
823, 758 cm–1. UV (CH2Cl2): λmax (lgε) = 326 (3.04), 312 (3.17),
296 (3.27), 232 (3.87) nm. MS (EI, 70 eV): m/z (%) = 308 (37) [M+],
266 (100), 250 (75), 210 (19), 168 (23), 149 (48), 114 (41), 83 (22),
57 (35). HRMS (EI, 70 eV): calcd. for C18H12O5 308.06848; found
308.06816.
Diacetoxy-methoxy Spiro Ketal 23b: A solution of the diol 23a
(100 mg, 0.272 mmol) was treated according to the General Pro-
cedure 2 to yield the diacetate 23b as a white solid (118 mg, 96%);
m.p. 178–180 °C. 1H NMR (500 MHz, CDCl3): δ = 2.11 (s, 3 H,
CH3CO2), 2.15 (s, 3 H, CH3CO2), 2.19 (ddd, J8-ax,8-eq = 14.8,
J8-ax,7-ax = 12.4, J8-ax,8a-eq = 2.4 Hz, 1 H, 8-Hax), 2.32 (ddd,
J8-eq,8-ax = 14.8, J8-eq,8a-eq = 8.4, J8-eq,7-ax = 4.2 Hz, 1 H, 8-Heq), 2Ј), 113.5 (s, C-8aЈ), 121.0 (d, C-5Ј), 121.3 (d, C-4Ј), 127.5 (d, C-
2.83 (ddd, J8a-eq,8-eq = 8.4, J8a-eq,4a-ax = 4.3, J8a-eq,8-ax = 2.4 Hz, 1 6Ј), 127.6 (d, C-3Ј), 131.8 (d, C-3), 133.2 (s, C-4a), 134.1 (d, C-5),
H, 8a-Heq), 3.22 (dd, J4a-ax,5-eq = 9.8, J4a-ax,8a-eq = 4.3 Hz, 1 H, 4a- 134.2 (s, C-4aЈ), 144.2 (d, C-2), 146.5 (s, C-8Ј), 147.0 (s, C-1Ј), 170.1
Hax), 3.69 (s, 3 H, OCH3), 3.90 (t, J = 9.8 Hz, 1 H, 5-Heq), 4.98
(dd, J6-eq,5-eq = 9.7, J6-eq,7-ax = 2.8 Hz, 1 H, 6-Heq), 5.52 (m, 1 H,
7-Hax), 6.01 (d, J = 10.3 Hz, 1 H, 3-H), 6.70 (d, J = 10.3 Hz, 1 H,
2-H), 6.91 (d, J = 7.5 Hz, 1 H, 7Ј-H), 6.95 (d, J = 7.5 Hz, 1 H, 2Ј-
(s, CO), 170.3 (s, CO), 184.5 (s, C-4) ppm. IR (KBr): ν = 2929,
˜
1750, 1688, 1641, 1610, 1424, 1382, 1238, 1201, 1124, 1098, 1056,
928, 829, 767, 627 cm–1. UV (CH2Cl2): λmax (lgε) = 326 (3.18), 312
(3.30), 296 (3.40), 232 (4.00) nm. MS (EI, 70 eV): m/z (%) = 420
H), 7.42 (t, J = 7.5 Hz, 1 H, 6Ј-H), 7.44 (t, J = 7.5 Hz, 1 H, 3Ј-H), (81) [M]+, 360 (36), 318 (98), 266 (40), 197 (22), 160 (100), 149 (59),
7.51 (d, J = 7.5 Hz, 2 H, 5Ј-H, 4Ј-H) ppm. 13C NMR (125 MHz, 97 (68), 57 (82). HRMS (EI, 70 eV): calcd. for C24H20O7 420.12091;
CDCl3): δ = 21.0 (q, CH3CO2), 21.1 (q, CH3CO2), 26.4 (t, C-8),
found 420.12127.
Eur. J. Org. Chem. 2011, 1176–1188
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1185

A. Aslan, S. Altun, I. Ahmed, U. Flörke, B. Schulz, K. Krohn
FULL PAPER
Diacetoxy-methoxy Spiro Ketal 26b: A solution of the diol 26a (de-
rived from palmarumycin CP2 methyl ether 20) (100 mg,
0.275 mmol) was treated as according to General Procedure 2 to
yield a white solid of 26b (120 mg, 98%); m.p. 85–87 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.97 (s, 3 H, CH3CO2), 2.09 (s, 3 H,
CH3CO2), 3.99 (s, 3 H, OCH3), 5.92 (d, J = 2.6 Hz, 1 H, 3-H), 6.07
(d, J = 10.3 Hz, 1 H, 2-H), 6.90 (dd, J = 7.5, 1.0 Hz, 1 H, 7Ј-H),
6.97 (dd, J = 7.5, 1.0 Hz, 1 H, 2Ј-H), 7.41 (t, J = 7.5 Hz, 6Ј-H),
7.45 (t, J = 7.5 Hz, 3Ј-H), 7.48 (d, J = 7.5 Hz, 5Ј-H), 7.51 (d, J =
7.5 Hz, 4Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 25.2 (q,
CCH3), 25.5 (t, C-6), 27.3 (q, CCH3), 39.6 (d, C-5), 49.5 (d, C-4a),
58.1 (q, OCH3), 72.5 (d, C-7), 76.2 (d, C-8a), 77.5 (d, C-8), 97.9 (s,
(d, J = 2.6 Hz, 1 H, 2-H), 6.92 (d, J = 7.6 Hz, 1 H, 7Ј-H), 6.98 (d, C-1), 108.6 (s, Cacetal), 109.1 (d, C-7Ј), 110.0 (d, C-2Ј), 113.4, (s, C-
J = 7.6 Hz, 1 H, 2Ј-H), 7.18 (d, J = 8.1 Hz, 1 H, 6-H), 7.44 (t, J =
7.6 Hz, 1 H, 6Ј-H), 7.46 (t, J = 7.6 Hz, 1 H, 3Ј-H), 7.57 (d, J =
8aЈ), 120.8 (d, C-5Ј), 120.9 (d, C-4Ј), 127.4 (d, C-6Ј), 127.6 (d, C-
3Ј), 130.8 (d, C-3), 134.2 (s, 4aЈ), 141.2 (d, C-2), 146.8 (s, C-8Ј),
7.6 Hz, 2 H, 5Ј-H, 4Ј-H), 7.59 (dd, J = 8.1, 0.8 Hz, 1 H, 8-H), 7.73 147.2 (s, C-1Ј), 197 (s, C-4) ppm. IR (KBr): ν = 2991, 2934, 2893,
˜
(t, J = 8.1 Hz, 1 H, 7-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 1703, 1615, 1413, 1393, 1279, 1227, 1155, 1098, 1041, 948, 824,
20.4 (q, CH3CO2), 20.4 (q, CH3CO2), 56.3 (q, OCH3), 69.7 (d, C- 767 cm–1. UV (CH2Cl2): λmax (lgε) = 327 (3.17), 312 (3.29), 298
3), 73.5 (d, C-2), 97.9 (s, C-1), 109.3 (d, C-7Ј),109.6 (d, C-2Ј), 112.9
(s, C-8aЈ), 114.2 (d, C-6), 119.3 (s, C-4a), 119.7 (d, C-8), 121.5 (d,
C-5Ј), 121.7 (d, C-4Ј), 127.5 (d, C-6Ј), 127.6 (d, C-3Ј), 134.2 (s, C-
4aЈ), 135.8 (d, C-7), 139.8 (s, C-8a), 146.4 (s, C-8Ј), 146.8 (s, C-1Ј),
159.7 (s, C-5), 169.0 (s, CO), 169.6 (s, CO), 186.8 (s, C-4) ppm. IR
(3.39), 234 (3.99) nm. MS (EI, 70 eV): m/z (%) = 408 (4) [M]+, 371
(30), 279 (8), 188 (44), 167 (22), 149 (60), 126 (21), 97 (20), 84 (100),
73 (61), 57 (52). HRMS (EI, 70 eV): calcd. for C24H24O6 408.15729;
found 408.15678.
(Dimethylmethylenedioxy) Spiro Ketal 25c: A solution 25a (100 mg,
0.297 mmol) was treated according to General Procedure 3 to yield
25c as a white solid (108 mg, 97%); m.p. 194–196 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.28 (s, 3 H, CCH3), 1.35 (s, 3 H, CCH3),
2.24 (ddd, J8-ax,8-eq = 14.3, J8-ax,7-ax = 11.3, J8-ax,8a-eq = 2.2 Hz, 1
(KBr): ν = 2925, 1756, 1715, 1610, 1594, 1412, 1378, 1270, 1209,
˜
1082, 1055, 1030, 950, 817, 758, 730 cm–1. UV (CH2Cl2): λmax (lgε)
= 326 (3.23), 312 (3.31), 298 (3.41), 230 (4.01) nm. MS (EI, 70 eV):
m/z (%) = 448 (98) [M]+, 406 (8), 364 (20), 322 (10), 275 (17), 247
(11), 205 (48) 160 (39), 131 (70), 97 (62), 57 (100). HRMS (EI,
70 eV): calcd. for C25H20O8 448.11581; found 448.11571.
H, 8-Hax), 2.59 (ddd, J8-eq,8-ax = 14.3, J8-eq,8a-eq = 8.5, J8-eq,7-ax
=
4.5 Hz, 1 H, 8-Heq), 3.49 (m, 1 H, 8a-Heq), 4.51 (m, 1 H, 7-H), 4.69
(m, 1 H, 6-H), 6.10 (d, J = 10.4 Hz, 3-H), 6.73 (dd, J = 7.5, 0.8 Hz,
1 H, 7Ј-H), 6.81 (d, J = 10.4 Hz, 1 H, 2-H), 6.91 (m, 1 H, 5-H),
6.92 (d, J = 7.5 Hz, 1 H, 2Ј-H), 7.31 (t, J = 7.5 Hz, 1 H, 6Ј-H),
7.38 (t, J = 7.5 Hz, 3Ј-H), 7.41 (d, J = 7.5 Hz, 5Ј-H), 7.45 (d, J =
7.5 Hz, 4Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 23.7 (t, C-
8), 26.5 (q, CCH3), 28.1 (q, CCH3), 38.8 (d, C-8a), 71.7 (d, C-7),
71.8 (d, C-8), 97.2 (s, C-1), 109.2 (d, C-2Ј), 109.3 (d, C-7Ј), 110.1
[s, C(CH3)], 113.6 (s, C-8aЈ), 120.9 (d, C-5Ј), 121.1 (d, C-4Ј), 127.5
(d, C-6Ј), 127.6 (d, C-3Ј), 131.2 (s, C-4a), 132.2 (d, C-3), 134.2 (s,
C-4aЈ), 135.4 (d, C-5), 143.8 (d, C-2), 146.7 (s, C-8Ј), 146.9 (s, C-
General Procedure 3 for the Acetonide Formation: Perchloric acid
(60%, 0.01 mL) was added under cooling with ice to a suspension
of the diol in acetone (10 mL) und 2,2-dimethoxypropane
(0.14 mmol). The mixture was stirred at 0 °C under Ar for 6–12 h.
The solution was then neutralized by addition of concd. aqueous
NH4OH (1 mL). After stirring for 30 min, the organic phase was
dried (Na2SO4), the solvent removed under reduced pressure, and
the residue purified by column chromatography on silica gel.
(Dimethylmethylenedioxy) Spiro Ketal 21c: Diol 21a (100 mg,
0.35 mmol) was treated as described in General Procedure 3 to
yield a white oil of 21c (74 mg, 66%). 1H NMR (500 MHz, CDCl3):
δ = 1.44 (s, 3 H, CCH3), 1.46 (s, 3 H, CCH3), 4.65 (d, J = 5.2 Hz,
1 H, 5-H), 4.89 (dd, J = 5.2, 2.3 Hz, 1 H, 6-H), 6.22 (d, J = 10.4 Hz,
1 H, 3-H), 6.84 (dd, J = 10.4, 2.3 Hz, 1 H, 2-H), 6.88 (d, J = 7.5 Hz,
1 H, 7Ј-H), 7.15 (d, J = 7.5 Hz, 1 H, 2Ј-H), 7.42 (t, J = 7.5 Hz, 1
H, 6Ј-H), 7.48 (t, J = 7.5 Hz, 1 H, 3Ј-H), 7.53 (d, J = 7.5 Hz, 1 H,
5Ј-H), 7.55 (d, J = 7.5 Hz, 1 H, 4Ј-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 26.1 (q, CCH3), 27.5 (q, CCH3), 75.2 (d, C-5), 77.0
(d, C-6), 96.3 (s, C-1), 109.3 (d, C-7Ј), 110.5 (d, C-2Ј), 112.4 (s,
Cacetal), 113.6 (s, C-8aЈ), 121.4 (d, C-5Ј), 121.5 (d, C-4Ј), 127.4 (d,
C-6Ј), 127.7 (d, C-3Ј), 131.0 (d, C-3), 134.2 (s, C-4aЈ), 142.7 (d, C-
1Ј), 184.8 (s, C-4) ppm. IR (KBr): ν = 2930, 1681, 1633, 1608, 1587,
˜
1411, 1380, 1275, 1098, 1064, 1032, 825, 754 cm–1. UV (CH2Cl2):
λmax (lgε) = 326 (3.13), 312 (3.25), 296 (3.35), 237 (3.95) nm. MS
(EI, 70 eV): m/z (%) = 376 (92) [M+], 361 (12), 318 (100), 300 (69),
273 (30), 197 (85), 131 (79), 103 (21), 43 (34). HRMS (EI, 70 eV):
calcd. for C23H20O5 376.13107; found 376.13121.
(Dimethylmethylenedioxy)-methoxy Spiro Ketal 26c: A solution of
diol 26a (100 mg, 0.275 mmol) was treated according to General
Procedure 3 to yield a white solid of 26c (109 mg, 98%); m.p. 200–
202 °C. 1H NMR (500 MHz, CDCl3): δ = 1.20 (s, 3 H, CCH3), 1.36
(s, 3 H, CCH3), 3.86 (q, 3 H, OCH3), 4.80 (d, J = 7.5 Hz, 1 H, 3-
H), 5.07 (d, J = 7.5 Hz, 1 H, 2-H), 6.80 (dd, J = 7.5, 0.7 Hz, 1 H,
7Ј-H), 6.93 (d, J = 8.2 Hz, 1 H, 6-H), 7.13 (dd, J = 7.0, 1.4 Hz, 1
H, 2Ј-H), 7.14 (dd, J = 7.8, 0.7 Hz, 1 H, 8-H), 7.31 (d, J = 8.2 Hz,
1 H, 7-H), 7.34 (t, J = 8.2 Hz, 1 H, 6Ј-H), 7.44 (d, J = 8.2 Hz, 1
H, 5Ј-H), 7.45 (d, J = 8.2 Hz, 1 H, 4ЈH) 7.47 (t, J = 8.2 Hz, 1 H,
3Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 25.4 (q, CCH3), 26.4
(q, CCH3), 56.3 (q, OCH3) 77.1 (d, C-3), 78.8 (d, C-2), 98.1 (s, C-
1), 108.9 (d, C-7Ј), 109.2 (d, C-2Ј), 113.0 (d, C-6), 113.6 [s,
C(CH3)2], 118.2 (d, C-8), 120.9 (d, C-5Ј), 120.9 (d, C-4Ј), 121.0 (s,
2), 145.7 (s, C-8Ј), 146.2 (s, C-1Ј), 194.3 (s, C-4) ppm. IR (KBr): ν
˜
= 2924, 1703, 1610, 1585, 1418, 1393, 1284, 1227, 1087, 1062, 1010,
824, 762 cm–1. UV (CH2Cl2): λmax (lgε) = 327 (3.07), 312 (3.19),
296 (3.29), 233 (3.89) nm. MS (EI, 70 eV): m/z (%) = 324 (13)
[M]+, 196 (11), 155 (7), 141 (9), 84 (100), 47 (35), 35 (12). HRMS
(EI, 70 eV): calcd. for C19H16O5 324.09976; found 324.09976.
(Dimethylmethylenedioxy)-methoxy Spiro Ketal 24c: A solution of
diene 24a in acetone (100 mg, 0.272 mmol) was treated according
to General Procedure 3 to afford a white solid of 24c (109 mg,
1
98%); m.p. 168–170 °C. H NMR (500 MHz, CDCl3): δ = 1.40 (s, C-4aЈ, C-8aЈ), 127.4 (d, C-6Ј), 127.6 (d, C-3Ј), 133.3 (d, C-7), 134.0
3 H, CCH3), 1.53 (s, 3 H, CCH3), 2.08 (ddd, J6-ax,6-eq = 15.8,
(s, C-4aЈ), 139.7 (s, C-8a), 146.5 (s, C-8Ј), 147.1 (s, C-1Ј), 158.5 (s,
J6-ax,5-ax = 12.3, J6-ax,7-eq = 3.5 Hz, 1 H, 6-Hax), 2.38 (ddd, C-5), 190.1 (s, C-4) ppm. IR (KBr): ν = 2935, 1711, 1607, 1478,
˜
J6-eq,6-ax = 14.5, J6-eq,7-eq = 5.0, J6-eq,5-ax = 2.6 Hz, 1 H, 6-Heq), 2.86
(ddd, J5-ax,6-ax = 12.3, J5-ax,4a-eq = 6.1, J5-ax,6-eq = 2.6 Hz, 1 H, 5- (CH2Cl2): λmax (lgε) = 326 (3.16), 312 (3.29), 298 (3.38), 232 (3.98)
Hax), 3.05 (dd, J4a-eq,5-ax = 6.1, J4a-eq,8a-ax = 4.1 Hz, 1 H, 4a-Heq),
nm. MS (EI, 70 eV): m/z (%) = 404 (40) [M]+, 346 (38), 318 (23),
1412, 1379, 1272, 1213, 1087, 1062, 1032, 891, 817, 753 cm–1. UV
3.59 (s, 3 H, OCH3), 4.09 (dd, J8a-ax,8-ax = 6.1, J8a-ax,4a-eq = 4.1 Hz, 275 (27), 246 (10), 211 (11), 159 (17), 149 (30), 83 (58), 43 (100),
1 H, 8a-Hax), 4.35 (dd, J8-ax,8a-ax = 6.1, J8-ax,7-eq = 4.1 Hz, 1 H, 8- 29 (23). HRMS (EI, 70 eV): calcd. for C24H20O6 404.12598; found
Hax), 4.51 (m, 1 H, 7-Heq), 6.00 (d, J = 10.3 Hz, 1 H, 3-H), 6.73 404.12607.
1186
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1176–1188

Biologically Active Nonnatural Palmarumycin Derivatives
Methoxy Spiro Alcohol 27: In a two-necked 100 mL flask commer-
cially available methylmagnesium chloride (0.15 mL, 3 m,
0.37 mmol) was added under Ar to THF (5 mL). After 15 min, a
solution of the enone 13a (0.10 g, 0.30 mmol) in THF (5 mL) was
added, and the mixture was stirred at room temp. for 2 h. The
reaction was then quenched by addition of aqueous ammonium
chloride (20 mL). The phases were separated, and the aqueous
phase was extracted with diethyl ether (20 mL). The combined or-
ganic phases were dried (Na2SO4), the solvent was removed under
reduced pressure, and the residue purified by column chromatog-
raphy on silica gel to yield a colorless solid of the tertiary alcohol
27 (0.08 g, 80%); m.p. 45–48 °C. 1H NMR (500 MHz, CDCl3): δ =
1.79 (s, 3 H, CH3), 4.05 (s, 3 H, OCH3), 6.08 (d, J = 10.0 Hz, 1 H,
3-H), 6.2 (d, J = 10.0 Hz, 1 H, 2-H), 6.9 (d, J = 8.2 Hz, 1 H, 6-H),
7.02 (d, J = 7.6 Hz, 1 H, 2Ј-H), 7.11 (d, J = 7.6 Hz, 1 H, 7Ј-H),
7.44 (t, J = 8.2 Hz, 1 H, 7-H), 7.47 (d, J = 7.6 Hz, 1 H, 8-H) 7.50
(t, J = 7.6 Hz, 1 H, 3Ј-H), 7.56 (t, J = 7.6 Hz, 1 H, 6Ј-H),7.65 (d,
J = 7.6 Hz, 1 H, 5Ј-H), 7.85 (d, J = 7.6 Hz, 1 H, 4Ј-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 29.8 (q, CH3), 55.8 (q, OCH3), 69.06
(C-4), 95.04 (s, C-1), 109.23 (d, C-2Ј, C-7Ј), 113.6 (d, C-6), 114.2
(s, C-8aЈ), 119.3 (s, C-4a), 120.6 1 (d, C-8), 121.6 (s, C-4Ј, C-5Ј),
127.99 (d, C-3Ј, C-6Ј), 128.8 (d, C-2), 135.6 (d, C-3), 134.5 (s, C-
4aЈ), 135.31 (d, C-7), 141.52 (s, C-8a), 147.8 (s, C-1Ј, C-8Ј), 156.26
3), 108.5 (d, C-7Ј), 110.7 (d, C-2Ј), 115.2 (s, C-4aЈ), 118.1 (d, C-8),
119.2 (d, C-5), 121.5 (d, C-5Ј), 122.7 (d, C-4Ј), 125.6 (d, C-6), 126.1
(d, C-7), 126.9 (s, C-8a), 127.3 (d, C-6Ј), 127.8 (d, C-3Ј), 127.9 (s,
C-4a), 137.0 (s, C-4aЈ), 142.8 (s, C-1), 153.1 (s, C-1Ј), 154.3 (s, C-
4), 156.6 (s, C-8Ј) ppm. IR (KBr): ν = 3426, 1630, 1607, 1581,
˜
1460, 1427, 1388, 1267, 1237, 1147, 1083, 1060, 1029, 812, 767,
748, 699 cm–1. UV (CH2Cl2): λmax (lgε) = 332 (2.90), 318 (3.13),
304 (3.25), 232 (3.84) nm. MS (EI, 70 eV): m/z (%) = 330 (97) [M+],
301 (100), 273 (50), 255 (30), 159 (18), 115 (98). HRMS (EI, 70 eV):
calcd. for C22H18O3 330.12561; found 330.12564.
Crystal Structure Determination of Epoxy-diene 18:[14] C20H14O4,
Mr = 318.3, monoclinic, space group P21/c, a = 12.031(3), b =
14.775(3), c = 8.3997(18) Å, β = 110.43(1)°, V = 1399.1(5) Å3, Z =
4, DX = 1.511 g/cm3, F(000) = 664, T = 120(2) K. Bruker-AXS
SMART APEX CCD, graphite monochromator, λ(Mo-Kα) =
0.71073 Å,
μ
=
0.105 mm–1,
colorless
crystal,
size
0.45ϫ0.42ϫ0.40 mm, 12875 intensities collected 1.8° Ͻ θ Ͻ 27.9°,
–15 Ͻ h Ͻ 15, –19 Ͻ k Ͻ 19, –10 Ͻ l Ͻ 11. Structure solved by
direct methods,[15] full-matrix least-squares refinement[15] with 3331
independent reflections based on F2 and 217 parameters, all but H
atoms refined anisotropically, H atoms from difference Fourier
maps refined with riding model in idealized positions with U =
1.2ϫUiso(C). Refinement converged at R1 [IϾ2σ(I)] = 0.055, wR2
(all data) = 0.139, S = 1.02, max(δ/σ) Ͻ 0.001, min/max density in
final ΔF map –0.30/0.27 eÅ–3. Figure 1 shows the molecular struc-
ture.
(s, C-5) ppm. IR (KBr): ν = 3402, 2906, 2830, 1732, 1601, 1574,
˜
1406, 1373, 927 cm–1. UV (CH2Cl2): λmax (lgε) = 286 (3.5), 293
(3.56), 306 (4.5), 301 (4.7) nm. MS (EI, 70 eV): m/z (%) = 346 (36)
[M+], 150 (100), 176 (70), 77 (30), 43 (50). HRMS (EI, 70 eV):
calcd. for C22H18O4 346.1205; found 346.1227.
Methoxy Spiro Oxime 28: A solution of enone 13a (0.030 g,
0.09 mmol) and (NH2OH)HCl (0.010 g, 0.10 mmol) in dry ethanol
(3 mL) was stirred under Ar at room temp. overnight. The solvent
was removed under reduced pressure to afford a white residue of
the oxime 28 (0.026 g, 95%); m.p. 170–175 °C. 1H NMR
(500 MHz, CDCl3): δ = 4.05 (s, 3 H, OCH3), 4.02 (d, J = 10.0 Hz,
1 H, 3-H), 6.31 (d, J = 10.0 Hz, 1 H, 2-H), 7.01 (dd, J = 7.6, J =
1.3 Hz, 2 H, 2Ј-H, 7Ј-H), 6. 5 (d, J = 8.2, J = 1.2 Hz, 1 H, 6-H),
6.9 (d, J = 8.2 Hz, 2 H, 8-H), 7.51 (d, J = 11.0, J = 1.3 Hz, 2 H,
4Ј-H, 5Ј-H), 7.54 (t, J = 7.4 Hz, 2 H, 3Ј-H, 6Ј-H), 7.44 (t, J =
8.2 Hz, 1 H, 7-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 53.4 (q,
OCH3) 94.82 (s, C-1), 110.23 (d, C-2Ј, C-7Ј), 113.50 (d, C-6), 114.2
(s, C-8aЈ), 115.3 (s, C-4a), 120.60 (d, C-8), 121.6 (s, C-4Ј, C-5Ј),
127.9 (d, C-3Ј, C-6Ј), 120.6 (d, C-3), 134.51 (s, C-4aЈ), 132.31 (d,
C-7), 132.6 (d, C-2), 139.52 (s, C-8a), 147.8 (s, C-1Ј, C-8Ј), 159.03
[1] Reviews: a) K. Krohn, Prog. Chem. Org. Nat. Prod. 2003, 85,
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Eur. J. Org. Chem. 2010, 4476–4481.
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[4] K. Krohn, K. Khanbabaee, J. Micheel, Liebigs Ann. 1995,
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[6] E. Weitz, A. Scheffer, Ber. Dtsch. Chem. Ges. 1921, 54, 2344–
2353.
[7] We thank Dr. Gennaro Pescitelli for the calculations. The
MMFF conformational search was run with Spartan’08, Wave-
function, Inc., Irvine, CA, and the DFT geometry optimiza-
tions [DFT, B3LYP/6-31G(d)] with M. J. Frisch, G. W. Trucks,
H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman,
G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H.
Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov,
J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr.,
J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tom-
asi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pom-
elli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G.
Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dap-
prich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J.
Cioslowski, D. J. Fox, Gaussian 09, Revision A.02, Gaussian,
Inc., Wallingford, CT, 2009.
(s, C-5), 164.4 (s, C-4) ppm. IR (KBr): ν = 3048, 2983, 1263, 746,
˜
693 cm–1. UV (CH2Cl2): λmax (lgε) = 328 (2.7), 309 (4.2), 306 (4.5),
301 (5.0) nm. MS (EI, 70 eV): m/z (%) = 345.2 (74) [M+], 330.2
(100), 329 (26), 300.2 (22). HRMS (EI, 70 eV): calcd. for
C21H15NO4 345.100; found 345.098.
1Ј-(4Ј-Ethoxynaphthalen-1-yloxy)naphthalen-8Ј-ol (29): A solution
of the Diels–Alder adduct 2 (50 mg, 0.15 mmol) in dry ethanol
(20 mL) was treated with TMSCl (0.1 mL), and the solution was
kept at 40 °C for 6 h (TLC monitoring, CH2Cl2). The solvent was
removed under reduced pressure and the residue purified by col-
umn chromatography on silica gel (CH2Cl2) to yield a white solid
of naphthol 29 (33.7 mg, 68%); m.p. 136–138 °C. 1H NMR
(200 MHz, CDCl3): δ = 1.60 (t, J = 13.9 Hz, 3 H, CH3), 4.25 (q, J
= 13.9, 6.9 Hz, 2 H, CH2), 6.43 (d, J = 8.2 Hz, 1 H, 7Ј-H), 6.80 (d,
J = 8.2 Hz, 1 H, 3-H), 7.02 (dd, J = 8.2, 1.0 Hz, 1 H, 2Ј-H), 7.10
(t, J = 8.2 Hz, 1 H, 6Ј-H), 7.24 (d, J = 8.2 Hz, 1 H, 2-H), 7.39 (dd,
J = 8.2, 1.0 Hz, 1 H, 5Ј-H), 7.42–7.49 (m, 3 H, 3Ј-H, 4Ј-H, 6-H),
7.53 (t, J = 8.2 Hz, 1 H, 7-H), 7.94 (d, J = 8.2 Hz, 1 H, 8-H), 8.38
(d, J = 8.2 Hz, 1 H, 5-H), 9.35 (s, 1 H, OH) ppm. 13C NMR
(125 MHz, CDCl3): δ = 14.8 (q, CH3), 64.2 (t, CH2), 104.0 (d, C-
[8] A. G. M. Barrett, F. Blaney, A. D. Campbell, D. Hamprecht,
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2002, 67, 2735–2746.
[9] Barret et al.[8] noted 23% ee (recorded by chiral HPLC) and
[α] = 67 for the methoxy epoxide ([α] = 291 for 100% ee).
Eur. J. Org. Chem. 2011, 1176–1188
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1187

A. Aslan, S. Altun, I. Ahmed, U. Flörke, B. Schulz, K. Krohn
FULL PAPER
[10] V. Van Rheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett.
1976, 17, 1494.
[14] CCDC-775676 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[15] SMART (Version 5.62), SAINT (Version 6.02), Bruker AXS
Inc., Madison, Wisconsin, USA, 2002.
[11] K. Krohn, A. Michel, U. Flörke, H.-J. Aust, S. Draeger, B.
Schulz, Liebigs Ann. Chem. 1994, 1093–1097.
[12] K. Krohn, A. Michel, U. Flörke, H.-J. Aust, S. Draeger, B.
Schulz, Liebigs Ann. Chem. 1994, 1099–1108.
[13] W. R. Hertler, T. V. Rajan Babu, J. Am. Chem. Soc. 1988, 110,
5841–5853.
Received: November 9, 2010
Published Online: January 11, 2011
1188
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1176–1188