Total synthesis of neoaltenuene

Article abstract of DOI:10.1002/ejoc.200900125

The total synthesis of neoaltenuene, a toxin produced by alternaria fungi, has been achieved for the first time in 14 steps in a yield of 10 % starting from quinic acid and phloroglucinic acid, the longest linear sequence consisting of 10 steps. The key r

Full text of DOI:10.1002/ejoc.200900125

FULL PAPER
DOI: 10.1002/ejoc.200900125
Total Synthesis of Neoaltenuene
Martina Altemöller[a] and Joachim Podlech*[a]
Dedicated to Professor Dr. János Rétey on the occasion of his 75th birthday
Keywords: Cross-coupling / Palladium / Total synthesis / Toxins
The total synthesis of neoaltenuene, a toxin produced by al-
ternaria fungi, has been achieved for the first time in 14 steps
in a yield of 10% starting from quinic acid and phloroglucinic
acid, the longest linear sequence consisting of 10 steps. The
key reaction was a palladium-catalyzed Suzuki-type coup-
ling of an arene boronate with an iodinated cyclohexene.
4a-epi-Neoaltenuene, a non-natural isomer has been synthe-
sized similarly.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
toxicity of these mycotoxins is low compared with others
(e.g., aflatoxins),[2] infestation with Alternaria sp. leads to
significant crop losses through the fouling of tomatoes,
apples, and other fruit.[3]
Introduction
The resorcylic lactones alternariol (1) and alternariol 9-
methyl ether (2) are the main secondary metabolites of
toxin-producing Alternaria fungi (Figure 1).[1] Although the
Numerous investigations have been published on al-
ternariol (1) and alternariol 9-methyl ether (2),[4] and total
syntheses have been reported for these compounds.[5] Much
less is known about minor Alternaria toxins such as alten-
uene (3),[1b,6–9] isoaltenuene (4),[8,10] neoaltenuene (5),[11] 5Ј-
epialtenuene (6),[11–13] or the recently isolated 4Ј-epialten-
uene (7),[9,13] which have been isolated from infested fruits
in submilligram amounts. Although we have previously
published the total syntheses of altenuene (3) and isoalten-
uene (4),[14] neither report details biological data[15] or their
absolute configurations, nor have the total syntheses of the
compounds 5–7 been published. To provide sufficient
amounts of material for toxicological and biological testing,
we have established a total synthesis of neoaltenuene (5),
which is described herein.
Results and Discussion
A retrosynthetic analysis of neoaltenuene revealed that a
Suzuki coupling of an arene boronate and an iodoalkene
should be promising.[16] The synthesis of boronate A has
been published previously[14] and an approach to halide B
should be possible starting from tartaric acid (9) or, alterna-
tively, quinic acid (10, Scheme 1). The use of tartaric acid
would have the advantage of both enantiomers being avail-
able as starting materials.
Marco-Contelles et al. published a synthesis of cyclohex-
enone 13 starting from tartaric acid (ent-9).[17] The key step
was the radical cyclization of iodo alkyne 12. We planned
to use a similar approach using a cyclization precursor 14
Figure 1. Metabolites in Alternaria fungi.
[a] Institut für Organische Chemie, Universität Karlsruhe (TH),
Karlsruher Institut für Technologie (KIT),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-608-7652
E-mail: joachim.podlech@ioc.uka.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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M. Altemöller, J. Podlech
FULL PAPER
catalyzed rearrangement.[24] As only the minor isomer 19b
formed in the methyllithium addition was prone to isomer-
ization, a poor yield of 40% was achieved and isomer 19a
was cleanly recovered. The reason for the observed differ-
ence in reactivity is not quite clear. Inspection of the struc-
tures of 19a and 19b obtained from molecular modeling
optimizations revealed that the steric hindrance at the allyl
acetate moiety should be essentially the same in both 19a
and 19b.[24e,25] Nevertheless, formation of the S-configured
isomer 20 was confirmed by NOE experiments. Saponifica-
tion of allyl acetate 20 and subsequent oxidation of the in-
termediate allyl alcohol with tetrapropylperruthenate/N-
methylmorpholine N-oxide (TPAP/NMO) led to enone 21
(9% from quinic acid).
Scheme 1. Retrosynthetic analysis of neoaltenuene (PG: protecting
group).
bearing an additional methyl group, which was available
from tartaric acid in six steps in 14% yield (Scheme 2). A
6-endo-dig cyclization yielding a six-membered ring should
be favored according to Baldwin’s rules,[18] whereas the al-
ternative 5-exo-dig cyclization to give a five-membered ring
is hardly possible due to the unfavored formation of two
trans-fused five-membered rings. Depending on the cycliza-
tion conditions we expected to obtain allyl acetate 15 or its
iodinated derivative 16. Unfortunately, none of the various
conditions[19] tested, including atom-transfer conditions,[20]
led to the clean formation of a six-membered ring suitable
for further use.
Scheme 3. Synthesis of enone 21 starting from quinic acid.
Enone 21 was alternatively obtained by a sequence start-
ing from β-hydroxy ketone 17. Addition of methylmagne-
sium bromide led to a single isomer,[23] most likely because
attack from the bottom is prevented by steric hindrance
(Figure 2).[26] Oxidation and elimination furnished cyclo-
hexenone 21 in a superior 27% yield starting from quinic
acid.
Scheme 2. Attempted synthesis of neoaltenuene starting from tar-
taric acid.
Consequently we used an alternative approach starting
from quinic acid (10). Compound 17 bearing a free hydroxy
group and enone 18, both suitably protected as 2,3-butane
diacetals (BDA),[21] were accessible by synthesis according
to a previously published procedure (Scheme 3).[22] 1,2-Ad-
dition of methyllithium[23] to enone 18 followed by acyl-
Figure 2. Proposed rationale for the addition of methylmagnesium
bromide to ketone 17.
We tested the iodination of the commercially available 3-
ation led to allyl acetate 19 suitable for a palladium(II)- methylcyclohex-2-enone with iodine, pyridine, and phenyl-
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Total Synthesis of Neoaltenuene
iodine(III) bis(trifluoroacetate)[27] and achieved a 50% acid yielded neoaltenuene (5). Starting from the dia-
yield. Although application of these conditions to enone 21 stereomeric iodide 24 these reaction conditions provided
was not successful, a satisfactory 75% yield for the prepara- 4a-epi-neoaltenuene (28), a derivative that has not been
tion of iodo enone 23 was obtained with trimethylsilyl azide identified as a natural product to date. The total synthesis
(TMSN3) and iodine followed by the addition of pyridine of neoaltenuene has thus been achieved in 14 steps and in
(Scheme 4).[28]
10% yield starting from quinic acid and phloroglucinic
acid, the longest linear sequence consisting of 10 steps.
Synthetic neoaltenuene (5) shows a specific optical rota-
tion of +66.4 (CHCl3). Nevertheless, because no data were
given in the original communication reporting this com-
pound,[11] a comparison with the natural product is not
possible. The specific optical rotation of 4a-epi-neoalten-
uene (28) was measured to be –311.3 (DMSO). The NMR
spectroscopic data are significantly dependent on the sol-
vents used. Changing the solvent from CDCl3/[D6]DMSO
to CDCl3 caused a shift in the coupling constants from, for
example, 6.2 to 8.8 Hz (3J3H–4H). A detailed comparison of
published and measured NMR spectroscopic data, given in
the Supporting Information, conclusively proves that the
herein synthesized neoaltenuene (5) is identical to the com-
pound previously reported in the literature, which was iso-
lated from a microbiological preparation.[11]
Scheme 4. Identification of the “southeastern” coupling partner.
Reduction of iodo enone 23 with sodium borohydride in
the presence of cerium(III) chloride[29] yielded the neoalten-
uene precursor 24a,b with 9:1 diastereoselectivity. The use
of diisobutylaluminium hydride (DIBAL-H)[30] as reducing
agent on the other hand gave alcohol 24b suitable for the
synthesis of non-natural 4a-epi-altenuene as a single isomer
in an excellent 98% yield. K-Selectride, which has proven
successful in similar transformations,[31] led to significant
over-reduction when applied to iodo enone 23.
The “northwestern” boronate 25 was prepared according
to a published procedure starting from phloroglucinic acid
in four steps.[14] For the Suzuki coupling[32] we used a pro-
tocol that has already proven to be successful in the synthe-
ses of altenuene and isoaltenuene.[14] The coupling of bo-
ronate 25 with iodide 24b in the presence of palladium(II)
acetate, caesium carbonate, and SPhos (2-dicyclohexyl-
phoshanyl-2Ј,6Ј-dimethoxybiphenyl)[32b] yielded biaryl 26 in
which the lactone was concomitantly formed under these
Experimental Section
General: Tetrahydrofuran (THF) was distilled from sodium benzo-
phenone ketyl radical and CH2Cl2 was distilled from CaH2. All
moisture-sensitive reactions were carried out under oxygen-free ar-
gon using oven-dried glassware and a vacuum line. Flash column
chromatography was carried out using Merck silica gel 60 (230–
400 mesh) and thin-layer chromatography was carried out by using
commercially available Merck F254 pre-coated sheets. 1H and 13C
NMR spectra were recorded with Bruker Cryospek WM-250, AM-
400, and DRX 500 spectrometers. Chemical shifts are given in ppm
downfield of tetramethylsilane. 13C NMR spectra were recorded
with broad-band proton-decoupling and were assigned by using
DEPT experiments. Melting points were measured with a Büchi
apparatus and are not corrected. IR spectra were recorded with a
Bruker IFS-88 spectrometer. Elemental analyses were performed
with a Heraeus CHN-O-rapid apparatus. Electrical ionization and
high-resolution mass spectra were recorded with a Finnigan MAT-
90 spectrometer. Optical rotations were recorded with a Perkin–
conditions (Scheme 5). Deprotection with trifluoroacetic Elmer 241 polarimeter [using the sodium D line (589 nm) or Hg
Scheme 5. Suzuki coupling and synthesis of neoaltenuene and epi-neoaltenuene.
Eur. J. Org. Chem. 2009, 2275–2282
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2277

M. Altemöller, J. Podlech
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lines (365 and 436 nm)] and specific optical rotations [α]D are given
in units of 10–1 degcm2 g–1. UV/Vis spectra were recorded with a
Perkin–Elmer Lambda 2 spectrophotometer. The extinction coeffi-
cient ε is given for quantitative measurements.
(400 MHz, CDCl3): δ = 1.44 (s, 3 H, CH3), 1.49 (s, 3 H, CH3), 1.88
(d, 5J = 2.3 Hz, 3 H, 4-CH3), 2.13 (s, 3 H, OAc), 3.36 (dd, 2J =
10.8, 3J = 5.3 Hz, 1 H, 1ЈЈ-HAHB), 3.49 (dd, 2J = 10.8, 3J = 4.3 Hz,
3
3
1 H, 1ЈЈ-HAHB), 3.97 (dd, J = 7.3, J = 3.4 Hz, 1 H, 4Ј-H), 4.03
(ddd, 3J = 7.3, 3J = 5.3, 3J = 4.3 Hz, 1 H, 5Ј-H), 5.60 (dq, 3J =
General Procedure for the Grignard Reactions (GP 1): The Grignard
reagent (2.5 equiv.) was added at –78 °C under argon to a solution
of the carbonyl compound (1 mmol) in anhydrous THF (20 mL).
The mixture was stirred and warmed slowly until TLC indicated
complete consumption of the starting material. A saturated aque-
ous NH4Cl solution (15 mL) was added and the solution was ex-
tracted with EtOAc (3ϫ15 mL), dried (Na2SO4), concentrated,
and purified by chromatography.
5
3.4, J = 2.3 Hz, 1-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 3.7
(q), 6.9 (t), 20.9 (q), 27.0 (q), 27.6 (q), 63.2 (d), 76.1 (d), 73.0 (s),
81.6 (d), 84.4 (s), 110.4 (s), 169.5 (s) ppm. Minor isomer (selected
1
data): H NMR (400 MHz, CDCl3): δ = 1.43 (s, 3 H, CH3), 3.36
2
3
3
5
(dd, J = 10.8, J = 5.3 Hz, 1 H, 1ЈЈ-HAHB), 5.50 (dq, J = 6.6, J
= 2.3 Hz, 1 H, 1-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 3.7
(q), 7.4 (t), 20.9 (q), 27.1 (q), 17.6 (q), 64.9 (d), 73.2 (s), 76.9 (d),
81.3 (d), 84.5 (s), 110.7 (s), 169.5 (s) ppm.
General Procedure for the Suzuki Cross-Coupling Reactions (GP 2):
Degassed solvent (dioxane/H2O, 6:1) was added under argon to a
mixture of aryl bromide (1 equiv.), boronate 25 (1.3 equiv.),
Cs2CO3 (3 equiv.), Pd(OAc)2 (0.03 equiv.), and SPhos (0.06 equiv.).
The solution was heated at 80 °C for 2–6 h (monitoring with TLC).
After cooling to room temp., a saturated aqueous NH4Cl solution
was added and the mixture was extracted with EtOAc. The organic
layers were dried (Na2SO4) and concentrated and the residue was
purified by chromatography (silica gel).
Mixture of Isomers: R = 0.21 (hexanes/EtOAc, 2:1). IR (film): ν =
˜
f
2987 (m), 2935 (m), 2239 (w), 1746 (s, C=O), 1433 (m), 1371 (s),
1325 (w), 1226 (s), 1156 (m), 1069 (m), 1022 (m) cm–1. MS (FAB):
m/z (%) = 353 (15) [M + H]+, 337 (32) [M – CH3]+, 241 (32) [M –
C6H7O2]+, 235 (39), 123 (100), 85 (83). HRMS (FAB): calcd. for
12
C
12
1H18127I16O4 353.0249; found 353.0247. C12H17IO4: C 40.93,
H 4.87; found C 41.27, H 5.14.
(2S,3S,4aR,6S,8aR)- and (2S,3S,4aR,6R,8aR)-2,3-Dimethoxy-2,3,6-
trimethyl-2,3,4a,5,6,8a-hexahydro-1,4-benzodioxin-6-ol: MeLi
(1.6  in Et2O, 10.7 mL, 17.1 mmol) was added at –78 °C under
argon to a solution of ketone 18 (3.19 g, 13.2 mmol) in anhydrous
THF (40 mL) and the solution was stirred for 3 h at this tempera-
ture. The mixture was extracted after addition of a saturated aque-
ous NH4Cl solution (30 mL) with EtOAc (3ϫ30 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated and the
residue was purified by chromatography (silica gel, hexanes/EtOAc,
6:1 to 3:1) to give the title compound (2.04 g, 7.89 mmol, 60%) as
(4ЈS,5ЈR)-1-(5-Iodomethyl-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-yn-
1-ol (29): Aldehyde 11 (2.10 g, 7.78 mmol, 1.0 equiv.) was treated
with propynylmagnesium bromide (0.5  in Et2O, 46.6 mL,
23.3 mmol, 3.0 equiv.) in accord with GP 1. After stirring for 5 h,
warming to room temp., work-up, and concentration, the residue
was purified by chromatography (silica gel, hexanes/EtOAc, 4:1) to
yield the title compound (57:43) as a colorless oil (2.01, 6.48 mmol,
83 %). The isomers could not be separated. Major isomer: 1H
NMR (400 MHz, CDCl3): δ = 1.45 (3 H, CH3), 1.50 (s, 3 H, CH3),
1.88 (d, 5J = 2.2 Hz, 3 H, 4-CH3), 2.27 (d, 3J = 4.5 Hz, 1 H, 1-
1
a mixture of isomers (60:40). Major isomer: H NMR (400 MHz,
2
3
CDCl3): δ = 1.31 (s, 3 H, CH3), 1.33 (s, 3 H, 6-CH3), 1.56 (s, 3 H,
OH), 3.40 (dd, J = 10.8, J = 5.4 Hz, 1 H, 1ЈЈ-HAHB), 3.53 (dd,
3
2
2J = 10.8, 3J = 4.0 Hz, 1 H, 1ЈЈ-HAHB), 3.87 (dd, 3J = 7.5, 3J =
CH3), 1.70 (dd, J = 13.1, J = 12.5 Hz, 1 H, 5-HaxHeq) 1.98 (br.
2
3
4
4.1 Hz, 1 H, 4Ј-H), 4.01 (ddd, 3J = 7.5, J = 5.4, J = 4.0 Hz, 1 H,
5Ј-H), 4.57 (ddq, 3J = 4.5, 3J = 4.1, 5J = 2.2 Hz, 1-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 3.6 (q), 7.8 (t), 27.2 (q), 27.6 (q),
62.0 (d), 75.7 (d), 75.8 (s), 82.9 (d), 83.9 (s), 109.9 (s) ppm. Minor
3
3
s, 1 H, OH), 2.08 (ddd, J = 12.5, J = 3.4, J = 1.2 Hz, 1 H, 5-
HaxHeq), 3.26 (s, 3 H, OCH3), 3.27 (s, 3 H, OCH3), 3.72 (ddd, J
3
3
3
3
3
= 13.1, J = 9.0, J = 3.4 Hz, 1 H, 4a-H), 4.26 (dd, J = 9.0, J =
2.2 Hz, 1 H, 8a-H), 5.47 (dd, 3J = 10.1, 3J = 2.2 Hz, 1 H, 8-H),
5.50 (dd, 3J = 10.1, 4J = 1.2 Hz, 1 H, 7-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.9 (q, 2 C), 29.5 (q), 42.5 (t), 47.9 (q, 2
C), 68.1 (d), 69.7 (d), 72.1 (s), 100.0 (s), 100.4 (s), 126.3 (d), 135.5
1
isomer: H NMR (400 MHz, CDCl3): δ = 1.44 (s, 3 H, CH3), 1.50
(s, 3 H, CH3), 1.88 (d, 5J = 2.2 Hz, 3 H, 4-CH3), 2.34 (d, 3J =
5.6 Hz, 1 H, 1-OH), 3.34 (dd, 2J = 10.7, 3J = 5.4 Hz, 1 H, 1ЈЈ-
HAHB), 3.46 (dd, 2J = 10.7, 3J = 4.7 Hz, 1 H, 1ЈЈ-HAHB), 3.86 (dd,
1
(s) ppm. Minor isomer: H NMR (400 MHz, CDCl3): δ = 1.33 (s,
3J = 7.0, J = 5.8 Hz, 1 H, 4Ј-H), 3.95 (ddd, J = 7.0, J = 5.4, J
3
3
3
3
3 H, CH3), 1.34 (s, 3 H, CH3), 1.38 (s, 3 H, 6-CH3), 1.70 (br. s, 1
H, OH), 1.86 (dd, 2J = 13.2, 3J = 12.8 Hz, 1 H, 5-HaxHeq), 2.00
3
3
5
= 5.4 Hz, 1 H, 5Ј-H), 4.44 (ddq, J = 5.8, J = 5.6, J = 2.2 Hz, 1
H, 1-H) ppm. 13C NMR (100 MHz, CDCl3): d = 3.6 (q), 6.9 (t),
27.4 (q), 27.6 (q), 63.6 (d), 75.8 (s), 76.3 (d), 83.7 (s), 83.9 (s), 110.4
(s) ppm. Mixture of isomers: Rf = 0.22 (hexanes/EtOAc, 2:1). IR
2
3
4
(ddd, J = 13.2, J = 3.6, J = 1.3 Hz, 1 H, 5-HaxHeq), 3.27 (3 H,
OCH3), 3.28 (3 H, OCH3), 3.90 (ddd, 3J = 12.8, 3J = 9.0, 3J =
3.6 Hz, 1 H, 4a-H), 4.12 (dd, 3J = 9.0, 3J = 2.3 Hz, 1 H, 8a-H),
3
3
3
3
5.59 (ddd, J = 9.9, J = 2.3 Hz, 1 H, 7-H), 5.65 (dd, J = 9.9, J
= 1.3 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.9 (q, 2
C), 29.9 (q), 40.6 (t), 47.9 (q), 48.0 (q), 66.4 (d), 69.7 (d), 70.5 (s),
100.0 (s), 100.5 (s), 127.9 (d), 134.2 (d) ppm. Both isomers: Rf =
(film): ν = 3447 (s, OH), 2986 (s), 2934 (m), 2917 (m), 2227 (w),
˜
1.664 (w), 1412 (w), 1373 (s), 1308 (w), 1238 (s), 1151 (m) cm–1.
MS (FAB): m/z (%) = 311 (77) [M + H]+, 295 (56) [M – CH3]+,
241 (100) [M – C4H5O]+, 235 (30), 183 (36) [M – I]+, 137 (50), 108
12
1H16127I16O3 311.0141; found
0.50 (hexanes/EtOAc, 1:1). IR (DRIFT): ν = 3316 (s, OH), 2996
˜
(46). HRMS (FAB): calcd. for
311.0144.
5.07.
C
10
C
1H15127I16O3: C 38.73, H 4.88; found C 38.90, H
10
12
(s), 2946 (s), 2865 (s), 2833 (m), 2585 (w), 2079 (w), 1900 (w), 1734
(w), 1645 (w), 1463 (s), 1373 (s), 1324 (w), 1275 (s), 1119 (s) cm–1.
MS (FAB): m/z (%) = 258 (35) [M + H – CH3OH]+, 101 (100).
(4ЈS,5ЈR)-1-(5-Iodomethyl-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-ynyl
Ethanoate (14): Ac2O (1.23 mL, 12.9 mmol, 2.0 equiv.), pyridine
(1.05 mL, 12.9 mmol, 2.0 equiv.), and DMAP (10 mol-%) were
added to the alkyne as synthesized above (mixture of isomers,
2.01 g, 6.48 mmol, 1.0 equiv.) in anhydrous CH2Cl2 (15 mL) at 0 °C
and the mixture was stirred for 2 h at 0 °C. The mixture was con-
centrated and purified by chromatography (silica gel, hexanes/
EtOAc, 6:1) to yield 14 (1.90 g, 5.90 mmol, 91%) as a yellowish
1
HRMS (FAB): calcd. for 12C12 H1916O4: 227.1283; found 227.1281.
C13H22O5 (258.31): calcd. C 60.45, H 8.58; found C 60.26, H 8.46.
(2S,3S,4aR,6R,8aR)- and (2S,3S,4aR,6S,8aR)-2,3-Dimethoxy-2,3,6-
trimethyl-2,3,4a,5,6,8a-hexahydro-1,4-benzodioxin-6-yl Ethanoate
(19a,b): Ac2O (2.40 mL, 25.4 mmol), pyridine (1.54 mL,
19.1 mmol), and DMAP (155 mg, 1.27 mmol) were added at 0 °C
to a solution of the tertiary alcohol as synthesized above (3.28 g,
12.7 mmol) in anhydrous CH2Cl2 (15 mL) and the mixture was
1
oil. The isomers could not be separated. Major isomer: H NMR
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Total Synthesis of Neoaltenuene
2
3
3
stirred overnight. The solution was concentrated and the residue
was purified by chromatography (silica gel, hexanes/EtOAc, 5:1) to
give 19 as a mixture of isomers (3.07 g, 10.2 mmol, 80%). Major
(ddq, J = 16.8, J = 10.4, J = 1.2 Hz, 1 H, 8-HaxHeq), 2.27 (ddq,
2J = 16.8, 3J = 10.4, 3J = 0.6 Hz, 1 H, 8-HaxHeq), 3.25 (s, 3 H,
OCH3), 3.27 (s, 3 H, OCH3), 3.59 (ddd, 3J = 10.8, 3J = 4.0, J =
1
3
3
3
isomer 19a: H NMR (400 MHz, CDCl3): δ = 1.31 (s, 3 H, CH3),
0.5 Hz, 1 H, 4a-H), 4.17 (dddd, J = 10.8, J = 10.4, J = 6.1, J =
4
1.33 (s, 3 H, CH3), 1.56 (d, J = 1.0 Hz, 3 H, 6-CH3), 1.98 (s, 3 H, 0.5 Hz, 1 H, 8a-H), 4.20–4.21 (m, 1 H, 6-H), 5.54–5.57 (m, 1 H, 5-
6-OAc), 2.19 (ddd, 2J = 12.2, 3J = 3.8 Hz, 1 H, 5-HaxHeq), 2.33 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.8 (q), 17.9 (q), 23.4
3
2
4
(ddd, J = 13.1, J = 12.2, J = 1.0 Hz, 1 H, 5-HaxHeq), 3.26 (s, 3
(q), 35.5 (t), 47.8 (q), 47.9 (q), 62.7 (d), 65.7 (d), 71.2 (d), 99.0 (s),
99.9 (s), 120.9 (d), 137.9 (s) ppm. IR (DRIFT): ν = 3481 (s, OH),
3
3
3
H, OCH3), 3.27 (s, 3 H, OCH3), 3.72 (ddd, J = 13.1, J = 9.0, J
˜
3
= 3.8 Hz, 4a-H), 4.35 (d, J = 9.0 Hz, 1 H, 8a-H), 5.66–5.68 (m, 2 2990 (s), 2948 (s), 2831 (s), 1086 (w), 1667 (s), 1440 (s), 1375 (s),
H, 7-H, 8-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.8 (q, 2
C), 22.2 (q), 27.5 (q), 38.3 (t), 47.9 (q), 48.0 (q), 67.5 (d), 69.3 (d),
81.2 (s), 100.0 (s), 100.3 (s), 127.8 (d), 131.6 (d), 169.9 (s) ppm.
1331 (m), 1296 (w), 1221 (m), 1196 (m), 1122 (s) cm–1. MS (EI,
70 °C): m/z (%) = 258 (1) [M]+, 227 (28) [M – CH3OH]+, 110 (81)
[M – C6H12O4]+, 109 (59), 101 (55), 92 (24), 95 (100), 81 (43), 75
1
12
Minor isomer 19b: H NMR (400 MHz, CDCl3): δ = 1.32 (s, 3 H,
(33), 58 (14), 43 (45). HRMS (EI): calcd. for
C
1H2216O5
13
2
CH3), 1.34 (s, 3 H, CH3), 1.60 (s, 3 H, 6-CH3), 1.63 (d, J = 13.3, 258.1467; found 258.1465.
2
3J = 12.9 Hz, 1 H, 5-HaxHeq), 1.94 (s, 3 H, 6-OAc), 2.26 (ddd, J
3
= 13.3, J = 3.4, 4J = 1.7 Hz, 1 H, 5-HaxHeq), 3.27 (s, 3 H, OCH3),
(2S,3S,4aS,8aR)-2,3-Dimethoxy-2,3,7-trimethyl-2,3,8,8a-tetra-
hydro-4aH-1,4-benzodioxin-5-one (21) by Oxidation: The secondary
alcohol as synthesized above (250 mg, 0.91 mmol), NMO (183 mg,
1.35 mmol), and molecular sieves (4 Å, 4.75 mg) were dissolved in
anhydrous CH2Cl2 (10 mL) and stirred for 10 min. TPAP (16.0 mg,
0.045 mmol) was added and the mixture was filtered through a Ce-
lite pad and concentrated. The residue was purified by chromatog-
raphy (silica gel, CH2Cl2/MeOH, 50:1) to yield enone 21 as a color-
less solid (198 mg, 0.73 mmol, 80%). Rf = 0.46 (CH2Cl2/MeOH,
20:1). M.p. 140–143 °C. [α]2D0 = +106.0 (c = 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.29 (s, 3 H, CH3), 1.39 (s, 3 H, CH3), 1.98
3
3
3
3.28 (s, 3 H, OCH3), 3.96 (ddd, J = 12.9, J = 9.1, J = 3.4 Hz, 1
3
3
3
H, 4a-H), 4.13 (ddd, J = 9.1, J = 2.5, J = 3.4 Hz, 1 H, 8a-H),
5.17 (dd, 3J = 10.1, 4J = 1.7 Hz, 1 H, 7-H), 6.19 (ddd, 3J = 10.1, 3J
= 2.5, 4J = 1.8 Hz, 1 H, 8-H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 17.8 (q, 2 C), 22.1 (q), 25.9 (q), 39.6 (t), 47.8 (q), 47.9 (q), 65.8
(d), 69.5 (d), 80.2 (s), 100.1 (s), 100.5 (s), 129.3 (d), 130.8 (d), 170.0
(s) ppm. Both isomers: Rf = 0.58 (hexanes/EtOAc, 1:1). IR
(DRIFT): ν = 3012 (s), 2991 (s), 2831 (m), 2075 (w), 1870 (w), 1733
˜
(s, C=O), 1449 (s), 1370 (s), 1242 (s), 1207 (s), 1121 (s) cm–1. MS
(FAB): m/z (%) = 301 (1) [M + H]+, 269 (52) [M + H – CH3-
2
3
OH]+, 123 (29), 115 (42), 101 (100), 93 (89) [C7H9]+. HRMS (FAB):
(s, 3 H, 7-CH3), 2.49 (dd, J = 17.6, J = 5.9 Hz, 8-HaxHeq), 2.59
(dddd, J = 17.6, J = 10.2, J = 2.4, J = 1.2 Hz, 8-HaxHeq), 3.23
2
3
4
4
12
calcd. for
C
14
1H2116O5: 269.1389; found 269.1388. C15H24O6: C
3
3
(s, 3 H, OCH3), 3.28 (s, 3 H, OCH3), 4.05 (dddd, J = 11.3, J =
59.98, H 8.05; found C 59.88, H 7.96.
10.1, 3J = 5.9, J = 1.2 Hz, 8a-H), 4.19 (dd, J = 11.4, 4J = 1.0 Hz,
4
3
(2S,3S,4aS,5R,8aR)-2,3-Dimethoxy-2,3,7-trimethyl-2,3,4a,5,8,8a-
hexahydro-1,4-benzodioxin-5-yl Ethanoate (20): [Pd(CH3CN)2Cl2]
(86.0 mg, 0.33 mmol) was added under argon to 19 (mixture of
isomers, see above, 1.00 g, 3.33 mmol, 1.0 equiv.) in anhydrous
THF (16.2 mL) and the mixture was stirred for 5 d at room temp.
The catalyst was removed by filtration through Celite and the fil-
trate was concentrated and purified by chromatography (silica gel)
to yield a diastereomerically pure product 20 (392 mg, 1.31 mmol,
1 H, 4a-H), 5.88 (dd, J = 2.4, J = 1.2 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.6 (q), 17.7 (q), 24.3 (q), 36.3 (t), 48.0
(q), 48.4 (q), 65.8 (d), 74.1 (d), 99.2 (s), 100.2 (s), 126.2 (d), 157.9
4
4
(s), 193.9 (s) ppm. IR (DRIFT): ν = 3349 (m), 2991 (s), 2956 (s),
˜
2852 (s), 2832 (s), 2080 (w), 2038 (w), 1896 (m), 1686 (s, C=O),
1625 (s), 1440 (s), 1376 (s), 1272 (s), 1120 (s) cm–1. MS (FAB):
m/z = 279 [M + Na + H]+, 225 (100). HRMS (FAB): calcd. for
12
C
1H2016O5Na 279.1208; found 279.1206. C13H20O5 (256.30):
13
40%) as a colorless oil. Rf = 0.74 (hexanes/EtOAc, 2:1). [α]2D0
=
calcd. C 60.92, H 7.87; found C 60.78, H 7.77.
–36.8 (c = 0.5, CHCl3) ppm. 1H NMR (400 MHz, CDCl3): δ = 1.27
(s, 3 H, CH3), 1.29 (s, 3 H, CH3), 1.74 (s, 3 H, CH3, 7-CH3), 2.08
(s, 3 H, CH3, OAc), 2.15 (dd, 2J = 17.4, 3J = 10.4 Hz, 1 H, 8-
(2S,3S,4aR,5R,7S,8aR)-2,3-Dimethoxy-2,3,7-trimethyloctahydro-
1,4-benzodioxine-5,7-diol: Ketone 17 (3.00 g, 11.5 mmol, 1.0 equiv.)
was treated with MeMgBr (3  in Et2O, 15.4 mL, 46.3 mmol) in
accord with GP 1 and the reaction was quenched after 4 h at 0 °C.
Purification by chromatography (silica gel) yielded the title com-
pound as a single isomer (1.60 g, 5.79 mmol, 50%). Rf = 0.20 (hex-
anes/EtOAc, 1:1). M.p. 113–115 °C. [α]2D0 = +155.0 (c = 0.5,
2
3
HaxHeq), 2.32 (dd, J = 17.4, J = 6.3 Hz, 1 H, 8-HaxHeq), 3.25 (s,
3 H, OCH3), 3.27 (s, 3 H, OCH3), 3.69 (dd, 3J = 10.6, 3J = 4.4 Hz,
1 H, 4a-H), 4.13 (ddd, 3J = 10.6, 3J = 10.4, 3J = 6.3 Hz, 8a-H),
3
3
3
5.37 (dd, J = 5.4, J = 4.4 Hz, 1 H, 5-H), 5.51 (dm, J = 5.4 Hz,
1 H, 6-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.7 (q), 17.9
(q), 21.3 (q), 23.3 (q), 35.6 (t), 47.8 (q), 47.9 (q), 63.2 (d), 67.7 (d),
69.2 (d), 99.0 (s), 99.5 (s), 118.4 (d), 139.8 (s), 170.9 (s) ppm. IR
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 1.24 (d, J = 0.5 Hz, 3
2
H, 7-CH3), 1.30 (s, 3 H, CH3), 1.33 (s, 3 H, CH3), 1.50 (dd, J =
(DRIFT): ν = 3448 (w), 2992 (m), 2949 (s), 2832 (m), 1733 (s,
˜
3
2
3
12.8, J = 12.6 Hz, 1 H, 8-HaxHeq), 1.56 (ddd, J = 14.9, J = 3.0,
C=O), 1663 (w), 1444 (s), 1376 (s), 1241 (s), 1218 (s), 1120 (s) cm–1.
3J = 1.8 Hz, 1 H, 6-HaxHeq), 1.98 (ddd, J = 12.8, J = 4.5, J =
2
3
4
MS (EI, 40 °C): m/z (%) = 300 (5) [M]+, 109 (18), 101 (37), 94 (20),
3.1 Hz, 1 H, 8-HaxHeq), 2.07 (ddd, 2J = 14.9, 3J = 3.2, J = 3.1 Hz,
4
93 (74), 92 (62), 91 (27), 75 (100), 43 (32). HRMS (EI): calcd. for
3
2
1 H, 6-HaxHeq), 2.87 (dd, J = 1.8, J = 1.5 Hz, 1 H, 5-OH), 3.25
12
C
15
1H2416O6: 300.1573; found 300.1579.
(s, 3 H, OCH3), 3.26 (s, 3 H, OCH3), 3.52 (dd, 3J = 10.1, 3J =
3
(2S,3S,4aS,5R,8aR)-2,3-Dimethoxy-2,3,7-trimethyl-2,3,4a,5,8,8a-
hexahydro-1,4-benzodioxin-5-ol: A solution of acetate 20 (300 mg,
2.9 Hz, 1 H, 4a-H), 4.08 (br. s, 1 H, 7-OH), 4.15 (dddd, J = 3.2,
3J = 2.9, J = 1.5, J = 0.5 Hz, 1 H, 5-H), 4.26 (dddd, J = 12.6, J
2
3
3
1.00 mmol) in 10% KOH (EtOH/H2O, 1:1, 5 mL) was stirred for = 10.1, 3J = 4.6, J = 0.4 Hz, 1 H, 8a-H) ppm. 13C NMR (100 MHz,
2 h and neutralized with 1  HCl. The mixture was extracted with
EtOAc (3ϫ10 mL) and the organic layers were dried (Na2SO4),
concentrated, and purified by chromatography (silica gel, hexanes/
CDCl3): δ = 17.7 (q), 17.9 (q), 30.1 (q), 40.9 (t), 42.4 (t), 47.9 (q),
48.0 (q), 63.1 (d), 70.0 (d), 71.7 (s), 73.2 (d), 99.6 (s), 100.3 (s) ppm.
IR (DRIFT): ν = 3430 (s, OH), 3258 (s, OH), 2950 (s), 2828 (s),
˜
EtOAc, 6:1) to yield the title compound (230 mg, 0.89 mmol, 89%) 1717 (w), 1449 (s), 1405 (m), 1378 (m), 1296 (w), 1201 (s) cm–1. MS
as a colorless solid. Rf = 0.31 (hexanes/EtOAc, 1:1). M.p. 82–82 °C.
(FAB): m/z = 299 [M + Na]+, 245 (100), 101 (85). HRMS (FAB):
1
12
[α]2D0 = +60.2 (c = 0.5, CHCl3). H NMR (400 MHz, CDCl3): δ =
calcd. for
C
13
1H2416O6Na 299.1470; found 299.1467. C13H24O6
1.30 (s, 3 H, CH3), 1.35 (s, 3 H, CH3), 1.74 (m, 3 H, CH3), 2.14 (276.33): calcd. C 56.51, H 8.75; found C 56.50, H 8.54.
Eur. J. Org. Chem. 2009, 2275–2282
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2279

M. Altemöller, J. Podlech
FULL PAPER
(2S,3S,4aS,7R,8aR)-7-Hydroxy-2,3-dimethoxy-2,3,7-trimethylhexa-
(24a,b): CeCl3·7H2O (780 mg, 2.09 mmol) and NaBH4 (87.1 mg,
hydro-4aH-1,4-benzodioxin-5-one (22): A mixture of the tertiary 2.30 mmol) were added at –40 °C to a solution of iodo enone 23
alcohol as synthesized above (500 mg, 1.81 mmol), NMO (366 mg,
2.71 mmol), and molecular sieves (4 Å, 905 mg) in anhydrous
(800 mg, 2.09 mmol) in MeOH (25 mL) and the mixture was stirred
for 1 h at this temperature. H2O (20 mL) was added and the mix-
CH2Cl2 (15 mL) was stirred for 10 min and TPAP (31.8 mg, ture was extracted with EtOAc (3 ϫ 20 mL). The organic layers
0.09 mmol) was added. The mixture was filtered after 12 h through
Celite and the filtrate was concentrated and purified by chromatog-
raphy (silica gel, CH2Cl2/MeOH, 50:1) to yield ketone 22 (397 mg,
1.45 mmol, 80%) as a colorless solid. Rf = 0.51 (CH2Cl2/MeOH,
10:1). M.p. 131–133 °C. [α]2D0 = +271.3 (c = 0.15, CHCl3). 1H NMR
were dried (Na2SO4), concentrated, and purified by chromatog-
raphy (silica gel, hexanes/EtOAc, 2:1) to yield a mixture of isomers
(90:10, 642 mg, 1.67 mmol, 80 %) as a solid. Recrystallization
(Et2O/hexanes) yielded the major isomer 24a (526 mg, 1.37 mmol,
65%). Major isomer 24a: Rf = 0.61 (hexanes/EtOAc, 1:1). M.p.
1
(400 MHz, CDCl3): δ = 1.31 (s, 3 H, OCH3), 1.40 (s, 3 H, OCH3), 155–158 °C. [α]2D0 = +97.2 (c = 0.5, CHCl3). H NMR (400 MHz,
2
1.42 (s, 3 H, 7-CH3), 1.70 (br. s, 1 H, 7-OH), 1.96 (dd, J = 13.3,
CDCl3): δ = 1.31 (s, 3 H, CH3), 1.35 (s, 3 H, CH3), 1.95 (s, 3 H,
2
3
4
3
3J = 11.7 Hz, 1 H, 8-HaxHeq) 2.12 (ddd, J = 13.3, J = 4.6, J =
CH3), 2.35–2.40 (m, 2 H, 8-H), 2.64 (d, J = 3.9 Hz, 1 H, 5-OH),
2
4
3
3
2.9 Hz, 1 H, 8-HaxHeq), 2.45 (dd, J = 14.3, J = 2.9 Hz, 1 H, 6-
HaxHeq), 2.58 (dd, J = 14.3, J = 1.4 Hz, 1 H, 6-HaxHeq), 3.24 (s, = 7.8 Hz, 1 H, 4a-H), 3.84 (ddd, J = 10.8, J = 8.1, J = 8.1 Hz,
3.27 (s, 3 H, OCH3), 3.31 (s, 3 H, OCH3), 3.72 (dd, J = 10.8, J
2
4
3
3
3
3
3
3
3
5
5
3 H, OCH3), 3.36 (s, 3 H, OCH3), 4.24 (ddd, J = 11.7, J = 10.2, 1 H, 8a-H), 4.26 (dddd, J = 7.8, J = 3.9, J = 3.8, J = 1.9 Hz, 1
3J = 4.6 Hz, 1 H, 8a-H), 4.36 (dd, 3J = 10.2, 4J = 1.4 Hz, 4a-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.6 (q), 17.8 (q), 31.0
(q), 41.4 (t), 48.0 (q), 48.3 (q), 53.2 (t), 67.3 (d), 71.8 (s), 77.2 (d),
H, 5-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.7 (q, 2 C), 29.1
(q), 36.6 (t), 48.0 (q), 48.1 (q), 64.7 (d), 73.3 (d), 75.0 (d), 99.2 (s),
99.3 (s), 102.2 (s), 138.6 (s) ppm. IR (DRIFT): ν = 3539 (s, OH),
˜
99.5 (s), 100.5 (s), 201.9 (s) ppm. IR (DRIFT): ν = 3489 (s, OH), 2953 (s), 2908 (s), 2889 (s), 2835 (s), 2075 (w), 1894 (w), 1634 (m),
˜
2951 (s), 2246 (s), 1735 (s, C=O), 1452 (s), 1379 (s), 1310 (m), 1273
1436 (s), 1374 (s), 1337 (m), 1310 (m), 1208 (s) cm–1. MS (FAB):
(m), 1209 (m), 1136 (s) cm–1. MS (FAB): m/z = 297 [M + Na + H] m/z (%) = 383 (1) [M – H]+, 353 (75) [M – CH3OH]+, 154 (35),
12
12
+, 243 (100). HRMS (FAB): calcd. for
found 297.131.
C
1H2216O6Na 297.131;
136 (28), 101 (100). HRMS (FAB): calcd. for
C
1H20127I16O5
13
13
383.0355; found 383.0351. C13H21IO5 (384.21): calcd. C 40.64, H
5.51; found C 40.65, H 5.51.
(2S,3S,4aS,8aR)-2,3-Dimethoxy-2,3,7-trimethyl-2,3,8,8a-tetra-
hydro-4aH-1,4-benzodioxin-5-one (21) by Elimination of Alcohol 22:
Ac2O (100 µL, 1.06 mmol), iPr2EtN (282 µL, 1.71 mmol), and
DMAP (5.0 mg, 0.041 mmol) were added at 0 °C to a solution of
alcohol 22 (223 mg, 0.813 mmol) in anhydrous CH2Cl2 (10 mL)
and the mixture was stirred overnight. Aqueous saturated NaHCO3
solution (10 mL) was added and the mixture was extracted with
CH2Cl2 (3ϫ). The combined organic layers were dried (Na2SO4),
concentrated, and purified by chromatography (silica gel, CH2Cl2/
MeOH, 50:1) to yield enone 21 (187 mg, 0.73 mmol, 90%) as a
colorless solid. For spectroscopic data see above.
(2S,3S,4aR,5S,8aR)-6-Iodo-2,3-dimethoxy-2,3,7-trimethyl-
2,3,4a,5,8,8a-hexahydro-1,4-benzodioxin-5-ol (24b): DIBAL-H (1 
in toluene, 1.69 mL, 1.69 mmol) was added slowly at –78 °C to a
solution of iodo enone 23 (322 mg, 0.84 mmol) in anhydrous THF
(10 mL). The reaction was quenched after 1.5 h by the addition of
a saturated aqueous NH4Cl solution (10 mL) at –78 °C. The mix-
ture was extracted with EtOAc (3ϫ15 mL) and the organic layers
were dried (Na2SO4), concentrated, and purified by chromatog-
raphy (silica gel, hexanes/EtOAc, 2:1) to yield diastereoisomer 24b
(320 mg, 0.83 mmol, 98%) as a colorless solid. Rf = 0.61 (hexanes/
EtOAc, 1:1). M.p. 152–154 °C. [α]2D0 = +34.4 (c = 0.5, CHCl3). H
1
(2S,3S,4aS,8aR)-6-Iodo-2,3-dimethoxy-2,3,7-trimethyl-2,3,8,8a-
tetrahydro-4aH-1,4-benzodioxin-5-one (23): TMSN3 (325 µL,
2.47 mmol) was added at 0 °C to a solution of enone 21 (253 mg,
0.99 mmol) in CH2Cl2 (5 mL). After 2 h at 0 °C I2 (625 mg,
2.47 mmol) in pyridine/CH2Cl2 (1:1, 10 mL) was added. The mix-
ture was allowed to warm to room temp. overnight and diluted
with Et2O (20 mL), washed with H2O (20 mL), 1  HCl (20 mL),
saturated aqueous NaHCO3 solution (20 mL), and an aqueous
NaS2O3 solution (20 mL). The organic layers were dried (Na2SO4),
concentrated, and purified by chromatography (silica gel, hexanes/
EtOAc, 6:1) to yield iodide 23 (282 mg, 0.740 mmol, 75%) as a
yellowish solid. Rf = 0.53 (hexanes/EtOAc, 1:1). M.p. 131–132 °C.
[α]2D0 = +2.0 (c = 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
1.32 (s, 3 H, CH3), 1.41 (s, 3 H, CH3), 2.29 (dd, 4J = 1.2, 4J =
NMR (500 MHz, CDCl3): δ = 1.30 (s, 3 H, CH3), 1.33 (s, 3 H,
2
3
CH3), 1.92 (s, 3 H, CH3), 2.28 (dd, J = 17.0, J = 10.4 Hz, 1 H,
2
3
8-HaxHeq), 2.50 (ddd, J = 17.0, J = 6.0 Hz, 1 H, 8-HaxHeq), 2.73
(br. s, 1 H, 5-OH), 3.25 (s, 3 H, OCH3), 3.27 (s, 3 H, OCH3), 3.74
3
3
3
3
(dd, J = 11.0, J = 4.0 Hz, 1 H, 4a-H), 4.17 (ddd, J = 11.0, J =
10.2, 3J = 6.0 Hz, 8a-H), 4.45 (d, 3J = 4.0 Hz, 5-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.7 (q), 17.8 (q), 28.9 (q), 31.0 (t), 48.0
(q), 48.1 (q), 62.0 (d), 70.8 (d), 76.3 (d), 95.0 (s), 99.1 (s), 100.1 (s),
141.2 (s) ppm. IR (DRIFT): ν = 3513 (s, OH), 2995 (s), 2937 (s),
˜
2867 (s), 2830 (s), 2086 (w), 1899 (w), 1634 (m), 1448 (m), 1375 (s),
1332 (s), 1290 (w), 1218 (m), 1197 (m), 1133 (s) cm–1. MS (FAB):
m/z (%) = 407 (8) [M + Na]+, 353 (47) [M – CH3OH]+, 235 (32)
[M – C6H12O4]+, 136 (57), 101 (100). HRMS (FAB): calcd. for
12
1H21127I16O5Na 407.0331; found 407.0329. C13H21IO5
2
3
4
C
0.5 Hz, 3 H, 7-CH3), 2.72 (ddd, J = 17.7, J = 10.3, J = 1.2 Hz,
13
2
3
4
(384.21): calcd. C 40.64, H 5.51; found C 40.70, H 5.51.
1 H, 8-HaxHeq), 2.80 (ddd, J = 17.7, J = 5.8, J = 0.5 Hz, 1 H,
8-HaxHeq), 3.24 (s, 3 H, OCH3), 3.30 (s, 3 H, OCH3), 4.05 (ddd, 3J
(2S,3S,4aS,4bS,12aR)-7-Hydroxy-2,3,9-trimethoxy-2,3,11-tri-
methyl-2,3,4a,4b,12,12a-hexahydro-6H-benzo[c][1,4]dioxino[2,3-h]-
chromen-6-one (26): Iodide 24a (209 mg, 0.55 mmol) was treated
with boronate 25 (273 mg, 0.816 mmol) in accord with GP 2. Work-
up after 2.5 h and purification by MPLC (silica gel, hexanes/
EtOAc, 8:1) yielded protected epi-neoaltenuene 26 (190 mg,
0.47 mmol, 87%) as a colorless solid. Rf = 0.56 (hexanes/EtOAc,
1:1). M.p. 153–155 °C. [α]2D0 = –49.0 (c = 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.32 (s, 3 H, CH3), 1.34 (s, 3 H, CH3), 2.02
3
3
3
= 11.5, J = 10.3, J = 5.8 Hz, 1 H, 8a-H), 4.29 (d, J = 11.5 Hz,
1 H, 4a-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.6. (q), 17.7
(q), 31.3 (q), 38.2 (t), 48.1 (q), 48.5 (q), 66.2 (d), 72.9 (d), 99.3 (s),
100.4 (s), 104.8 (s), 160.9 (s), 187.7 (s) ppm. IR (DRIFT): ν = 2993
˜
(m), 2949 (s), 2834 (m), 2247 (w), 2107 (w), 1701 (s, C=O), 1589
(s), 1457 (m), 1429 (m), 1376 (s), 1116 (s) cm–1. MS (FAB): m/z =
381 [M + H]+, 351 [M – CH3OH]+ (100). HRMS (FAB): calcd. for
12
C
12
1H16127I16O5 351.0093; found 351.0089. C13H19IO5 (382.19):
5
2
3
calcd. C 40.85, H 5.01; found C 40.66, H 5.28.
(d, J = 1.4 Hz, 3 H, 11-CH3), 2.43 (dd, J = 17.9, J = 9.8 Hz, 1
2
3
(2S,3S,4aR,5R,8aR)- and (2S,3S,4aR,5S,8aR)-6-Iodo-2,3-dimeth-
oxy-2,3,7-trimethyl-2,3,4a,5,8,8a-hexahydro-1,4-benzodioxin-5-ol 3.27 (s, 3 H, OCH3), 3.37 (s, 3 H, OCH3), 3.83 (ddd, J = 11.0, J
H, 12-HaxHeq), 2.48 (dd, J = 17.9, J = 6.5 Hz, 1 H, 12-HaxHeq),
3
3
2280
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2275–2282

Total Synthesis of Neoaltenuene
3
3
3
= 9.8, J = 6.5 Hz, 1 H, 12a-H), 4.04 (dd, J = 11.0, J = 7.4 Hz,
343 (36), 275 (38), 257 (70), 240 (80) [M – C8H6O4]+, 115 (100),
3
5
5
12
1 H, 4a-H), 5.01 (ddq, J = 7.4, J = 2.5, J = 1.4 Hz, 1 H, 4b-H),
101 (61). HRMS (FAB): calcd. for
C
21
1H2716O8 407.1706; found
6.39 (d, 4J = 2.4 Hz, 1 H, Ar-H), 6.41 (d, 4J = 2.4 Hz, 1 H, Ar-H), 407.1701. 7,7Ј-Dimethoxy-2,2,2Ј,2Ј-tetramethyl-5,5Ј-bi[1,3-benzo-
11.31 (s, 1 H, 7-OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.7
(q), 17.7 (q), 21.4 (q), 37.1 (t), 48.1 (q), 48.3 (q), 55.6 (q), 63.9 (d),
72.1 (d), 76.7 (s), 80.3 (d), 99.2 (s), 99.3 (d), 99.8 (s), 107.4 (d),
dioxinyl]-4,4Ј-dione (Side Product): Rf = 0.37 (hexanes/EtOAc, 2:1).
Mp. 158–160 °C. 1H NMR (400 MHz, CDCl3): δ = 1.73 (s, 6 H,
4
CH3), 1.76 (s, 6 H, CH3), 3.85 (s, 6 H, OMe), 6.46 (d, J = 2.5 Hz,
120.8 (s), 137.0 (s), 138.4 (s), 164.2 (s), 165.0 (s), 169.1 (s) ppm. IR 2 H, Ar-H), 6.48 (d, 4J = 2.5 Hz, Ar-H) ppm. 13C NMR (100 MHz,
(DRIFT): ν = 2949 (s), 2834 (m), 1674 (s, C=O), 1616 (s), 1576 (s), CDCl3): δ = 24.0 (q, 2 C), 27.1 (q, 2 C), 55.7 (q, 2 C), 100.7 (d, 2
˜
1521 (m), 1431 (m), 1365 (s), 1309 (s), 1258 (s), 1230 (s), 1202 (s),
C), 112.3 (d, 2 C), 105.7 (s, 4 C), 145.2 (s, 2 C), 158.3 (s, 2 C), 159.9
(s, 2 C), 164.9 (s, 2 C) ppm. IR (DRIFT): ν = 3279 (w), 3086 (m),
˜
1163 (s), 1136 (s) cm–1. MS (FAB): m/z (%) = 407 (15) [M + H]+,
375 (30) [M + H – CH3O]+, 275 (42), 257 (100), 240 (85), 229 3001 (m), 2943 (m), 2847 (m), 1744 (s, C=O), 1718 (s, C=O), 1609
12
(57), 133 (95), 101 (57). HRMS (FAB): calcd. for
407.1706; found 407.1701.
C
21
1H2716O8 (s), 1582 (s), 1431 (m), 1377 (s), 1327 (s), 1283 (s), 1215 (s), 1175
(s) cm–1. MS (FAB): m/z = 415 (60) [M + H]+, 91 (100) [C7H7]+.
12
HRMS (FAB): calcd. for
C
22
1H2316O8 415.1392; found 415.1388.
(3R,4S,4aR)-3,4,7-Trihydroxy-9-methoxy-1-methyl-2,3,4,4a-tetra-
hydro-6H-benzo[c]chromen-6-one, epi-Neoaltenuene (28): Acetal 26
(88 mg, 0.22 mmol) was dissolved in TFA/H2O (6:1) and stirred for
15 min at room temp. The mixture was concentrated and purified
by chromatography (silica gel, CH2Cl2/MeOH, 30:1) to yield epi-
neoaltenuene (28; 54 mg, 0.18 mmol, 85%) as a colorless solid. Rf
= 0.23 (CH2Cl2/MeOH, 20:1). M.p. 202–205 °C. [α]2D0 = –311.3 (c
C22H22O8 (414.41): calcd. C 63.76, H 5.35; found C 63.32, H 5.24.
(3R,4S,4aS)-3,4,7-Trihydroxy-9-methoxy-1-methyl-2,3,4,4a-tetra-
hydro-6H-benzo[c]chromen-6-one, Neoaltenuene (5): Acetal 27
(33 mg, 0.08 mmol) was dissolved in TFA/H2O (6:1) and stirred for
15 min at room temp. The mixture was concentrated and purified
by chromatography (silica gel, CH2Cl2/MeOH, 30:1) yielding neo-
altenuene 5 (20 mg, 0.07 mmol, 85%) as a colorless solid. Rf = 0.31
(CH2Cl2/MeOH, 30:1). M.p. 171–174 °C. [α]2D0 = +66.4 (c = 0.5,
1
= 0.275, DMSO). H NMR (400 MHz, CDCl3): δ = 1.98 (s, 3 H,
CH3), 2.25 (ddm, 2J = 18.1, 3J = 10.0 Hz, 1 H, 2-HaxHeq), 2.51
2
3
3
1
(dd, J = 18.1, J = 4.9 Hz, 1 H, 2-HaxHeq), 3.51 (dddd, J = 10.5,
CHCl3). H NMR (400 MHz, CDCl3): δ = 1.68 (br. s, 1 H, OH),
3J = 10.0, J = 4.9, J = 4.9 Hz, 1 H, 3-H), 3.62 (ddd, J = 10.5,
3
3
3
2.04 (s, 3 H, CH3), 2.39 (dd, 2J = 17.9, 3J = 7.5 Hz, 1 H, 2-HaxHeq),
3J = 6.9, 3J = 4.9 Hz, 1 H, 4-H), 3.84 (s, 3 H, OMe), 4.82–4.86
2
3
2.64 (dd, J = 17.9, J = 4.9 Hz, 2-HaxHeq), 2.78 (br. s, 1 H, OH),
3.86 (s, 3 H, OMe), 3.94 (dd, 3J = 8.8, 3J = 4.7 Hz, 1 H, 4-H), 4.05
(ddd, 3J = 8.8, 3J = 7.5, 3J = 4.9 Hz, 1 H, 3-H), 5.00 (dm, 3J =
4.7 Hz, 4a-H), 6.41 (d, 4J = 2.4 Hz, 1 H, 8-H), 6.43 (d, 4J = 2.4 Hz,
1 H, 10-H), 11.06 (br. s, 1 H, 7-OH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.2 (q, 1-CH3), 39.1 (t, C-2), 55.7 (q, 9), 67.5 (d, C-
3), 71.0 (d, C-4), 77.2 (d, C-4a), 99.6 (d, C-8), 101.7 (s, C-6a), 107.2
(d, C-10), 120.6 (s, C-10b), 137.2 (s, C-1), 140.1 (s, C-10a), 164.5
(s, C-7), 165.3 (s, C-9), 169.3 (s, C-6) ppm. UV/Vis (MeOH): λ (ε)
= 196 (12993), 241 (18940), 282 (4501), 318 (2357) nm. IR
3
(dm, J = 6.9 Hz, 1 H, 4a-H), 5.06–5.08 (br. m, 1 H, 4-OH), 6.48–
6.50 (m, 2 H, 10-H, 8-H), 11.28 (br. s, 1 H, 7-OH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 20.7 (q, CH3-1), 40.7 (t, C-2), 55.7 (q, 9-
OMe), 66.9 (d, C-3), 74.8 (d, C-4), 83.9 (d, C-4a), 99.9 (d, C-8),
100.9 (s, C-7), 106.5 (d, C-10), 119.9 (s, C-10b), 138.2 (s, C-1), 138.8
(s, C-10a), 163.1 (s, C-6a), 164.7 (s, C-9), 169.0 (s, 6) ppm. UV/
Vis (MeOH): λ (ε) = 195 (18311), 241 (38600), 281 (5540), 319
(2890 dm3 mol–1 cm–1) nm. IR (DRIFT): ν = 3320 (m, OH), 2979
˜
(w), 2916 (m), 2883 (w), 1668 (s, C=O), 1620 (s), 1578 (s), 1493
(m), 1460 (m), 1438 (s), 1365 (s), 1302 (m), 1257 (s), 1222 (s), 1206
(DRIFT): ν = 3404 (s. OH), 3011 (w), 2969 (w), 2923 (m), 2261
˜
(s), 1164 (s) cm–1. MS (FAB): m/z (%) = 293 (60) [M + H]+, 257
(w), 2128 (w), 1673 (s, C=O), 1654 (s), 1622 (s), 1579 (s), 1433 (s),
1337 (m), 1301 (s), 1256 (s), 1224 (s), 1206 (s), 1163 (m), 1133
12
(25), 154 (100), 136 (63). HRMS (FAB): calcd. for
293.1025; found 293.1028.
C
15
1H1716O6
(m) cm–1. MS (FAB): m/z (%) = 292 (37) [M + H]+, 136 (63).
12
HRMS (FAB): calcd. for
C
15
1H1716O6 293.1025; found 293.1023.
(2S,3S,4aS,4bR,12aR)-7-Hydroxy-2,3,9-trimethoxy-2,3,11-tri-
methyl-2,3,4a,4b,12,12a-hexahydro-6H-benzo[c][1,4]dioxino[2,3-h]-
chromen-6-one (27): Iodide 24b (232 mg, 0.60 mmol) was treated
with boronate 25 (262 mg, 0.79 mmol) in accord with GP 2. Work-
up after 2.5 h and purification by chromatography (silica gel, hex-
anes/EtOAc, 10:1 to 3:1) and recrystallization (Et2O/hexanes) gave
a biaryl side-product as colorless needles. Concentration of the
mother liquor yielded protected neoaltenuene 27 (mg, 0.37 mmol,
61%) as a colorless solid. Rf = 0.32 (hexanes/EtOAc, 2:1). M.p.
116–119 °C. [α]2D0 = +68 (c = 0.5, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.30 (s, 3 H, CH3), 1.36 (s, 3 H, CH3), 1.97 (s, 3 H,
11-CH3), 2.36 (dd, 2J = 17.2, 3J = 5.6 Hz, 1 H, 12-HaxHeq), 2.47
Supporting Information (see also the footnote on the first page of
this article): Comparison of NMR spectroscopic data for the origi-
nally proposed and synthesized neoaltenuene (5) and epi-neoalten-
uene (28). Experimental details, spectroscopic data, and spectra for
all synthesized compounds.
Acknowledgments
This work was supported by the Jürgen-Manchot-Stiftung (stipend
to M. A.).
2
3
5
(ddd, J = 17.2, J = 10.4, J = 1.2 Hz, 1 H, 12-HaxHeq), 3.25 (s, 3
3
H, OCH3), 3.30 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 3.87 (dd, J
= 10.8, J = 4.8 Hz, 1 H, 4a-H), 4.12 (ddd, 3J = 10.8, J = 10.4, J
3
3
3
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5
5
= 5.6 Hz, 1 H, 12a-H), 4.82 (ddq, J = 4.8, J = 1.2, J = 1.0 Hz,
1 H, 12a-H), 6.35 (d, 4J = 2.4 Hz, 1 H, Ar-H), 6.38 (s, 4J = 2.4 Hz,
1 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.6 (q), 17.9
(q), 20.8 (q), 37.8 (t), 47.9 (q), 48.1 (q), 53.5 (q), 63.1 (d), 68.5 (d),
76.0 (d), 99.3 (s), 99.5 (d), 100.7 (s), 102.4 (s), 106.4 (d), 122.1 (s),
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˜
(s, C=O), 1620 (s), 1577 (s), 1435 (m), 1369 (s), 1335 (m), 1294 (m),
1254 (s), 1224 (s), 1203 (s), 1133 (s) cm–1. MS (FAB): m/z (%) =
429 (20) [M + Na]+, 407 (20) [M + H]+, 375 (97) [M – CH3OH]+,
Eur. J. Org. Chem. 2009, 2275–2282
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2281

M. Altemöller, J. Podlech
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Received: February 5, 2009
Published Online: March 24, 2009
2282
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Eur. J. Org. Chem. 2009, 2275–2282