Total synthesis of altenuene and isoaltenuene

Article abstract of DOI:10.1002/ejoc.200500904

Total synthesis of altenuene and isoaltenuene, toxins produced by various alternaria fungi, were achieved for the first time in ten steps, starting with quinic acid and commercially available acetal-protected phloroglucinic acid, with the longest linear sequence consisting of seven steps. The key reactions are palladium-catalyzed Suzuki-type couplings between an arene boronate and iodinated cyclohexenes. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500904

FULL PAPER
DOI: 10.1002/ejoc.200500904
Total Synthesis of Altenuene and Isoaltenuene
Martina Altemöller,[a] Joachim Podlech,*[a] and Dieter Fenske[b]
Keywords: Mycotoxins / Suzuki coupling / Biaryls / Total synthesis / Alternaria toxins
Total synthesis of altenuene and isoaltenuene, toxins pro-
duced by various alternaria fungi, were achieved for the first
time in ten steps, starting with quinic acid and commercially
available acetal-protected phloroglucinic acid, with the long-
est linear sequence consisting of seven steps. The key reac-
tions are palladium-catalyzed Suzuki-type couplings be-
tween an arene boronate and iodinated cyclohexenes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
The resorcylic lactones alternariol (1) and alternariol 9-
methyl ether (2) are main secondary metabolites of toxin-
producing alternaria fungi (Figure 1).[1–3] Although the tox-
icities of these mycotoxins are low in comparison with
others (such as aflatoxins),[4,5] infestation with alternaria
spp. is a cause of significant crop losses through fouling of
tomatoes, apples, and other fruits.[6–8] Numerous investi-
gations on alternariol (1) and alternariol 9-methyl ether (2)
have been published and total syntheses have been provided
for these compounds.[9–11] Much less is known about minor
alternaria toxins such as dehydroaltenusin (3),[12–14] alten-
uene (4),[2,13,15,16] isoaltenuene (5),[17–19] epialtenuene (6),[20]
or neoaltenuene (7),[20] which have been isolated from in-
fested fruits in sub-milligram amounts. While a total syn-
thesis of dehydroaltenusin (3) has been published,[21,22] nei-
ther detailed biological data are available for the latter tox-
ins, nor has their absolute configuration been reported. Al-
tenuene was reported to show cytotoxicity,[13] and a more
detailed investigation showed it to be active towards HeLa
cells (ID50: 0.5–28 µg ml–1).[3] To provide sufficient amounts
of material for toxicological and biological testing, we have
established total syntheses of altenuene and isoaltenuene,
which we wish to present in this paper.
Figure 1. Toxins produced in alternaria fungi (absolute configura-
tions for compounds 6 and 7 have not been reported; compound 3
racemizes under physiological conditions).
altenuene and isoaltenuene. Since we had no reliable infor-
mation on the absolute configurations of these natural
products, we decided on a venture directed towards the
enantiomers depicted in Figure 1, which would allow us to
use inexpensive quinic acid as starting material. It was
planned to construct the central C–C bond by Suzuki cross
coupling between a boronic ester A and a cyclohexenyl io-
dide B (Scheme 1).
We chose acetals as protecting groups for both frag-
ments, since these should be cleavable to liberate the final
products without the acid-sensitive methyl ether being af-
fected. It was expected that a boronic ester of type A should
Results and Discussion
Our intent was to develop a convergent synthesis, start-
ing with identical building blocks, to give access to both
[a] Institut für Organische Chemie der Universität Karlsruhe (TH),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-608-7652
E-mail: joachim.podlech@ioc.uka.de
[b] Institut für Anorganische Chemie der Universität Karlsruhe
(TH),
Engesserstraße 15, 76131 Karlsruhe, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Total Synthesis of Altenuene and Isoaltenuene
FULL PAPER
Table 1. Optimization in the preparation of boronate 10.
Scheme 1. Retrosynthetic analysis for altenuene and isoaltenuene.
be easily preparable from the corresponding triflate, used in
the total synthesis of dehydroaltenusin (3).[21,22] A similar
strategy was used by us in the synthesis of alternariol (1)
and alternariol 9-methyl ether (2).[11] From the commer-
cially available acetal 8,[23] triflate 9 is prepared in two steps
and in an overall yield of 74% (Scheme 2).[22,24] Triflates
have frequently been used for the palladium-catalyzed prep-
aration of boronic acids suitable for Suzuki cross coup-
ling,[25,26] but reports on the preparation of ortho-substi-
tuted boronic acids from their corresponding triflates are
nevertheless scarce.[27,28] Some efforts were necessary in or-
der to optimize this reaction and to achieve a satisfying
88% yield of boronate 10 (Scheme 2 and Table 1). 4,4,5,5-
zation of cesium carbonate (3 equiv.) gave a satisfactory
82% yield of coupled substrate 15 (Scheme 3). An even
higher 96% yield of chiral product 16 was obtained when
these conditions were applied to the coupling of arylboron-
ate 10 with chiral fragment 12. However, no procedure for a
clean formation of tertiary alcohol 17 could be established.
Tetramethyl-1,3,2-dioxaborolane
(“pinacolborane”,
3 equiv.) was used as boron source (Entries 3–5), and tetra-
kis(triphenylphosphane)palladium(0) [Pd(PPh3)4, 5 mol-%]
proved to give significantly higher yields than dichloro[1,1Ј-
bis(diphenylphosphanyl)ferrocene]palladium()
[PdCl2(dppf), Entries 1–3]. The suitability of triethylamine
as base had previously been proposed by Masuda et al.,[29]
and formation of the reduced side-product 20 could be sup-
pressed by reducing the reaction time from 4 to 2 h (En-
tries 4, 5). Accumulation of this side product had already
been reported by Suzuki.[25]
Scheme 3. Suzuki coupling of iodocyclohexenones.
Consequently, we inverted the intended sequence and
first methylated enone 12 to yield a product similarly appli-
Scheme 2. Synthesis of the western building block 10.
Iodinated substrate 12, which should be suitable for Su- cable in a Suzuki coupling. Treatment of enone 12 with
zuki cross coupling was prepared in four steps by published methylmagnesium bromide yielded adducts 13a and 13b
procedures, starting with quinic acid (11) (37% overall with an 86:14 selectivity (Scheme 4) without the sensitive
yield, Scheme 4).[24,30,31] To establish the best conditions for iodo substituent being affected. NMR spectroscopic investi-
cross coupling, we tested 2-iodocyclohex-2-enone (14)[32] in gations, including NOE spectroscopy, showed that the iso-
its reaction with boronate 10. No reaction was observed mer bearing the methyl group in an axial orientation (13a)
with 5 mol-% Pd(PPh3)4 and potassium carbonate,[27] bar- had been formed preferentially. (The conformation of the
ium hydroxide,[25] or potassium phosphate as base, but utili- substrates is rigid in this trans-decalin-type system.) We as-
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M. Altemöller, J. Podlech, D. Fenske
FULL PAPER
Table 2. Conditions tested for the Suzuki coupling of iodide 13a and boronate 10.
Entry
Catalyst[a]
Conditions[b]
Yield [%]
45
55
50
61
52
72
55
1
2
3
4
5
6
7
5 mol-% Pd(PPh3)4
5 mol-% Pd(PPh3)4
5 mol-% Pd(PPh3)4
1.5 mol-% Pd2(dba)3, 3.6 mol-% tBu3P
1.5 mol-% Pd2(dba)3, 3.6 mol-% tBu3P
2 mol-% Pd(OAc)2, 4 mol-% S-Phos
2 mol-% Pd(OAc)2, 4 mol-% S-Phos
THF/H2O (10:1), 70 °C, 4 h
THF/H2O (10:1), MW, 70 °C, 30 min
dioxane/H2O (5:1), 80 °C, 4 h
dioxane, 80 °C, 2 h
dioxane/H2O (5:1), 80 °C, 2 h
dioxane/H2O (5:1), 80 °C, 2 h
dioxane/H2O (5:1), MW, 80 °C, 2 h
[a] S-Phos: 2-(dicyclohexylphosphanyl)-2Ј,6Ј-dimethoxybiphenyl. [b] 1 equiv. iodinated compound, 1.3. equiv. boronate, 3 equiv. Cs2CO3,
MW: microwave.
sume that the selectivity is best explained in terms of hin-
drance through the flagpole hydrogen atom in 12 preventing
an approach of the nucleophile along the Bürgi–Dunitz
trajectory (Scheme 4). The two isomers of 13 were easily
separable by chromatographic methods, allowing for the
utilization of both isomers in the further course of the se-
quence.
Scheme 4. Synthesis of the eastern building blocks 13a and 13b.
Compounds 13a and 13b proved to be suitable for Suzuki
coupling, though the conditions described above
(Scheme 3) gave only 40 and 45% yields for 18 and 19,
respectively. To our great surprise, however, we observed the
Scheme 5. Suzuki coupling of iodo alcohols and liberation of the
natural products.
formation not only of the C–C bond but also concomitantly
of the corresponding lactones, with liberation of the pheno-
lic hydroxy groups previously protected as acetals. We set
out to optimize the Suzuki coupling, and obtained a 61% data,[1,17] which, on the other hand, gave evidence for the
yield of protected isoaltenuene 19 when we used tris(dibenz- constitutions and relative configurations proposed in the lit-
ylideneacetone)dipalladium [Pd2(dba)3] together with tri- erature. The configuration of the product was verified not
tert-butylphosphane (Table 2, Entry 4).[33] The best results, only through the configuration of the quinic acid starting
though, were obtained with palladium acetate in the pres- material (11), but additionally through an X-ray crystallo-
ence of S-Phos as ligand (72%, Entry 6, Scheme 5).[34] graphic analysis of isoaltenuene precursor 19 (Figure 2).[35]
These conditions were similarly applied to the formation of
Since the absolute configurations of altenuene and isoal-
altenuene precursor 18 (70%). The fortunate formation of tenuene had not been known before our investigations, we
the lactone during the Suzuki coupling left only one step measured the optical rotations of the synthesized substrates.
missing in the scheduled sequence – the cleavage of the re- While isoaltenuene (5) is not commercially available[36] and
maining diol-protecting acetal group, which was achieved so could not be compared with the synthesized material, we
with trifluoroacetic acid (TFA)/water within 10 min, yield- found to our great stupefaction that purchased, microbio-
ing altenuene (4) and isoaltenuene (5) in 55% and 62% logically prepared altenuene (4, from Sigma–Aldrich)
yields, respectively.
showed a specific rotation of about zero. On the other hand,
The identities of altenuene (4) and isoaltenuene (5) were altenuene synthesized by us showed a specific rotation of –4
unambiguously established by comparison with published (i.e., –0.4° cm2 g–1). For better quantification we measured
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Total Synthesis of Altenuene and Isoaltenuene
FULL PAPER
[α]D are given in units of 10–1 deg cm2 g–1. UV/Vis spectra were
recorded with a Perkin–Elmer Lambda 2 spectrometer. The extinc-
tion coefficient ε is given for quantitative measurements. Circular
dichroism spectra were recorded with a Jasco spectropolarimeter J-
810.
7-Methoxy-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)benzo[d][1,3]dioxin-4-one (10): Freshly distilled Et3N (210 mg,
1.50 mmol) and Pd(PPh3)4 (28 mg, 5 mol-%) were added to a solu-
tion of triflate 9 (178 mg, 0.500 mmol) in anhydrous dioxane
(30 mL). The solution was degassed under argon in a ultra-
sonication bath, and “pinacolborane” (1.07 g, 8.42 mmol) was
added dropwise over 5 min. The mixture was heated to 80 °C for
4 h and the solvent was removed in vacuo. Without further workup,
the residue was purified by chromatography on SiO2 (hexane/
EtOAc, 10:1) to yield the boronate 10 (90 mg, 0.26 mmol, 54%)
and a smaller fraction of the reduced side product 20 (23 mg, 22%).
Compound 10: Colorless solid, m.p. 108–110 °C. Rf (hexane/
Figure 2. X-ray crystal structure of isoaltenuene derivative 19.[35]
1
EtOAc, 2:1) = 0.39. H NMR (250 MHz, CDCl3): δ = 1.39 (s, 12
H, CH3), 1.72 (s, 6 H, CH3), 3.83 (s, 3 H, OMe), 6.40 (d, 4J =
2.4 Hz, 1 H), 6.67 (d, 4J = 2.4 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.8 (q), 25.8 (q), 55.7 (q), 84.5 (s), 101.6 (d), 106.2
(s), 108.7 (s), 113.7 (d), 157.7 (s), 161.8 (s), 165.6 (s) ppm. IR
circular dichroism spectra and normalized the measured
samples (for accurate comparison of the obtained data) by
evaluation of their UV spectra.[37] From this, the enantio-
meric excess of natural altenuene was determined to be only
ca. 2%. The reason for this astonishing finding is com-
pletely unclear to us. Obviously we were lucky that the en-
antiomer synthesized by us represents the major isomer
present in the genuine material. Since it is reasonable to
(DRIFT): ν = 2981 (s), 2947 (w), 2850 (w), 1725 (s, C=O), 1607
˜
(m), 1582 (s), 1448 (m), 1378 (s), 1326 (m), 1297 (m), 1273 (w),
1208 (m), 1145 (m), 1051 (s), 962 (w) cm–1. MS (EI, 70 °C): m/z
(%) = 334 (14) [M]+, 277 (15), 276 (100) [M – C3H6O]+, 275 (24),
218 (34), 217 (20), 208 (13), 194 (42), 193 (10), 177 (12), 176 (12),
153 (15), 150 (42), 122 (13), 107 (23), 83 (16), 77 (28), 51 (13), 43
assume that altenuene and isoaltenuene have common bio- (31). C17H23BO6 (334.16): calcd. C 61.45, H 6.94; found C 60.24,
H 6.59. HRMS (EI): calcd. 334.1588 amu; found: 334.1585 amu.
Compound 20: solid, m.p. 47–48 °C. Rf (hexane/EtOAc, 2:1) =
0.44. 1H NMR (400 MHz, CDCl3): δ = 1.73 (s, 6 H, CH3), 3.85 (s,
synthetic precursors (though this has yet to be confirmed)
we infer that the isoaltenuene synthesized by us should also
have the correct absolute configuration dominant in micro-
biologically produced isoaltenuene. Nevertheless, further in-
vestigations on, for example, the enantiopurity of natural
isoaltenuene would be highly desirable.
4
3 H, CH3), 6.43 (d, J = 2.4 Hz, 1 H, 8Ј-H), 6.65 (dd, 4J = 2.4 Hz,
3
3J = 8.8 Hz, 1 H, 6Ј-H), 7.87 (d, J = 8.7 Hz, 1 H, 5Ј-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 25.8 (q, 2 C), 55.7 (q), 101.0 (d),
106.2 (s), 106.3 (s), 110.3 (d), 131.2 (d), 157.9 (s), 161.0 (s); 166.3
(s) ppm. IR (DRIFT): ν = 3003 (s), 2952 (w), 1730 (s), 1614 (s),
˜
1503 (m), 1445 (w), 1379 (m), 1354 (w), 1301 (s), 1210 (m), 1155
(w), 1106 (m), 1050 (s), 1021 (m), 960 (m) cm–1. MS (EI, 25 °C):
m/z (%) = 208 (47) [M]+, 151 (26) [M – C3H5O]+, 150 (100) [M –
C3H6O]+, 122 (48) [M – C4H6O2]+, 107 (22) [C7H7O]+, 79 (13).
C11H12O4 (208.07): calcd. C 63.45, H 5.81; found C 63.24, H 5.76.
HRMS (EI): calcd. 208.0736 amu; found 208.0735 amu.
Experimental Section
General Remarks: An authentic sample of altenuene (4) was pur-
chased from Sigma–Aldrich. Tetrahydrofuran (THF) and Et2O
were distilled from sodium/benzophenone ketyl radical and CH2Cl2
was distilled from CaH2. All moisture-sensitive reactions were car-
ried out under oxygen-free argon or nitrogen with use of oven-dried
glassware and a vacuum line. Flash column chromatography was
carried out with Merck SiO2 60 (230–400 mesh) and thin layer
chromatography was carried out with commercially available
Merck F254 pre-coated sheets. Medium-pressure liquid chromatog-
raphy (MPLC): detection by UV absorption (Latek UVIS 200). 1H
and 13C NMR spectra were recorded with a Bruker Cryospek WM-
250, an AM 400, or a DRX 500. Chemical shifts are given in ppm
downfield from tetramethylsilane. 13C NMR spectra were recorded
with broad-band proton decoupling and were assigned through
DEPT 135 and DEPT 90 experiments. Melting points were mea-
sured with a Büchi apparatus and are not corrected. IR spectra
were recorded with a Bruker IFS-88 spectrometer. Elemental analy-
ses were performed with a Heraeus CHN-O-rapid instrument. Elec-
trical ionization and high-resolution mass spectra were recorded
with a Finnigan MAT-90 machine. MALDI-TOF spectra were re-
corded in negative, linear mode with a Bruker REFLEX IV spec-
trometer with a 2,5-dihydroxybenzoic acid (DHB) matrix. Optical
rotations were recorded with a Perkin–Elmer 241 polarimeter (with
use of the sodium D line at 589 nm), and specific optical rotations
7-Methoxy-2,2-dimethyl-5-(6-oxocyclohex-1-enyl)benzo[d][1,3]di-
oxin-4-one (15): Iodocyclohexenone 14 (67 mg, 0.30 mmol), bo-
ronate 10 (130 mg, 0.390 mmol), Cs2CO3 (390 mg, 1.20 mmol), and
Pd(PPh3)4 (17 mg, 5 mol-%) in THF/H2O (10:1, 10 mL) were
heated under argon at 70 °C for 4 h and then cooled to room temp.
Saturated NH4Cl solution (10 mL) was added and the mixture was
extracted with EtOAc (3×10 mL). The combined organic layers
were dried (Na2SO4), the solvents were removed in vacuo, and the
residue was purified by chromatography on SiO2 (hexane/EtOAc,
6:1) to yield product 15 (74 mg, 0.24 mmol, 82%). Compound 15:
1
brownish solid, m.p. 89–91 °C. Rf (hexane/EtOAc, 2:1) = 0.21. H
NMR (400 MHz, CDCl3): δ = 1.74 (s, 6 H, 2 CH3), 1.97–2.80 (m,
6 H, 3Ј-H2, 4Ј-H2, 5Ј-H2), 3.84 (s, 3 H, OMe), 6.40, 6.82–6.85 (m,
3 H, 2Ј-H, 6-H, 8-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.7
(t), 24.1 (q), 26.2 (t), 38.5 (t), 55.7 (q), 100.5 (d), 105.6 (s), 106.0
(s), 112.3 (d), 141.3 (s), 142.0 (s), 144.2 (d), 158.2 (s), 160.3 (s),
165.1 (s), 197.8 (s) ppm. IR (DRIFT): ν = 3446 (w), 3081 (w), 3006
˜
(w), 2982 (w), 2953 (m), 2893 (w), 2842 (w), 1733 (s), 1679 (s), 1611
(s), 1582 (m), 1469 (w), 1440 (w), 1425 (m), 1392 (w), 1381 (w),
1331 (m), 1284 (s), 1252 (m), 1204 (m), 1166 (s), 1095 (w), 1052
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M. Altemöller, J. Podlech, D. Fenske
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(w), 1033 (s) cm–1. MS (EI, 30 °C): m/z (%) = 302 (12) [M]+, 276
(42), 244 (56), 218 (20), 208 (25), 194 (28), 166 (25), 153 (43), 150
m/z (%) = 410 (11) [M + Na]+. Compound 13b: Rf (hexane/EtOAc,
1
2:1) = 0.40. [α]2D0 = +125.2 (c = 1.0, CHCl3). H NMR (500 MHz,
(100), 136 (24), 122 (35), 110 (33), 108 (37), 107 (60). C17H18O5 CDCl3): δ = 1.30 (s, 3 H, CH3), 1.32 (s, 3 H, CH3), 1.37 (s, 3 H,
2
3
(302.12): calcd. C 67.54, H 6.00; found C 66.54, H 6.05. HRMS
(EI): calcd. 302.1154 amu; found 302.1153 amu.
CH3), 1.87 (dd, J = 12.8 Hz, J = 13.1 Hz, 1 H, 5-HaxHeq), 2.28
(dd, 3J = 3.6 Hz, 3J = 13.1 Hz, 1 H, 5-HaxHeq), 3.25 (s, 3 H, OMe),
3.27 (s, 3 H, OMe), 3.91 (ddd, 3J = 3.6 Hz, 3J = 9.0 Hz, 3J =
(2ЈS,3ЈS,4ЈaR,8ЈaR)-5-(2,3-Dimethoxy-2,3-dimethyl-6-oxo-
2,3,4a,5,6,8a-hexahydrobenzo[b][1,4]dioxin-7-yl)-7-methoxy-2,2-di-
methyl-4H-benzo[d][1,3]dioxin-4-one (16): Iodo compound 12
(110 mg, 0.300 mmol), boronate 10 (154 mg, 0.420 mmol), Cs2CO3
(390 mg, 1.20 mmol), and Pd(PPh3)4 (17 mg, 5 mol-%) in THF/
H2O (10:1, 10 mL) were heated under argon at 70 °C for 4 h and
then cooled to room temp. Saturated NH4Cl solution (10 mL) was
added and the mixture was extracted with EtOAc (3×5 mL). The
combined organic layers were dried (Na2SO4), the solvents were
removed in vacuo, and the residue was purified by chromatography
on SiO2 (hexane/EtOAc, 6:1) to yield product 16 (130 mg,
0.290 mmol, 96%). Compound 16: yellowish solid, m.p. 90–93 °C.
3
3
12.8 Hz, 1 H, 4a-H), 4.10 (dd, J = 1.8 Hz, J = 9.0 Hz, 1 H, 8a-
H), 6.34 (d, 3J = 1.8 Hz, 1 H, 8-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 17.7 (q), 17.8 (q), 33.0 (t), 38.4 (q), 48.0 (q), 49.1 (q),
65.3 (d), 71.3 (d), 74.2 (s), 100.0 (s), 100.6 (s), 111.5 (s), 138.8 (d)
ppm. IR (DRIFT): ν = 3471 (s), 2950 (s), 2833 (w), 2082 (w), 1612
˜
(m), 1456 (m), 1375 (s), 1334 (w), 1301 (w), 1205 (m), 1135 (s),
1080 (w), 1039 (m), 987 (s), 881 (s) cm–1. MS (FAB): m/z (%) =
353 (29), 236 (18), 154 (40), 115 (22), 101 (100), 89 (12). MS
(MALDI): m/z (%) = 410 (28) [M + Na]+.
(6aR,7aR,9S,10S,11aR)-4-Hydroxy-2,9,10-trimethoxy-7a,9,10-tri-
methyl-6a,7,7a,9,10,11a-hexahydro-5H-benzo[c][1,4]dioxino[2,3-g]-
chromen-5-one (18): Iodide 13b (384 mg, 1.00 mmol), boronate 10
(434 mg, 1.30 mmol), Cs2CO3 (98 mg, 3.0 mmol), Pd(OAc)2 (5 mg,
2 mol-%), and 2-(dicyclohexylphosphanyl)-2Ј,6Ј-dimethoxybi-
Rf (hexane/EtOAc, 2:1) = 0.18. [α]2D0 = +30.5 (c = 1.0, CHCl3). H
1
NMR (500 MHz, [D6]DMSO): δ = 1.25 (s, 3 H, CH3), 1.27 (s, 3
H, CH3), 1.68 (s, 6 H, CH3), 2.53 (m, 1 H), 2.65–2.68 (m, 1 H),
3.19 (s, 3 H, OMe), 3.26 (s, 3 H, OMe), 3.85 (s, 3 H, OMe), 3.99– phenyl (S-Phos, 17 mg, 4 mol-%) were dissolved in dioxane/H2O
4.13 (m, 1 H), 4.52 (dd, J = 1.6 Hz, J = 9.2 Hz, 1 H), 6.64 (d, J = (5:1, 24 mL) and the mixture was heated under argon at 80 °C for
2.4 Hz, 1 H), 6.56 (d, J = 1.9 Hz, 1 H), 6.78 (m, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): 2 rotamers, signals found at δ = 17.8,
24.1, 24.5, 24.9, 26.7, 27.0, 41.1, 43.0, 48.2, 48.3, 55.8, 67.2, 68.0,
69.2, 69.5, 75.0, 99.54, 99.9, 100.6, 100.8, 101.0, 101.6, 105.8, 111.4,
112.3, 140.1, 140.4, 140.8, 141.7, 141.8, 158.0, 158.3, 158.3, 160.0,
2 h. Hydrolysis with saturated NH4Cl solution (20 mL), extraction
with EtOAc (3×20 mL), drying of the organic layer (Na2SO4), re-
moval of the solvents in vacuo, and purification of the residue by
MPLC on SiO2 (hexane/EtOAc, 8:1) yielded lactone 18 (288 mg,
0.709 mmol, 71 %) as a white solid. Compound 18: Rf (hexane/
EtOAc, 2:1) = 0.56. [α]2D0 = +68.1 (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.32 (s, 6 H, CH3), 1.34 (s, 3 H, CH3), 1.89
(dd, 3J = 13.0 Hz, 2J = 14.4 Hz, 1 H, 7-HaxHeq), 2.48 (dd, 3J =
160.1, 160.4, 165.2, 194.6 ppm. IR (DRIFT): ν = 3519 (m), 2991
˜
(s), 2949 (w), 2836 (w), 1731 (s), 1693 (m), 1610 (s), 1580 (m), 1431
(m), 1378 (m), 1328 (w), 1284 (s), 1229 (w), 1209 (m), (1165 (w),
1143 (s), 1082 (w), 1051 (w), 1051 (w) cm–1. MS (EI, 90 °C): m/z
(%) = 448 (2) [M]+, 242 (37), 85 (16), 59 (100), 57 (18), 43 (24), 41
(10). C23H28O9 (448.17): calcd. C 61.60, H 6.29; found C 61.17, H
7.02. HRMS (EI): calcd. 448.1733 amu; found 448.1739 amu.
2
4.5 Hz, J = 14.4 Hz, 1 H, 7-HaxHeq), 3.26 (s, 3 H, OMe), 3.31 (s,
3
3 H, OMe), 3.87–3.98 (m, 4 H, OMe, 9-H), 4.24 (dd, J = 1.6 Hz,
3
3J = 8.9 Hz, 1 H, 10-H), 6.14 (d, J = 1.6 Hz, 1 H, 12-H), 6.42 (d,
4J = 2.3 Hz, 1 H), 6.48 (d, 4J = 2.3 Hz, 1 H), 11.32 (s, 1 H, OH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 17.7 (q), 17.8 (q), 28.2 (q),
38,8 (t), 48.1 (q), 48.2 (q), 55.6 (q), 66.0 (d), 69.5 (d), 81.3 (s), 99.9
(s), 100.3 (s), 100.4 (s), 100.7 (d), 102 (d), 128.6 (d), 138.9 (s), 164.0
(2S,3S,4aR,6S,8aR)- and (2S,3S,4aR,6R,8aR)-7-Iodo-2,3-dimeth-
oxy-2,3,6-trimethyl-2,3,4a,5,6,8a-hexahydrobenzo[b][1,4]dioxin-6-ol
(13a/13b): MeMgBr (0.66 mL of a 3  solution in Et2O, 2 mmol)
was added dropwise by syringe at –40 °C, with exclusion of moist-
ure and air, to a solution of iodide 12 (368 mg, 1.00 mmol) in anhy-
drous THF (10 mL). The temperature was allowed to rise to room
temp. over 6 h by removal of the cooling bath, and the mixture was
hydrolyzed with saturated NH4Cl solution (10 mL) and extracted
with EtOAc (3×10 mL). The combined organic layers were dried
(Na2SO4), the solvents were removed in vacuo, and the residue was
purified by MPLC on SiO2 (hexane/EtOAc, 8:1) to yield dia-
stereomer 13a (185 mg, 0.50 mmol, 50 %) and diastereomer 13b
(69 mg, 0.18 mmol, 18%) as slightly yellow oils. Compound 13a:
(s), 166.1 (s), 168.9 (s) ppm. IR (DRIFT): ν = 3434 (w), 2951 (s),
˜
2835 (w), 2249 (w), 1667 (s), 1621 (m); 1579 (m), 1502 (w), 1440
(m),1378 (w), 1353 (m), 1314 (w), 1268 (m), 1229 (w), 1206 (m),
1164 (w), 1135 (s), 1089 (w), 1052 (m) cm–1. UV/Vis (EtOH): λ =
193, 242, 278, 319 nm. MS (EI, 90 °C): m/z (%) = 406 (0.6) [M]+,
258 (58), 241 (30), 240 (100), 212 (17), 197 (9), 101 (12), 43 (8).
HRMS (EI): calcd. 406.1628 amu; found 406.1632 amu.
(6aS,7aR,9S,10S,11aR)-4-Hydroxy-2,9,10-trimethoxy-6a,9,10-tri-
methyl-6a,7,7a,9,10,11a-hexahydro-5H-benzo[c][1,4]dioxino[2,3-g]-
chromen-5-one (19): Iodide 13a (95 mg, 0.25 mmol), boronate 10
(108 mg, 0.33 mmol), Cs2CO3 (244 mg, 0.75 mmol), Pd(OAc)2
(1.20 mg, 2 mol-%), and 2-(dicyclohexylphosphanyl)-2Ј,6Ј-dimeth-
oxybiphenyl (S-Phos, 4 mg, 4 mol-%) were dissolved in dioxane/
1
Rf (hexane/EtOAc, 2:1) = 0.41. [α]2D0 = +141 (c = 1.0, CHCl3). H
NMR (500 MHz, CDCl3): δ = 1.30 (s, 3 H, CH3), 1.30 (s, 3 H,
CH3), 1.44 (d, 4J = 0.9 Hz, 3 H, C 6-CH3), 2.04 (ddd, 4J = 0.9 Hz,
3
3
2J = 12.3 Hz, J = 13.2 Hz, 1 H, 5-HaxHeq), 2.25 (dd, J = 3.2 Hz, H2O (5:1, 6 mL) and the mixture was heated under argon at 80 °C
2J = 12.3 Hz, 1 H, 5-HaxHeq), 3.24 (s, 3 H, OMe), 3.25 (s, 3 H, for 2 h. Hydrolysis with saturated NH4Cl solution (5 mL), extrac-
3
3
3
OMe), 3.76 (ddd, J = 3.2 Hz, J = 8.9 Hz, J = 13.2 Hz, 1 H, 4a-
tion with EtOAc (3×5 mL), drying of the organic layer (Na2SO4),
removal of the solvents in vacuo, and purification of the residue by
MPLC on SiO2 (hexane/EtOAc, 8:1) yielded lactone 19 (72 mg,
0.18 mmol, 72%) as a white solid. Compound 19: yellowish solid,
m.p. 196–200 °C. Rf (hexane/EtOAc, 2:1) = 0.61. [α]2D0 = +94.4 (c
= 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.36 (s, 3 H,
3
3
3
H), 4.21 (dd, J = 1.9 Hz, J = 8.9 Hz, 1 H, 8a-H), 6.26 (d, J =
1.9 Hz, 1 H, 8-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.8
(q), 30.1 (q), 39.6 (t), 47.9 (q), 48.0 (q), 66.4 (d), 71.2 (d), 75.0 (s),
100.1 (s), 100.6 (s), 114.2 (s), 137.4 (d) ppm. IR (film): ν = 3484
˜
(s), 2990 (w), 2949 (s), 2832 (m), 1724 (s), 1683 (m), 1615 (w), 1452
(s), 1376 (s), 1299 (w), 1265 (w), 1205 (w), 1134 (s), 1037 (s), 1000 CH3), 1.38 (s, 3 H, CH3), 1.62 (d, 3 H, 3J = 3.5 Hz, CH3), 2.27
(s), 929 (w), 911 (s), 881(s) cm–1. MS (EI, 60 °C): m/z (%) = 369
(dd, 1 H, J = 3.5 Hz, J = 12.0 Hz, 7-HaxHeq), 2.36 (ddd, 1 H, J
3
2
4
(25), 355 (32), 353 (24), 267 (22), 237 (38), 236 (97), 235 (38), 221
(84), 109 (100), 108 (64), 101 (81), 94 (81), 91 (19), 84 (47), 80 (31), OMe), 3.84 (s, 3 H, OMe), 3.89 (ddd, J = 3.5 Hz, J = 9.1 Hz, J
75 (30), 73 (37), 69 (28), 56 (36), 43 (99), 41 (50). MS (MALDI):
= 0.9 Hz, 2J = 12.0 Hz, 3J = 13.0 Hz, 7-HaxHeq), 3.31 (s, 6 H, 2
3
3
3
= 13.0 Hz, 1 H, 7a-H), 4.51 (dd, 3J = 2.1 Hz, 3J = 9.1 Hz, 1 H,
1682
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1678–1684

Total Synthesis of Altenuene and Isoaltenuene
FULL PAPER
2.3 Hz, 1 H), 11.35 (s, 1 H, OH) ppm. 13C NMR (100 MHz,
11a-H), 6.11 (d, 3J = 2.1 Hz, 1 H, 12-H), 6.44 (d, J = 2.3 Hz, 1
4
3
H), 6.52 (d, J = 2.3 Hz, 1 H), 11.31 (s, 1 H, OH) ppm. 13C NMR
CDCl3): δ = 26.8 (q), 42.8 (t), 55.7 (q), 71.7 (d), 73.79 (d), 82.1 (s),
(100 MHz, CDCl3): δ = 17.7 (q), 17.8 (q), 27.1 (q), 39.8 (t), 48.0 100.3 (s), 101.3 (d), 103.0 (d), 127.3 (d), 134.0 (s), 137.3 (s), 164.3
(q), 48.1 (q), 55.6 (q), 66.5 (d), 69.5 (d), 82.4 (s), 100.3 (s), 100.4 (s), 166.2 (s), 168.1 (s) ppm. IR (DRIFT): ν = 3409 (s), 2980 (w),
(s), 100.8 (s), 101.3 (d), 102.7 (d); 126.2 (d), 134.0 (s), 138.0 (s), 164 2944 (w), 1666 (s), 1620 (w), 1579 (m), 1496 (w), 1439 (m), 1357
˜
(s), 166.1 (s), 168.2 (s) ppm. IR (DRIFT): ν = 3341 (w), 3018 (w),
(m), 1317 (w), 1263 (s), 1208 (m), 1165 (m), 1133 (w), 1060 (s), 955
(m) cm–1. UV/Vis (EtOH): λ (ε) = 193 (6.674), 243 (10.694), 279
(3.324), 323 (1.829) nm. MS (EI, 100 °C): m/z (%) = 293 (11) [M
+ 1]+, 292 (65) [M]+, 257 (20), 256 (100), 229 (25), 228 (63), 220
˜
2993 (w), 2947 (s), 2907 (w), 2863 (m), 2836 (m), 2081 (w), 1677
(s), 1621 (m), 1577 (m), 1501 (w), 1438 (m), 1379 (w), 1349 (m),
1258 (m), 1207(m), 1147 (s), 1075 (m), 1051 (m), 976 (s), 890 (s)
cm–1. UV/Vis (EtOH): λ = 193, 243, 279, 322 nm. MS (EI, 70 °C): (21), 219 (30), 204 (28), 191 (20), 177 (31), 159 (25), 149 (23), 77
m/z (%) = 240 (50), 236 (39), 226 (26), 224 (30), 221 (18), 208 (29). HRMS (EI): calcd. 292.0947 amu; found 292.0946 amu. The
(25.63), 186 (35), 167 (15), 166 (93), 150 (90), 143 (34), 138 (33), spectroscopic data for isoaltenuene (5) are in full agreement with
130 (68), 129 (21), 124 (23), 122 (29), 116 (53), 115 (19), 110 (38),
109 (41), 108 (18), 107 (18), 101 (72), 95 (24), 75 (25), 73 (23), 43
(100). C21H30O8 (406.43): calcd. C 62.06, H 6.45; found C 61.49,
H 6.48.
the reported data.[17]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and 1H NMR spectroscopic data for
all known substances. UV/Vis and CD spectra of authentic and
1
synthesized altenuene. H and 13C NMR spectra of altenuene and
(2R,3R,4aR)-2,3,7-Trihydroxy-9-methoxy-4a-methyl-2,3,4,4a-tetra-
hydrobenzo[c]chromen-6-one (Altenuene, 4): The protected precur-
sor 18 (169 mg, 0.42 mmol) was dissolved in TFA/H2O (5:1, 5 mL)
and the mixture was stirred at room temp. for 10 min. The solvents
were removed in vacuo and the residue was purified by MPLC
on RP-18 SiO2 (MeOH/H2O, 3:2), yielding altenuene (4, 67 mg,
0.23 mmol, 55%) as a colorless, highly viscous oil. Compound 4:
Rf (CH2Cl2/MeOH, 20:1) = 0.61. [α]2D0 = –4.0 (c = 0.1, MeOH).
CD: λ (∆ε [l mol–1 cm–1]) = 232 (+7.6), 277 (–4.2) nm (synthesized).
CD: λ (∆ε [l mol–1 cm–1]) = 232 (+0.75), 277 nm (–0.47) (purchased
isoaltenuene.
Acknowledgments
This work was supported by the Jürgen-Manchot-Stiftung (stipend
for M. A.). We thank Prof. Dr. C. Richert and P. Grünefeld for the
MALDI spectra and for providing a microwave apparatus and Prof.
Dr. A. Ulrich and Dr. J. Bürck for the CD spectra. We thank Prof.
Dr. A. S. K. Hashmi for his help and for valuable discussions.
1
from Sigma–Aldrich). H NMR (400 MHz, [D6]DMSO): δ = 1.47
3
2
(s, 3 H, CH3), 1.95 (dd, J = 7.4 Hz, J = 14.0 Hz, 1 H, 4-HaHb),
2.26 (dd, 3J = 3.4 Hz, 2J = 14.0 Hz, 1 H, 4-HaHb), 3.67–3.72 (ddm,
[1] Handbook of Toxic Fungal Metabolites (Eds.: R. J. Cole, R. H.
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[4] R. W. Pero, H. Posner, M. Blois, D. Harvan, J. W. Spalding,
Environ. Health Perspect. 1973, 87–94.
3J = 3.4 Hz, J = 7.4 Hz, 1 H, 3-H), 3.86 (3 H, OMe), 3.93–3.97
3
(m, 1 H, 2-H), 5.16 (d, 3J = 3.7 Hz, 1 H, 2-OH), 5.32 (d, 3J =
3
4
6.1 Hz, 1 H, 3-OH), 6.30 (d, J = 3.3 Hz, 1 H, 1-H), 6.50 (d, J =
2.3 Hz, 1 H), 6.75 (d, 4J = 2.3 Hz, 1 H), 11.30 (s, 1 H, 7-OH) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 27.4 (q, CH3), 38.5 (t, C-
4), 55.8 (q, OMe), 68.7 (d, C-3), 69.4 (d, C-2), 81.1 (s, C-4a), 99.9
(s), 100.8 (d), 102.3 (d), 130.9 (d, C-1), 131.7 (s), 139.1 (s), 162.9
[5] V. M. Davis, M. E. Stack, Appl. Environ. Microbiol. 1994, 60,
(s), 165.8 (s), 168.1 (s) ppm. IR (DRIFT): ν = 3404 (s), 2980 (w),
˜
3901–3902.
2936 (w), 1757 (w), 1661(s), 1621 (w), 1578 (m), 1493 (w), 1438
(m), 1355 (m), 1316 (w), 1266 (w), 1210 (m), 1165 (s), 1129 (w),
1067 (m), 1043 (w) cm–1. UV/Vis (EtOH): λ = 194, 241, 278,
319 nm. MS (EI, 100 °C): m/z (%) = 293 (10) [M + 1]+, 292 (48)
[M]+, 248 (30), 220 (34), 219 (32), 218 (24), 206 (30), 177 (34), 149
(32), 97 (26), 85 (24), 83 (27), 81 (26), 71 (24), 69 (51), 59 (75), 57
(53), 55 (43), 43 (100). HRMS (EI): calcd. 292.0947 amu; found
292.0947 amu. The spectroscopic data for altenuene (4) are in
agreement with reported data, although one value for a signal in
the 13C NMR was obviously misprinted in the original literature.
Instead of 99.9 (s) for a quaternary carbon atom, 143.6 (s) was
given there.[1]
[6] M. Combina, A. Dalcero, E. Varsavsky, A. Torres, M. Etchev-
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2924.
[9] T. M. Harris, J. V. Hay, J. Am. Chem. Soc. 1977, 99, 1631–1637.
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Nakata, F. Sugawara, Bioorg. Med. Chem. 2004, 12, 5355–5359.
[13] C. Murakami-Nakai, N. Maeda, Y. Yonezawa, I. Kuriyama, S.
Kamisuki, S. Takahashi, F. Sugawara, H. Yoshida, K. Sakagu-
chi, Y. Mizushina, Biochim. Biophys. Acta 2004, 1674, 193–199
and refs. cited therein.
(2R,3R,4aS)-2,3,7-Trihydroxy-9-methoxy-4a-methyl-2,3,4,4a-tetra-
hydrobenzo[c]chromen-6-one (Isoaltenuene, 5): The protected pre-
cursor 19 (90 mg, 0.22 mmol) was dissolved in TFA/H2O (5:1,
5 mL) and the mixture was stirred at room temp. for 10 min. The
solvents were removed in vacuo and the residue was purified by
MPLC on RP-18 SiO2 (MeOH/H2O, 3:2) yielding isoaltenuene (5,
71 mg, 0.18 mmol, 72 %). Compound 5: white solid, m.p. 102–
105 °C. Rf (CH2Cl2/MeOH, 20:1) = 0.7; Rf (MeOH/H2O, 1:1) =
0.27. [α]2D0 = +25.0 (c = 1.0, MeOH). 1H NMR (500 MHz, CDCl3):
δ = 1.62 (d, 4J = 0.7 Hz, 3 H, CH3), 2.31 (dd, 4J = 0.7 Hz, 3J =
[14] R. W. Pero, R. G. Owens, S. W. Dale, D. Harvan, Biochim. Bio-
phys. Acta 1971, 230, 170–179.
[15] G. F. Griffin, F. S. Chu, Appl. Environ. Microbiol. 1983, 46,
1420–1422.
[16] A. T. McPhail, R. W. Miller, D. Harvan, R. W. Pero, J. Chem.
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[17] A. Visconti, A. Bottalico, M. Solfrizzo, F. Palmisano, Myco-
toxin Res. 1989, 5, 69–76.
2
3
2
6.7 Hz, J = 12.5 Hz, 1 H, 4-HaxHeq), 2.37 (dd, J = 3.8 Hz, J =
12.5 Hz, 1 H, 4-HaxHeq), 2.33–2.69 (br., 2 OH), 3.79–3.90 (m, 4 H,
[18] F. Palmisano, A. Sibilia, A. Visconti, Chromatographia 1990,
29, 333–337.
3
3
CH3, 3-H), 4.39 (dd, J = 2.4 Hz, J = 8.0 Hz, 1 H, 2-H), 6.12 (d,
[19] S. Nawaz, K. A. Scudamore, S. C. Rainbird, Food Addit. Con-
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3J = 2.4 Hz, 1 H, 1-H), 6.46 (d, 4J = 2.3 Hz, 1 H), 6.56 (d, 4J =
Eur. J. Org. Chem. 2006, 1678–1684
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1683

M. Altemöller, J. Podlech, D. Fenske
FULL PAPER
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[21] S. Takahashi, S. Kamisuki, Y. Mizushina, K. Sakaguchi, F. Su-
gawara, T. Nakata, Tetrahedron Lett. 2003, 44, 1875–1877.
[30] L. M. Murray, P. O’Brien, R. J. K. Taylor, Org. Lett. 2003, 5,
1943–1946.
[31] M. T. Barros, C. D. Maycock, M. R. Ventura, J. Chem. Soc.,
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Kuramochi, S. Kobayashi, K. Sakaguchi, T. Nakata, F. Suga-
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[23] Acetal 8 can be prepared from 2,4,6-trihydroxybenzoic acid
(phloroglucinic acid), but in several runs we obtained yields
significantly lower (Յ 20%) than those reported in the litera-
ture; see ref.[22] and: S. Danishefsky, S. J. Etheredge, J. Org.
Chem. 1979, 44, 4716–4717.
69–77; F. S. Ruel, M. P. Braun, C. R. Johnson, Org. Synth.
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[34] T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J.
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[35] CCDC-290037 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.
[24] Revised procedures for the preparation of known substances
are given in the Supporting Information.
[25] A. Suzuki, Proc. Jpn. Acad. 2004, 80, 359–371.
[26] J. Takagi, K. Takahashi, T. Ishiyama, N. Miyaura, J. Am.
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[36] Specific rotations have not been published for altenuene (4) and
isoaltenuene (5).
[27] M. Penhoat, V. Levacher, G. Dupas, J. Org. Chem. 2003, 68,
[37] UV/Vis and CD spectra of authentic and synthesized altenuene
(4) are depicted in the Supporting Information.
Received: November 17, 2005
9517.
[28] A. N. Cammidge, K. V. L. Crepy, J. Org. Chem. 2003, 68, 6832–
6835.
Published Online: February 3, 2006
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1684
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Eur. J. Org. Chem. 2006, 1678–1684