Isolation, structural elucidation, and synthesis of curcutetraol

Article abstract of DOI:10.1002/ejoc.200400336

The new natural products (+)-curcutetraol and (-)-curcutriolamide were isolated from the bacterium CNH-741 and the fungus CNC-979, isolated from marine sediment. (+)-Curcutetraol is a polar compound and contains a tertiary benzylic alcohol moiety at the single stereogenic center, which was retained without racemization by avoiding chromatography on silica. The absolute configuration of (+)-curcutetraol was determined by comparison of its experimental CD spectrum with the spectra predicted by quantum-chemical CD calculations. Phenolic bisabolane sesquiterpenoids from marine sources were previously known only from gorgonians and sponges. A short total synthesis of racemic curcutetraol has been developed. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400336

FULL PAPER
Isolation, Structural Elucidation, and Synthesis of Curcutetraol
Tanja Mülhaupt,[a] Hannelore Kaspar,[a] Sabine Otto,[a] Matthias Reichert,[b]
Gerhard Bringmann,[b] and Thomas Lindel*[a]
Keywords: Alcohols / Natural products / Stereochemical analysis / Terpenoids / Total synthesis
The new natural products (+)-curcutetraol and (−)-curcutriol-
mental CD spectrum with the spectra predicted by quantum-
amide were isolated from the bacterium CNH-741 and chemical CD calculations. Phenolic bisabolane sesquiter-
the fungus CNC-979, isolated from marine sediment. (+)-
Curcutetraol is a polar compound and contains a tertiary
benzylic alcohol moiety at the single stereogenic center,
which was retained without racemization by avoiding
chromatography on silica. The absolute configuration of (+)-
penoids from marine sources were previously known only
from gorgonians and sponges. A short total synthesis of
racemic curcutetraol has been developed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
curcutetraol was determined by comparison of its experi- Germany, 2005)
Introduction
Microorganisms isolated from the marine environment
have been the source of an impressive variety of biologically
active natural products.[1] In particular, the possibility of
fermentation of microorganisms promises to provide large
amounts of any particular secondary metabolite for further
studies. Consequently, there is also pronounced interest in
the discovery of microbial natural products that are biogen-
etically related to metabolites isolated earlier from difficult-
to-grow marine invertebrates. In the course of our investi-
gations on the constituents of microorganisms collected
from marine sediments, we have found two new sesquiterp-
enes closely related to natural products isolated earlier from
gorgonians and sponges (Figure 1).
Results and Discussion
The EtOAc extract obtained from an overall 20 L fer-
mentation of a co-culture of the bacterial strain CNH-741
and the fungus CNC-979 (collected from marine sediment
at a depth of one meter in the Bahamas) was subjected to
repeated chromatography on RP-18 and RP-2 stationary
phases rather than silica gel. The new natural products 1
and 2 were isolated in 14.8 and 2.4 mg quantities, respec-
tively. The NMR spectroscopic data of compounds 1 and 2
Figure 1. Bisabolane-type sesquiterpenoids sharing a substituted
m-cresol partial structure
are summarized in Table 1. HREIMS analysis of the major
compound 1 gave the molecular formula C15H24O4. Con-
nectivity information derived from HSQC, COSY, and
HMBC experiments unambiguously determined its consti-
tution, with two tertiary, one phenolic, and one primary
alcohol moieties.
[a]
University of Munich, Department of Chemistry and
Biochemistry,
The 13C NMR spectrum of the minor compound 2
shows, in part, doubled or broadened signals, which indi-
cates the presence of two diastereomers and, thereby, of at
least two stereogenic centers. As the major difference with
1, a new methyl doublet at δH ϭ 1.05 ppm is observed in
Butenandtstr. 5Ϫ13, 81377 München, Germany
Fax: (internat.) ϩ 49-89-2180-7-7734
E-mail: thomas.lindel@cup.uni-muenchen.de
[b]
University of Würzburg, Institute of Organic Chemistry,
Am Hubland, 97074 Würzburg, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
1
the H NMR spectrum of 2, which couples to a methine
334
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400336
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Isolation, Structural Elucidation, and Synthesis of Curcutetraol
FULL PAPER
1
Table 1. 13C and H NMR spectroscopic data of (ϩ)-curcutetraol (1) and (Ϫ)-curcutriolamide (2) in CD3OD; assignments were made
on the basis of HMBC, HSQC, COSY, and DEPT experiments; coupling constants are given in Hz; nr: not resolved.
(ϩ)-Curcutetraol (1)
δ(1H) (mult., J)
(Ϫ)-Curcutriolamide (2)
δ(1H) (mult., J)
#
δ(13C)
HMBC (#)
δ(13C)
HMBC (#)
1
2
3
4
5
6
7
8
157.0
116.1
142.8
118.8
127.6
131.3
78.0
44.6
20.1
45.1
71.4
Ϫ
Ϫ
156.9[a]
116.0[b]
142.6
Ϫ
6.73 (s)
Ϫ
6.76 (d, 7.7)
7.08 (d, 7.7)
Ϫ
Ϫ
6.74 (d, 1.6)
Ϫ
6.77 (dd, 7.7, 1.6)
7.10 (d, 7.7)
Ϫ
1, 4, 6, 15
Ϫ
2, 15, 6
1, 2,[c] 3, 7
Ϫ
1, 4, 6, 15
Ϫ
2, 6, 15
1, 2[a], 3, 7
Ϫ
Ϫ
7, 9
118.6[a]
127.4[a]
131.0[b]
77.8[a]
44.6
Ϫ
Ϫ
Ϫ
1.79, 1.91 (nr)
1.32 (nr)
1.39 (nr)
Ϫ
1.09 (s)
1.10 (s)
1.58 (s)
4.50 (s)
6, 7, 9, 10, 14
8, 10
8,9, 11, 12, 13
Ϫ
10, 11
10, 11
6, 7, 8
2, 3, 4
1.79, 1.91 (nr)
1.30 (nr)
1.30 (nr)
2.27 (nr)
Ϫ
1.05 (d, 6.7)
1.56 (s)
4.50 (s)
9
22.9[b]
35.5[b]
41.3
8, 10
9, 11
10
11
12
13
14
15
9,[c] 10, 12, 13[c]
Ϫ
29.1
29.1
28.3
64.8
182.5
18.1[a]
29.1
10, 11, 12
6, 7, 8, 9[c]
2, 3, 4
64.7[a]
[a]
[b]
[c]
Broadened. Split. Weak intensity.
proton. Additionally, a carbonyl carbon signal is observed
A carbenium intermediate formed upon protonation and
at δC ϭ 182.5 ppm. The IR band at 1648 cmϪ1 suggested subsequent dehydration of 1 should be stabilized, thus ex-
the presence of an amide group. HRMS analysis was pos- posing the 7-position to facile exchange with nucleophiles.
sible only in the negative FAB mode and revealed the mo- Indeed, when a pure sample was passed through a normal-
lecular formula C15H23NO4. Upon treatment with Ac2O/ phase chromatography column with methanol-containing
pyridine, three acetyl moieties were incorporated solvent mixtures as the eluent, incorporation of a methoxy
[HRFAB(ϩ)MS], thus confirming the presence of three free group at the tertiary benzylic position took place. Earlier, a
hydroxy groups in 2.
2,2,6,6-tetrasubstituted tetrahydropyran has been reported
The two new natural products 1 and 2 belong to the ex- to be formed upon treatment of 15-deoxycurcutetraol with
tended group of bisabolane-type sesquiterpenoids. The dilute aqueous H2SO4.[13] Upon using solely reversed
underlying aromatic hydrocarbon α-curcumene, which had stationary phases, and strictly excluding acid, we were able
earlier been discovered in plants,[2] was the first bisabolane- to isolate optically active (ϩ)-curcutetraol (1). HPLC em-
type sesquiterpenoid isolated from marine organisms, the ploying the chiral stationary phases Chiralpak AD-H and
gorgonians Muricia elongata and Plexaurella nutans.[3] The Chiralcel OJ was monitored by a CD (circular dichroism)
first phenolic bisabolane sesquiterpenoids from marine or- detector and the CD trace was positive over the entire peak.
ganisms were reported by McEnroe and Fenical, who de- This indicates high enantiomeric purity of the natural
scribed (Ϫ)-curcuphenol (3), the corresponding (Ϫ)-cur- product 1.[14]
1
cuhydroquinone, and the oxidized (Ϫ)-curcuquinone from
Independently, a series of H NMR experiments in the
the gorgonian coral Pseudopterogorgia rigida.[4] Later, sev- presence of the shift reagent Pr(hfc)3 was performed.
eral groups isolated (ϩ)-curcudiol (4) from the marine Pr(hfc)3 has proven to be useful with regard to the determi-
sponges Didiscus sp.,[5] Epipolasis sp.,[6] and Arenochalina nation of the enantiomeric excess of the tertiary alcohol
sp.[7] Overall, sponges have been the most frequent sources tramadol,[15] and has been reported to be superior to
of phenolic bisabolane sesquiterpenoids from marine or- Eu(hfc)3.[16] Figure 2 shows the upfield shifts of the signals
ganisms.[8] Curcutetraol (1), with its four hydroxyl groups, corresponding to the aromatic protons 2-H, 4-H, and 5-H,
is the most polar member of the family, and curcutriolam- and to the hydroxymethyl protons 15-H. The shift experi-
ide (2) is the first amide in the series. Incorporation of nitro- ment was performed at 200 MHz because, under fast-ex-
gen into marine bisabolane sesquiterpenoids has only been change conditions, line broadening is proportional to the
observed for nonaromatized compounds.[7,9,10] To date, square of the magnetic field strength.[16]
none of the bisabolane sesquiterpenoids isolated from the
The presence of only three signals for the aromatic pro-
marine environment have been found to possess a tertiary tons at all tested concentrations of the shift reagent indi-
alcohol moiety in the o-position of a phenol. However, cated that only one kind of complex is formed. None of the
fungi isolated from land sources have provided a few struc- aromatic signals evolved into more than one peak. The sig-
tural analogs of cuructetraol (1). Among them, sydonol (5), nal of the hydroxymethyl group, which appears to take part
from Aspergillus sp.[11] and waraterpol (6), from Penicillium directly in complex formation, rapidly moved upfield and
sp.,[12] are the most similar to compounds 1 and 2. In both could not be identified any more at higher concentrations
cases, the absolute configuration of the tertiary, benzylic al- of Pr(hfc)3. We thus concluded that (ϩ)-curcutetraol (1)
cohol moiety has not yet been elucidated and remains a had been isolated in high enantiomeric purity. This was cor-
challenging task.
roborated by the high intensities of the two CD peaks of
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T. Mülhaupt, H. Kaspar, S. Otto, M. Reichert, G. Bringmann, T. Lindel
FULL PAPER
Figure 3. Cotton effects and assignments of the absolute configura-
tions of the bisabolane sesquiterpenoid (Ϫ)-ligustiphenol (7) and
of the atrolactic ester 8
analysis of secondary alcohols.[17] Comparison of the
specific optical rotation of 1 with those of structurally simi-
lar, but not closely analogous, compounds[18,19] can hardly
be trusted, and more-significant CD data suitable for com-
parison have only been described for compounds possessing
a carbonyl oxygen at C-8, which facilites the formation of
additional hydrogen bonds. For the plant sesquiterpenoid
(Ϫ)-ligustiphenol (7, ∆ε ϭ ϩ3.2, λ ϭ 285 nm), a 7S configu-
Figure 2. High-field shifts of the aromatic protons 2-H, 4-H, and
5-H on addition of the chiral NMR shift reagent Pr(hfc)3 to a solu-
tion of (ϩ)-curcutetraol (1) in CDCl3 (200 MHz)
(ϩ)-curcutetraol (1) at 281 nm (∆ε ϭ ϩ3.5) and 229 nm ration has been deduced by comparing its CD bands with
(∆ε ϭ ϩ2.6) in acetonitrile.
those of α-hydroxy-α-phenylketones (Figure 3).[19,20] How-
The single stereogenic center of (ϩ)-curcutetraol (1) is ever, the opposite (R)-configuration has been assigned to
situated at a tertiary, benzylic position. Extensive work on several atrolactic esters, such as 8, which also show positive
Mosher and related esters only covers the stereochemical CD bands at about 280 nm (ethanol) and are hydroxylated
Figure 4. Assignment of the absolute configuration of curcutetraol (1) by comparison of the experimental CD spectrum (in MeCN) with
the spectra calculated for (R)-1 (left) and (S)-1 (right) following the MD-CNDO/2S approach, using the TRIPOS (top) and the MM3
force fields (bottom), with subsequent calculation of the CD spectra using the CNDO/2S method
336
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Eur. J. Org. Chem. 2005, 334Ϫ341

Isolation, Structural Elucidation, and Synthesis of Curcutetraol
FULL PAPER
in the phenyl o-position, too.[21] Compounds 7 and 8 are
To verify the (S)-configuration of the stereocenter of 1, a
not fully suitable for comparison. However, they are among second computational CD study was launched, now based
the only tertiary benzylic alcohols with a phenolic hydroxy on a conformational analysis. In the course of this ap-
group in the o-position for which CD data can be found in proach, twelve conformers were found within an energetic
the literature.
cut-off of 3 kcal/mol above the global minimum, using the
Therefore, the absolute configuration of curcutetraol (1) semiempirical AM1[30] approach. For each conformer the
was determined by quantum-chemical circular dichroism respective CD spectrum was calculated, now with the
(CD) investigations.[22Ϫ25] Due to the flexibility of 1 our OM2[31] method, followed by their addition according to
first approach was based on molecular dynamics (MD) Boltzmann statistics. After ‘‘UV correction’’,[22] the overall
simulations,[23] arbitrarily starting with the (R)-enantiomer theoretical CD curve thus obtained for the (R)-enantiomer
and using the TRIPOS[26] and the MM3[27] force fields at was again opposite to the experimental spectrum (Figure 5,
virtual temperatures of 500 and 400 K, respectively. In both left), while the overall CD curve calculated for the (S)-en-
cases 1000 geometries were extracted from the trajectories antiomer again gave a good agreement with the measured
of motion. For all of these geometries the single CD spectra one (Figure 5, right). Consequently, the absolute stereos-
were calculated using the semiempirical CNDO/2S[28] tructure of 1 was assigned to be S as proven by two differ-
method. These spectra were then summed to give the over- ent theoretical approaches.
all theoretical CD curves, which, after ‘‘UV correction’’,[22]
The new, nitrogen-containing natural product (Ϫ)-curcu-
showed a reversed image behavior in comparison to the triolamide (2), which was isolated as a mixture of dia-
measured CD spectrum for both force fields (Figure 4, left), stereomers, possesses two stereogenic centers at C-7 and C-
while the spectrum calculated for the (S)-enantiomer was in 11. The CD spectrum of 2 shows a flat line above 230 nm
good accordance with the experimental one (Figure 4, indicating the presence of both epimers at the benzylic posi-
right).[29]
tion C-7. (Ϫ)-Curcutriolamide (2) shows optical activity
Figure 5. Confirmation of the absolute configuration of the stereocenter of 1 as S by comparison of the CD spectrum measured in
MeCN with the CD curves computed for (R)-1 (left) and (S)-1 (right) following the conformational-analysis-OM2 approach, considering
SCI (top) and SDCI calculations (bottom)
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T. Mülhaupt, H. Kaspar, S. Otto, M. Reichert, G. Bringmann, T. Lindel
FULL PAPER
and there should be a preference with regard to one of the 10. An NOE correlation between the protons 5-H and 10-
two possible configurations at C-11. Curcutriolamide (2) H, which can only be present in diastereomer 14a, allowed
may form a seven-membered ring intermediate by intra- the unambiguous assignment (Scheme 1). Of course, the
molecular nucleophilic attack of the amide oxygen or nitro- very low diastereoselectivity of the previous epoxidation
gen at C-7, leading to the formation of two dia- does not hamper the synthesis because the stereogenic
stereomers of 2. A similar reaction has been observed for center at C-10 is removed on regioselective reduction of the
waraterpol (6).[12] Due to scarce amounts of available mate- epoxide 13 with LiAlH4. Simultaneously, one of the two
rial, we were not able to derivatize the primary amide in TIPS protecting groups is lost. Generally, aryl silyl ethers
order to determine the configuration of the remaining stere- can cleaved with various nucleophiles, while alkyl silyl
ocenter C-11.
ethers are stable under those conditions.[32] Therefore, we
We also developed a short total synthesis of racemic cur- assigned the regioisomer 15 to the reduction product. The
cutetraol (rac-1), which secures the ready availability of the sequence was completed by cleavage of the remaining ali-
natural product (Scheme 1). The sequence starts with o- phatic silyl ether with TBAF to provide rac-curcutetraol
hydroxy-p-methylacetophenone, which has to be oxygen- (rac-1) in seven steps starting from 9.
ated in the benzylic position. While direct bromination of
the free phenol occurs at the aromatic ring, the acetylated
Experimental Section
phenol 9 is brominated in the benzylic position upon treat-
ment with NBS, to afford 10. This was followed by saponifi-
cation of the ester and the benzylic bromide with NaOH.
For the subsequent Grignard reaction employing homopre-
nyl bromide (11), TIPS protecting groups had to be intro-
duced. The tertiary alcohol 12 already possesses the com-
General: Optical rotations were measured on a PerkinϪElmer 241
Polarimeter. IR and UV spectra were recorded on a PerkinϪElmer
Spectrum 1000 and a PerkinϪElmer Lambda 16 UV/Vis spec-
trometer, respectively. CD spectra were obtained on a Jobin Yvon
CD6 circular dichroism spectrometer. 1H and 13C NMR spectra
plete sesquiterpenoid skeleton. Epoxidation of 12 with buff- were recorded on a Bruker AMX 600 (600.19 and 150.92 MHz,
respectively) or a Varian VRX 400S (399.9 MHz and 100.6 MHz,
respectively) spectrometer, with the solvent (CD3OD: δC ϭ 49.0
ppm; δH ϭ 3.31 ppm) as the internal standard. Mass spectra were
recorded on Finnigan MAT95Q and Varian MAT-311 spec-
trometers. HPLC isolations were performed using Varian Prep Star
218 or Varian Pro Star 320 UV/Vis detectors and an ELSD Sedex
75 light-scattering detector. As columns, Merck LiChroprep RP-
18, LiChroprep RP-2 (each 25Ϫ40 µm, 250 ϫ 210), and LiChrop-
rep Si-60 (25Ϫ40 µm, 250 ϫ 10 mm) were used. The position num-
bers of carbon atoms are given according to Figure 1.
ered m-CPBA provided the sensitive compound 13, which
had to be chromatographed on a reversed phase stationary
phase (RP-18). If 13 is chromatographed on silica, the two
diastereomeric tetrahydropyrans 14a and 14b are formed in
a ratio of 3:2 with regard to the configuration at position
Fermentation and Isolation: The bacterial strain CNH-741 and the
fungus CNC-979 were isolated from a sediment sample (collected
at a depth of one meter, Bahamas) using serial dilution and plating
techniques on medium A1 (1.6% agar, 1% starch, 0.4% yeast ex-
tract, 0.2% peptone, 100% seawater). A 20 L cultivation was ex-
tracted with EtOAc, and the solvent was concentrated to produce
3.7 g of crude extract, which was subjected to RP-18 flash chroma-
tography (water/MeOH/CH3CN) to produce distinct fractions. The
fraction eluting with water/MeOH (4:6) was further purified by RP-
18 HPLC (gradient; water/CH3CN, 7:3 to 1:1) and RP-2 HPLC
(isocratic; water/CH3CN, 6:4) to yield 14.8 mg of (ϩ)-curcutetraol
(1) and 2.4 mg of (Ϫ)-curcutriolamide (2).
(؉)-Curcutetraol (1): Brownish oil. [α]2D0 ϭ ϩ5.24 (c ϭ 7.4 mg/mL,
1
MeOH). H NMR (600.19 MHz, CD3OD): δ ϭ 1.09 (s, 3 H), 1.10
(s, 3 H), 1.32 (br., 2 H), 1.39 (br., 2 H), 1.58 (s, 3 H), 1.79 (m, J ϭ
11.3, 4.5, 1.2 Hz, 1 H), 1.91 (m, J ϭ 11.3, 4.5, 1.2 Hz, 1 H), 4.50
(s, 2 H), 6.74 (d, J ϭ 1.6 Hz, 1 H), 6.77 (dd, J ϭ 7.7, 1.6 Hz, 1 H),
7.10 (d, J ϭ 7.7 Hz, 1 H) ppm. 13C NMR (150.9 MHz, CD3OD):
δ ϭ 20.1 (CH2), 29.1 (3 CH3), 44.6 (CH2), 45.1 (CH2), 64.8 (CH2),
71.4 (Cq), 78.0 (Cq), 116.1 (CH), 118.8 (CH), 127.6 (CH), 131.3
(Cq), 142.8 (Cq), 157.0 (Cq) ppm. IR (KBr): ν˜ ϭ 3306, 2921, 1630,
1578, 1429, 1296, 1261, 1156, 1032, 942, 877, 816, 754 cmϪ1. UV
(MeOH): λmax (ε) ϭ 219 nm (13534), 278 (7490). CD (CH3CN): λ
(∆ε) ϭ 211 (Ϫ0.43, tr.), 229 (0.29, pk.), 249 (0.00, tr.), 281 (0.50,
pk.). EIMS: m/z (%) ϭ 268 (3) [M]ϩ, 250 (8) [M Ϫ H2O]ϩ, 232
(51) [M Ϫ 2H2O]ϩ, 217 (36) [M Ϫ 2H2O Ϫ CH3]ϩ, 189 (100), 167
(67). HREIMS, calcd. for [Mϩ] (C15H24O4): 268.1675; found
268.1661.
Scheme 1. Synthesis of rac-curcutetraol (1): (a) NBS, AIBN, CCl4,
reflux, 8 h, 63%; (b) 2 m NaOH, room temp., 12 h, 54%; (c) TIPSCl,
imidazole, DMF, room temp., 12 h, 87%; (d) 11, Mg, Et2O, room
temp. to 50 °C, 2 h, 74%; (e) m-CPBA, Na2HPO4, THF, room
temp., 12 h, 87%; (f) LiAlH4, THF, 0 °C to room temp., 30 min,
21%; (g) TBAF, THF, room temp., 3 h, 56%
338
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Isolation, Structural Elucidation, and Synthesis of Curcutetraol
FULL PAPER
(؊)-Curcutriolamide (2): Brownish oil. [α]2D0 ϭ Ϫ3.8 (c ϭ 0.3 mg/
mL; MeOH). H NMR (600.19 MHz, CD3OD): δ ϭ 1.05 (d, J ϭ and TIPSCl (0.46 g, 2.40 mmol, 0.50 mL) in dry DMF (4 mL) was
yl]ethan-1-one (0.19 g, 1.08 mmol), imidazole (0.37 g, 5.5 mmol),
1
6.7 Hz, 3 H), 1.30 (m, 4 H), 1.56 (s, 3 H), 1.79 (m, 1 H), 1.94 (m,
1 H), 2.27 (m, 1 H), 4.50 (s, 2 H), 6.73 (s, 1 H), 6.76 (d, J ϭ 7.7 Hz,
1 H), 7.08 (d, J ϭ 7.7 Hz, 1 H) ppm. 13C NMR (150.9 MHz,
stirred at room temp. for 12 h. The organic layer was then washed
with 2 m HCl (5 mL), diluted with water, and extracted with Et2O.
The ether phase was dried (MgSO4), concentrated, and the crude
CD3OD): δ ϭ 18.1 (br., CH3), 22.9/22.8 (CH2), 29.1 (CH3), 35.5 product was purified by chromatography (silica; isohexane/EtOAc,
(br., CH2), 41.3 (CH), 44.6 (CH2), 64.7 (br., CH2), 77.8 (br., Cq), 20:1) to yield a colorless oil (0.45 g, 0.94 mmol, 87%). 1H NMR
116.0/116.1 (CH), 118.6 (br., CH), 127.4 (br., CH), 131.0/131.1
(CDCl3, 400 MHz): δ ϭ 1.12 {m, 39 H, 12 CH3 and
(Cq), 142.6 (Cq), 156.9 (br., Cq), 182.5 (Cq) ppm. IR (KBr): ν˜ ϭ CH2OSi[CH(CH3)2]3}, 1.38 {m, 3 H, C1-OSi[CH(CH3)2]3}, 2.62 (s,
3
4
3369, 2920, 2853, 1648, 1427, 1032, 870, 712 cmϪ1. UV (MeOH):
3 H, Ac), 4.76 (s, 2 H, CH2), 6.82 (dd, J ϭ 7.9, J ϭ 0.9 Hz, 1 H,
4
3
λmax (ε) ϭ 203 nm (138523), 282 (18014). HRFAB(Ϫ)MS calcd. for 4-H), 7.01 (d, J ϭ 0.9 Hz, 1 H, 2-H), 7.59 (d, J ϭ 7.9 Hz, 1 H,
[M Ϫ H]Ϫ (C15H22NO4): 280.1549; found 280.1558.
5-H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 12.0 {3 C,
CH2OSi[CH(CH3)2]3}, 13.4 {3 C, C1-OSi[CH(CH3)2]3}, 17.9 {12
C, 2 OSi[CH(CH3)2]3}, 31.3 (Ac), 64.4 (CH2), 116.4 (C4) 117.8
(C2), 129.1 (C6), 130.0 (C5), 147.5 (C3), 155.8 (C1), 200.4 (CϭO)
ppm. MS (EI, 70 eV): m/z (%) ϭ 479 (20) [M ϩ H]ϩ, 438 (14), 437
(37), 436 (100), 263 (13), 262 (41), 115 (19), 87 (18), 73 (22), 59
(29). IR (KBr): ν˜ ϭ 2945, 2868, 2892, 1610, 1423, 883 cmϪ1. UV
(CHCl3): λmax (log ε) ϭ 255 nm (4.01), 306 (3.57). HRFABMS
(C27H51O3Si2): calcd. 479.3377; found 479.3380.
7-O-Methylcurcutetraol: This compound was obtained as a brown-
ish oil by chromatography of 1 on silica gel (MeOH/CHCl3, 9:1);
1
yield: 1.5 mg. H NMR (600.19 MHz, CD3OD): δ ϭ 1.09 (s, 3 H),
1.10 (s, 3 H), 1.28 (br., 2 H), 1.38 (br., 2 H), 1.58 (s, 3 H), 1.85 (m,
2 H), 3.21 (s, 3 H), 4.50 (s, 2 H), 6.78 (d, J ϭ 1.6 Hz, 1 H), 6.82
(dd, J ϭ 8.2, 1.6 Hz, 1 H), 7.10 (d, J ϭ 8.2 Hz, 1 H) ppm. 13C
NMR (150.9 MHz, CD3OD): δ ϭ 19.9 (CH2), 22.8 (CH3), 29.1 (2
CH3), 41.4 (CH2), 45.0 (CH2), 50.5 (CH3), 64.7 (CH2), 71.3 (Cq),
83.5 (Cq), 116.0 (CH), 119.0 (CH), 128.3 (CH), 128.8 (Cq), 143.7
(Cq), 156.9 (Cq) ppm. IR (KBr): ν˜ ϭ 3400, 2919, 1659, 1433, 876
cmϪ1. HRFAB(Ϫ)MS calcd. for [M Ϫ H]Ϫ (C16H26O4): 282.1831;
found 282.1812.
6-Methyl-2-[2-(triisopropylsilanyloxy)-4-(triisopropylsilanyloxy-
methyl)phenyl]hept-5-en-2-ol (12): Under dry conditions, 5-bromo-
2-methylpent-2-ene (11; 0.17 g, 1.05 mmol) was added to a suspen-
sion of Mg slices (26 mg, 1.05 mmol) in Et2O (10 mL). A solution
of 1-[2-triisopropylsilanyloxy-4-(triisopropylsilanyloxymethyl)-
phenyl]ethan-1-one (0.40 g, 0.84 mmol) in Et2O (4 mL) was added
and the reaction mixture was refluxed for 2 h. Ice water and satu-
rated NH4Cl solution (1 mL) were then added. The water phase
was extracted twice with Et2O and the combined organic layers
were washed with aqueous NaHSO3 and NaHCO3 (10%) solutions,
and then with water. The dried (MgSO4) ether phase was concen-
trated and the product purified by chromatography (silica; isohex-
ane/EtOAc, 20:1) to yield a colorless oil (0.35 g, 0.62 mmol, 74%).
1H NMR (CDCl3, 400 MHz): δ ϭ 1.06Ϫ1.15 {m, 39 H, 12 CH3
and CH2OSi[CH(CH3)2]3}, 1.41 {m, 3 H, C1-OSi[CH(CH3)2]3},
1.50 (br, s, 3 H, 11-CH3), 1.57 (br. s, 3 H, 7-CH3), 1.63 (br. s, 3 H,
11-CH3), 1.83 Ϫ2.00 (m, 2 H, 8-H2), 1.90Ϫ1.99 (m, 2 H, 9-H2),
4.49 (br. s, 1 H, OH), 4.76 (s, 2 H, CH2OSi), 5.04 (m, 1 H, 10-H),
1-[2-Acetoxy-4-(bromomethyl)phenyl]ethan-1-one (10): A solution of
NBS (1.11 g, 6.25 mmol), AIBN (40 mg, 0.24 mmol), and 9[33]
(1.00 g, 5.20 mmol) in CCl4 (30 mL) was refluxed for 8 h. The pre-
cipitate was filtered off and the filtrate washed with 1 m HCl, water,
and aqueous NaHCO3 solution. The organic layer was dried, con-
centrated, and the residue purified by chromatography (silica;
isohexane/EtOAc, 3:1) to give the product as a colorless oil (0.89 g,
1
3.30 mmol, 63%). H NMR (CDCl3, 400 MHz): δ ϭ 2.35 (s, 3 H,
OAc), 2.55 (s, 3 H, C6-Ac), 4.45 (s, 2 H, CH2), 7.15 (d, 4J ϭ 1.8 Hz,
3
3
1 H, 2-H), 7.33 (dd, J ϭ 8.1 Hz, 1 H, 4-H), 7.79 (d, J ϭ 8.1 Hz,
1 H, 5-H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 21.5 (OAc),
29.7 (C6-Ac), 31.6 (CH2), 124.8 (C2), 126.9 (C4), 130.8 (C6), 131.2
(C5), 143.8 (C3) 149.6 (C1), 169.7 (OAc), 197.2 (C6-Ac) ppm. MS
(FABϩ, NBA): m/z (%) ϭ 271/273 (20/21) [M ϩ H]ϩ, 231/229 (29/
33), 154/155 (100/24). IR (KBr): ν˜ ϭ 1769, 1682, 1651, 1615, 1567,
1368, 1284, 1252, 1196 cmϪ1. UV (CHCl3): λmax (log ε) ϭ 253 nm
(4.15), 290 (3.22). HRFABMS (C11H12BrO3): calcd. 270.9970;
found 270.9949.
3
4
4
6.78 (dd, J ϭ 8.0, J ϭ 1.5 Hz, 1 H, 4-H), 6.92 (d, J ϭ 1.5 Hz,
1 H, 2-H), 7.19 (d, 3J ϭ 7.9 Hz, 1 H, 5-H) ppm. 13C NMR
(CDCl3, 100 MHz):
δ ϭ 11.9 {3 C, CH2OSi[CH(CH3)2]3},
13.4 {3 C, CarOSi[CH(CH3)2]3}, 17.4 (11-CH3), 18.4 {12 C, 2
OSi[CH(CH3)2]3}, 23.8 (C-9), 26.1 (11-CH3), 27.6 (7-CH3), 42.6
(C8), 64.9 (CH2OSi), 75.6 (C7), 116.4 (C2), 118.3 (C4), 125.0 (C10),
127.2 (C5), 131.6 (C11), 134.3 (C6), 141.9 (C3), 153.7 (C1) ppm.
MS (EI, 70 eV): m/z (%) ϭ 562 (0.33) [M]ϩ, 480 (39), 436 (32), 372
(26), 157 (43), 145 (36), 115 (90), 87 (74). IR (KBr): ν˜ ϭ 2945,
2868, 683, 659 cmϪ1. UV (CHCl3): λmax (log ε) ϭ 259 nm (3.35),
272 (3.31), 280 (3.28). HREIMS (C30H53O2Si2): calcd. 501.3584;
found 501.3548.
1-[2-Hydroxy-4-(hydroxymethyl)phenyl]ethan-1-one: A solution of
10 (0.45 g, 270 mmol) in 2 n NaOH (5 mL) was stirred at room
temp. for 12 h. The reaction mixture was then adjusted to pH 2 by
addition of 2 m HCl. The aqueous phase was extracted with chloro-
form and the unified organic phases were dried (MgSO4). Chroma-
tography (silica; isohexane/ethyl acetate, 2:1) provided the product
1
as an oil (0.15 g, 0.90 mmol, 54%). H NMR (CDCl3, 400 MHz):
δ ϭ 1.87 (br. s, 1 H, CH2OH), 2.62 (s, 3 H, CH3), 4.70 (s, 2 H,
CH2), 6.89 (d, J ϭ 8.3 Hz, 1 H, 4-H), 6.91 (s, 1 H, 2-H), 7.71 (d,
4-Dimethyloxiranyl-2-[2-(triisopropylsilanyloxy)-4-(triisopropyl-
3
silanyloxymethyl)phenyl]butan-2-ol (13): At
0 °C, Na2HPO4
3J ϭ 8.3 Hz, 1 H, 5-H), 12.30 (s, 1 H, C1-OH) ppm. 13C NMR
(CDCl3, 100 MHz): δ ϭ 26.6 (CH3), 64.4 (CH2), 115.7 (C2), 116.8
(C4), 118.8 (C6), 130.9 (C5), 150.3 (C3), 162.7 (C1), 204.1 (CϭO)
ppm. MS (EI, 70 eV): m/z (%) ϭ 166 (59) [M]ϩ, 151 (100), 105
(17), 77 (11), 67 (7), 65 (6), 43 (16). IR (KBr): ν˜ ϭ 3480, 1634,
1574, 1460, 1417, 1368, 1328, 1299, 1253, 1220 cmϪ1. UV (CHCl3):
λmax (log ε) ϭ 259 nm (4.11), 327 (3.62). HREIMS (C9H10O3):
calcd. 166.0630; found 166.0629.
(32.0 mg, 0.22 mmol) was added to a solution of 12 (0.05 g,
0.09 mmol) in THF (4 mL). After 5 min, m-CPBA (39.0 mg,
0.22 mmol) was added and the reaction mixture was stirred for
12 h, before being washed with saturated aqueous NaHCO3 and
Na2S2O3 solutions (5 mL each). The mixture was then extracted
with dichloromethane and the combined organic phases were dried
with MgSO4. After concentration, the product was purified by
flash chromatography (RP-18; MeOH/water, 20:1) to afford a col-
orless oil (45.0 mg, 0.08 mmol, 87%). 1H NMR (CD3OD,
400 MHz): δ ϭ 1.06Ϫ1.24 (m, 39 H, 12 CH3 and CH2OSi[CH-
1-[2-(Triisopropylsilanyloxy)-4-(triisopropylsilanyloxymethyl)phen-
yl]ethan-1-one: A solution of 1-[2-hydroxy-4-(hydroxymethyl)phen-
Eur. J. Org. Chem. 2005, 334Ϫ341
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
339

T. Mülhaupt, H. Kaspar, S. Otto, M. Reichert, G. Bringmann, T. Lindel
FULL PAPER
(CH3)2]3), 1.14 (s, 3 H, 11-CH3), 1.17 (s, 3 H, 11-CH3), 1.41 {m, 3
OSi[CH(CH3)2]3}, 18.7 (C9), 27.7 (7-CH3), 27.8 (2C, 2 CH3), 43.1
H, CarOSi[CH(CH3)2]3}, 1.63 (s, 3 H, 7-CH3), 2.10Ϫ2.33 (m, 2 H, (C8), 43.7 (C10), 64.6 (CH2OTIPS), 70.0 (C11), 76.7 (C7), 113.9
3
8-H2), 1.74Ϫ2.20 (m, 2 H, 9-H2), 2.65 (dd, J ϭ 5.9 Hz, 1 H, 10-
(C2), 116.4 (C4), 126.0 (C5), 129.4 (C6), 141.6 (C3), 155.5 (C1)
H), 4.77 (s, 2 H, CH2OSi), 6.79 (dd, 3J ϭ 8.1, 4J ϭ 1.5 Hz, 1 H, 4- ppm. MS (EI, 70 eV): m/z (%) ϭ 424 (1) [M]ϩ, 363 (29), 345(29),
4
3
H), 6.97 (d, J ϭ 1.5 Hz, 1 H, 2-H), 7.47 (d, J ϭ 8.1 Hz, 1 H, 5-
323 (32), 289 (24) 281 (62), 267 (19), 217 (22), 215 (64), 173 (12),
H) ppm. 13C NMR (CD3OD, 100 MHz):
δ ϭ 11.9 {3 C, 159 (100). IR (KBr): ν˜ ϭ 3369, 2944, 2866, 1150, 1100, 961, 953,
CH2OSi[CH(CH3)2]3}, 13.4 {3 C, CarOSi[CH(CH3)2]3}, 17.2 {12 C, 672 cmϪ1
2 OSi[CH(CH3)2]3}, 17.4 (11-CH3), 23.6 (11-CH3), 26.1 (C9), 27.2 424.2979.
(7-CH3), 37.2 (C8), 58.8 (C11), 64.4 (CH2OH), 64.9 (C10), 73.8
. HREIMS (C24H44O4Si): calcd. 424.3009; found
rac-Curcutetraol (1): TBAF was added to a solution of 15 (35 mg,
0.08 mmol) in dry THF (2 mL). After 3 h at room temp., the reac-
tion mixture was concentrated and purified by flash chromatogra-
phy (RP-18; MeOH/water, 1:1). The racemate of the natural
product 1 was obtained as a colorless oil (12.0 mg, 0.05 mmol,
56%). With the exception of the absence of optical activity, the
spectroscopic data were identical to those reported for the isolated
natural product. HREIMS (C15H24O4): calcd. 268.1675; found
268.1681.
(C7), 115.5 (C2), 117.6 (C4), 126.8 (C5), 134.2 (C6), 141.4 (C3),
152.4 (C1) ppm. MS (EI, 70 eV): m/z (%) ϭ 577 (16) [M Ϫ H]ϩ,
564 (26), 563 (60), 435 (31), 433 (62), 387 (78), 361 (100), 346 (39),
345 (80), 301 (36), 161 (22). HREIMS (C33H61O4Si2): calcd.
577.4108; found 577.4108.
2,2,6-Trimethyl-6-[2-(triisopropylsilanyloxy)-4-(triisopropylsilanyl-
oxymethyl)phenyl]-tetrahydropyran-3-ol (14a and 14b): Chromatog-
raphy of the epoxide 13 on silica (isohexane/ethyl acetate, 4:1)
quantitatively affords a mixture the diastereomers 14a and 14b in
a ratio of 3:2. Small samples were purified for characterization.
Computational Methods: The MD simulations of 1 were performed
using the TRIPOS[26] (virtual temperature 500 K) and the MM3[27]
force fields (virtual temperature 400 K) as implemented in the mo-
lecular modeling package SYBYL 6.7,[26] with an overall simu-
lation time of 500 ps and an extraction of single geometries every
0.5 ps.
The conformational analysis was conducted on a Silicon Graphics
OCTANE R10000 workstation by means of the semiempirical
AM1[30] approach, as implemented in the program package VAMP
6.5,[34] starting from preoptimized structures generated by the TRI-
POS force field.
The wavefunctions required for the computation of the rotational
strengths for the electronic transitions from the ground state to
excited states were obtained by CNDO/2S[28] calculations followed
by single configuration interaction (SCI) calculations including 625
singly occupied configurations and the ground state determinant
in the case of the MD-based CD computations, and by OM2[31]
calculations followed by SCI and SDCI calculations including 900
singly and 256 doubly occupied configurations, respectively, and
the ground state determinant in the case of the conformational-
analysis-based ones. These computations were carried out with Li-
nux Pentium III workstations using the BDZDO/MCDSPD[35] pro-
gram package, and with Linux AMD MP 2400ϩ workstations with
the MNDO99[36] software package. In the case of the MD-based
calculations, the single CD spectra were summed up arithmetically,
while in the case of the conformational analysis they were addition-
ally weighted by following Boltzmann statistics, i.e., according to
the respective heats of formation. The rotational strengths were
transformed into ∆ε values and, for a better visualization, superim-
posed with a Gaussian band-shape function.
1
14a: Rf ϭ 0.40. H NMR (CDCl3, 400 MHz): δ ϭ 1.08Ϫ1.15 [m,
39 H, 12 CH3 (TIPS) and 3 CHSi], 1.17 (s, 3 H, 11-CH3), 1.32 (s,
3 H, 11-CH3), 1.40 (m, 3 H, 3 CHSi), 1.57 (s, 3 H, 7-CH3),
1.66Ϫ1.88 (m, 2 H, 9-H2), 2.13Ϫ2.43 (m, 2 H, 8-H2), 3.78 (dd, 3J ϭ
3
6.6, 7.8 Hz, 1 H, 10-H), 4.76 (s, 2 H, CH2OSi), 6.77 (dd, J ϭ 8.1,
4
4J ϭ 0.7 Hz, 1 H, 4-H), 6.90 (d, J ϭ 0.7 Hz, 1 H, 2-H), 7.47 (d,
3J ϭ 8.1 Hz, 1 H, 5-H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ
12.1 (3 C, CHSi), 13.5 (3 C, CHSi), 18.0 [6 C, CH3 (TIPS)], 18.2
[6 C, CH3 (TIPS)ϩ, 24.3 (11-CH3), 26.6 (C9), 27.4 (11-CH3), 27.9
(7-CH3), 38.6 (C8), 64.6 (CH2OSi), 71.0 (C11), 84.0 (C10), 84.7
(C7), 115.6 (C2), 117.4 (C4), 125.6 (C5), 135.4 (C6), 141.2 (C3),
152.2 (C1) ppm. IR (KBr): ν˜ ϭ 2945, 1418, 1174, 1066, 883 cmϪ1
.
1
14b: Rf ϭ 0.36. H NMR (CDCl3, 400 MHz): δ ϭ 1.08Ϫ1.15 [m,
39 H, 12 CH3 (TIPS) and 3 CHSi], 1.17 (s, 3 H, 11-CH3), 1.31 (s,
3 H, 11-CH3), 1.40 (m, 3 H, 3 CHSi), 1.52 (s, 3 H, 7-CH3),
3
1.70Ϫ2.19 (m, 2 H, 9-H), 2.13Ϫ2.41 (m, 2 H, 8-H), 3.93 (dd, J ϭ
7.5, 3J ϭ 7.8 Hz, 1 H, 10-H), 4.76 (s, 2 H, CH2OSi), 6.77 (dd, 3J ϭ
4
4
8.1, J ϭ 1.5 Hz, 1 H, 4-H), 6.90 (d, J ϭ 1.5 Hz, 1 H, 2-H), 7.56
(d, 3J ϭ 8.1 Hz, 1 H, 5-H) ppm. 13C NMR (CDCl3, 100 MHz):
δ ϭ 12.1 (3 C, CHSi), 13.6 (3 C, CHSi), 18.1 [6 C, CH3 (TIPS)],
18.2 [6 C, CH3 (TIPS)], 24.6 (11-CH3), 26.3 (C9), 26.8 (11-CH3),
27.3 (7-CH3), 38.0 (C8), 64.6 (CH2OSi), 71.7 (C11), 83.8 (C10),
84.7 (C7), 115.4 (C2), 117.4 (C4), 125.6 (C5), 135.9 (C6), 141.2
(C3), 151.8 (C1) ppm. IR (KBr): ν˜ ϭ 2944, 2866, 1463, 1162, 1100,
1068, 883 cmϪ1. MS (EI, 70 eV, mixture of both diastereomers):
m/z (%) ϭ 577 (40) [M]ϩ, 563 (20), 517 (65), 387 (50), 361 (100).
HREIMS (C33H62O4Si2): calcd. 578.4187; found 578.4165.
2-[2-Hydroxy-4-(triisopropylsilanyloxymethyl)phenyl]methylheptane-
2,6-diol (15): At 0 °C, a solution of the epoxide 13 (0.16 g,
0.28 mmol) in dry THF (5 mL) was slowly added to a suspension
of LiAlH4 in dry THF (4 mL). The reaction mixture was allowed
to warm up to 20 °C, was stirred for 60 min, and then cooled again
to 0 °C, before being quenched with water (1 mL). The mixture
was poured onto ice and extracted three times with DCM. The
combined organic layers were dried with MgSO4 and concentrated.
Supporting Information (see also footnote on the first page of this
article): Spectroscopic and spectrometric data of the natural prod-
ucts (ϩ)-curcutetraol (1) and (Ϫ)-curcutriolamide (2).
Acknowledgments
The residue was purified by flash chromatography (RP-18; MeOH/ This work was funded by the BMBF (Bonn, Germany, grant
water, 8:1) to provide a colorless oil (25.0 mg, 0.06 mmol, 21%). 1H
03F0254A), BASF AG (Ludwigshafen), the Fonds der Chemischen
NMR (CD3OD, 400 MHz): δ ϭ 1.06Ϫ1.15 (m, 24 H, 6 CH3 and Industrie (to G. B.), the Deutsche Forschungsgemeinschaft (Gradu-
2 CH3), 1.16Ϫ1.21 {m, 3 H, CH2OSi[CH(CH3)2]3}, 1.26Ϫ1.47 (m, iertenkolleg ‘‘Elektronendichte’’), and by the DAAD (short term
4 H, 9-H2, 10-H2), 1.58 (s, 3 H, 7-CH3), 1.75Ϫ2.00 (m, 2 H, 8-H2), stipend to T.M.). Special thanks go to Prof. Dr. William Fenical
4.74 (s, 2 H, CH2OTIPS), 6.75 (d, 3J ϭ 8.8 Hz, 1 H, 4-H), 6.77 (s, 1 and Paul Jensen (Scripps Institution of Oceanography, San Diego,
H, 2-H), 7.07 (d, 3J ϭ 8.8 Hz, 1 H, 5-H) ppm. 13C NMR (CD3OD, CA, USA) for providing us with fermentation broths and welcoming
100 MHz):
δ
ϭ
11.9 {3 C, OSi[CH(CH3)2]3}, 17.1 {6 C, T. M. in their laboratories. We also thank Dr. Martin Will and
340
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org Eur. J. Org. Chem. 2005, 334Ϫ341

Isolation, Structural Elucidation, and Synthesis of Curcutetraol
FULL PAPER
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Retention times 18.3 min (Chiralpak AD-H, 250 ϫ 4.6 mm;
heptane/EtOH/MeOH, 5:1:1; flow rate 1 mL/min, 30 °C) and
10.0 min (Chiralcel OJ, 250 ϫ 4.6 mm; heptane/EtOH/MeOH,
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Received May 12, 2004
Eur. J. Org. Chem. 2005, 334Ϫ341
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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