Total synthesis of yahazunol, zonarone and isozonarone

Article abstract of DOI:10.1016/S0040-4020(02)00346-0

The synthesis of the marine natural products zonarone and isozonarone was achieved via (+)-albicanic acid, a sesquiterpene of the drimane type. Coupling of the appropiate drimane-synthon with lithiated hydroquinone ethers led to sesquiterpene arenes, which were further modified to the target molecules. Stereoselective epoxidation followed by regioselective opening of the oxirane ring yielded yahazunol.

Full text of DOI:10.1016/S0040-4020(02)00346-0

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 4299±4309
Total synthesis of yahazunol, zonarone and isozonarone
p
È È
Thorsten Laube, Jorg Schroder, Ralf Stehle and Karlheinz Seifert
È È
Lehrstuhl fur Organische Chemie I/2, NW II, Universitat Bayreuth, D-95440 Bayreuth, Germany
Received 14 January 2002;revised 15 March 2002;accepted 26 March 2002
AbstractÐThe synthesis of the marine natural products zonarone and isozonarone was achieved via (1)-albicanic acid, a sesquiterpene of
the drimane type. Coupling of the appropiate drimane-synthon with lithiated hydroquinone ethers led to sesquiterpene arenes, which were
further modi®ed to the target molecules. Stereoselective epoxidation followed by regioselective opening of the oxirane ring yielded
yahazunol. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Yahazunol (1),9 zonarone (2) and zonarol (3) have been
obtained from the East Paci®c brown algae Dictyopteris
undulata Okamura.10 Isozonarone (4) and isozonarol (5)
have been isolated from the same species collected in the
Gulf of California.10 The key step of the synthesis
(Scheme 2) was the coupling of the sesquiterpene part
with the lithiated arene unit. The necessary aldehydes
(1)-albicanal ((1)-6) and (2)-drim-7-en-11-al ((2)-7)
were obtained from (1)-albicanic acid ((1)-8). This chiral
synthon was prepared starting from b-ionone via a known
route.11±13 Several steps of this procedure could be
improved.
The ®ve marine natural products yahazunol (1), zonarone
(2), zonarol (3), isozonarone (4) and isozonarol (5) have
been synthesised starting from (1)-albicanic acid ((1)-8)
(Scheme 1). Due to their broad spectrum of biological
activities1±7 sesquiterpene arenes and sesquiterpene
quinones8 draw attention as synthethic targets to realize a
thoroughly examination of their pharmacological proper-
ties. In this way the aim of this synthesis is a convenient
synthetic pathway to sesquiterpene arenes possessing a
drimane skeleton.
Scheme 1. Retrosynthesis of the marine natural compounds 1±5.
Keywords: terpenes;phenols;quinones;epoxidation.
Corresponding author. Tel.: 149-0921-553396;fax: 149-0921-555358;e-mail: karlheinz.seifert@uni-bayreuth.de
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00346-0

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T. Laube et al. / Tetrahedron 58 -2002) 4299±4309
Scheme 2. (a) With (1)-6: RˆMe: Et2O, 08C (9a, b);R ˆTHP: THF, 08C, (10a, b);with ( 2)-7: RˆTHP: THF, 208C (11a, b);(b) 5.3 equiv. Li, liqu. NH 3,
THF, NH4Cl, 2788C;(c) oxalic acid, H O, MeOH, ethyl acetate;(d) 3.0 equiv. CAN, MeCN/H O (1:1);(e) 12.3 equiv. CAN, DMF/MeCN/H O (1:1:1),
pyridine-2,6-dicarboxylic acid N-oxide;(f) 3.5 equiv. CAN, DMF/MeCN/H 2O (1:1:1);(g) THF/H 2O (3:2), Na2S2O4, re¯ux.
2
2
2
2. Results and discussion
group, we also worked with the methyl group. The depro-
tection of (^)-zonarol dimethyl ether ((^)-12) was a
challenge: Acidic conditions or Lewis acids (BBr3,
BF3´Et2O, etc.) led to complex mixtures. Finally, we
ended up with an one-pot-two-steps-procedure. Oxidative
demethylation of (^)-12 with CAN/pyridine-2,6-dicar-
boxylic acid N-oxide17 yielded (^)-zonarone ((^)-2),
which was reduced with sodium dithionite to (^)-zonarol
((^)-3) to give after puri®cation a total yield of 55% over
two steps. Zonarol (3) can easily be oxidised to the corre-
sponding quinone zonarone (2) using CAN in H2O/MeCN.
2.1. Synthesis of zonarol, zonarone, isozonarol and
isozonarone14
(1)-Albicanal ((1)-6) was coupled with 2-lithiohydro-
quinone dimethyl ether or 2-lithiohydroquinone di-THP-
ether to obtain in case of (1)-6 the benzylalcohols 9a, b,
10a, b or in case of (2)-7 11a, b as a mixture of dia-
stereomers (Scheme 2).
The benzylic desoxygenation of these compounds was
achieved by reduction with lithium in liquid NH3/THF
followed by treatment with excessive NH4Cl.15 The zonarol
di-THP-ether (13) (mixture of diastereomers) was depro-
tected following a procedure of Prelog et al.,16 which offered
mild conditions. Using stronger acids led to mixtures or
decomposition. To avoid the annoying mixtures of dia-
stereomers, obtained by using the THP moiety as protecting
Starting with (2)-drim-7-en-11-al (2)-7 and using the same
procedures we were able to obtain isozonarol (5) and
isozonarone (4) via 14.
2.2. Synthesis of yahazunol
We tried to synthesise (^)-yahazunol ((^)-1) from (^)-16,

T. Laube et al. / Tetrahedron 58 -2002) 4299±4309
4301
Scheme 3. Compound (^)-16 could not be transformed into (^)-yahazunol dimethyl ether ((^)-18). (a) Metal organyls);(b) Me SˆCH2, THF/DMSO,
2
2208C, 30 min;(c) LiAlH 4, Et2O, re¯ux.
which could be obtained from the synthon (^)-15
(Scheme 3). Due to the steric hindrance of the axial angular
methyl group 15 in position 10 of the 12-nordrimane
skeleton of (^)-16, the attack of metal organyls (cerium-,18
samarium-,19 titanium-20 or ytterbium21 organyls) gave
compound (^)-17, which possesses an axial instead of
the desired equatorial hydroxyl group in position 8 as
(^)-yahazunol dimethyl ether ((^)-18).
(Scheme 4). In the ®rst step of the reaction sequence, the
phenolic hydroxyl groups were benzylated.
The benzyl ether (1)-20 was treated with MCPBA in
23,24
CH2Cl2 to obtain the epoxides 21a, b as a mixture of
diastereomers. The ratio of 21a (desired isomer) to 21b was
1
82:18 (determined by H NMR spectroscopy). The oxirane
system in 21a, b was opened with LiAlH4 in re¯uxing
diethyl ether to give (2)-22 in 12% yield and (1)-23 as
major product in 56% yield. Compound (1)-23 was
debenzylated with H2 and Pd/C in EtOH to the desired
yahazunol (1) in 54% yield. A comparison of NMR data
and optical rotations of synthetic 1 with natural 19 showed
good agreement. Using the same reaction sequence we
synthesised in analogy to (1)-23 yahazunol dimethyl
ether (^)-18. In this case oxidative demethylation with
CAN/pyridine-2,6-dicarboxylic acid N-oxide followed by
reduction with sodium dithionite led to decomposition.
The reaction of (^)-16 with a sulfur ylide seemed to be a
promising alternative: This reaction is usually taken to
establish the oxygen of the carbonyl function in the equa-
torial position during the formation of the oxirane ring,
because the ylide is attacking axial.22 In opposite to the
expected result we got the undesired product (^)-19. The
stereochemistry of (^)-19 was proved by opening the
epoxide with LiAlH4 in diethyl ether, which led exclusively
to (^)-17. Due to these results, we started from zonarol (3)
Scheme 4. Synthesis of yahazunol (1). (a) BzBr, K2CO3, acetone;(b) MCPBA, CH 2Cl2;(c) LiAlH 4, Et2O, re¯ux;(d) H 2, Pd/C, EtOH.

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T. Laube et al. / Tetrahedron 58 -2002) 4299±4309
Scheme 5. (a) (i) EtMe2SiH, (Ph3P)3RhCl (0.5%), 50±558C, (ii) MeOH, K2CO3;(b) dimethyl carbonate, NaH, toluene, 100 8C;(c) 1.62 equiv. SnCl 4, CH2Cl2;
(d) methylenetriphenylphosphorane, toluene;(e) NaSEt, DMF, 150 8C;(f) and (g) separation of the racemate using ( 1)- and (2)-a-phenylethylamine as chiral
auxiliary.13
We also tried an alternative strategy using the acetyl instead
of the benzyl group as protecting group. We obtained
(^)-zonarol diacetate in good yield. Further on, we got
the epoxide but by opening the oxirane system to (^)-
yahazunol diacetate with LiAlH4 we were not able to
reproduce the reaction sequence.
yield of the cyclization of the b-ketoester 26 to (^)-27 was
72%. (^)-8-Oxo-12-nordriman-11-acid methyl ester ((^)-
27) was converted to (^)-28 via a Wittig reaction.12 The
solvolysis of the obtained (^)-albicanic acid methyl ester
((^)-28) seems to be trivial but it is amazingly dif®cult. As
reported before,12 (^)-28 is inert to normal saponi®cation
(KOH/MeOH, t-BuOK/t-BuOH, etc.). Using the described
DMF/LiI-method13 we obtained a maximum yield of 55% of
the desired albicanic acid (^)-8 after one recrystallization.
Using NaSEt/DMF the reaction time shortened signi®cantly
from 36 to 1 h and yielded 79% of (^)-8 after puri®cation.
For the cleavage of racemic (^)-8 into its enantiomers we
refer to the procedure described by Ragoussis et al.13
2.3. Preparation of &1)-albicanal and &2)-drim-7-en-11-al
The synthesis of described sesquiterpenes 1±5 needs the
preparation of the chiral synthon (1)-albicanic acid ((1)-
8) (Scheme 5).
This route was developed by Herlem et al.,11 hence we only
want to discuss some improvements. Herlem et al.11 used
Bu3SnH for the regioselective hydrogenation of b-ionone
(24) to dihydro-b-ionone. According to a procedure of
Ojima and Kogure25 we used Et3SiH or EtMe2SiH and
Wilkinson catalyst followed by MeOH/K2CO3 (solvolysis
of the silyl enol ether) to obtain pure 25 in 99% yield. The
Now the chiral building block (1)-8 had to be transformed
into (1)-albicanal ((1)-6) and (2)-drim-7-en-11-al ((2)-7)
(Scheme 6).
Quantitative esteri®cation of (1)-8 was carried out by trans-
ferring the free acid into its tetra-ethylammonium salt
Scheme 6. (a) (i) [Et4N]1OH2, MeOH, ii) dimethyl sulfate, THF;(b) Pd/CaCO 3 (5% Pd), Ph3P (2%), hydrogen atmosphere, room temperature, ethyl acetate;
(c) DIBAH, CH2Cl2, 08C;(d) PCC, CH 2Cl2, room temperature.

T. Laube et al. / Tetrahedron 58 -2002) 4299±4309
4303
followed by treatment with excessive dimethyl sulfate
(CAUTION: Cancer hazard!). The obtained (1)-albicanic
acid methyl ester ((1)-28) could be isomerised into drim-7-
en-11-acid methyl ester ((2)-30) using Pd/CaCO3 and Ph3P
under a hydrogen atmosphere. The esters (1)-28 and (2)-30
were reduced to the corresponding alcohols (2)-albicanol
((2)-29) and (1)-drim-7-en-11-ol ((1)-31) using diiso-
butylaluminium hydride (DIBAH) in CH2Cl2. Swern oxida-
tion26 of (2)-29 did not work well. Finally, we obtained the
desired (1)-albicanal ((1)-6) by oxidation of (2)-29 with
pyridinium chlorochromate (PCC) in CH2Cl2 in 98% yield.
Similary the oxidation of (1)-31 gave (2)-drim-7-en-11-al
(2)-7) with 97% yield.
(C-9), 57.0 (C-5), 44.6 (C-7), 42.6 (C-3), 41.4 (C-1), 40.6
(C-10), 33.9 (C-13), 33.8 (C-4), 28.0 (C-11), 24.6 (C-12),
21.9 (C-14), 21.2 (C-6), 19.1 (C-2), 15.9 (C-15).
3.2.2. Zonarone &2). To a well stirred solution of 3 (50 mg,
0.16 mmol) in 0.4 ml of MeCN was dropwise and slowly
added 0.4 ml of 1.2 M CAN (Ce(NH4)2(NO3)6) (0.48 mmol)
in H2O. After stirring for 30 min the mixture was diluted
with 10 ml of H2O. The yellow precipitate was ®ltered off
and washed with H2O to give 2 (48 mg, 0.15 mmol, 95%).
23
Yellow crystals (MeOH);mp 133±134 8C, [a]D ˆ165 (c
0.48, MeOH). Ref. 27: [a]Dˆ159 (MeOH). IR (cm21):
2940 (s), 2865 (m), 2843 (m), 1650 (s), 1597 (s), 1459
(m), 1327 (m), 1258 (s), 1210 (s), 1154 (m), 1099 (m),
1044 (s). MS m/z (%): 312 (58, M1z), 297 (14), 282 (5),
256 (12), 216 (17), 201 (19), 189 (100), 175 (39), 161
(36), 147 (26), 137 (67), 124 (66), 119 (27), 95 (40), 81
(40). HRMS: Calcd for C21H28O2 312.2089. Found
3. Experimental
3.1. General
1
312.2089. H NMR (CDCl3): d 6.71 (1H, d, Jˆ10.0 Hz,
H-30), 6.64 (1H, dd, Jˆ10.0, 2.4 Hz, H-40), 6.43 (1H, d,
Jˆ2.4 Hz, H-60), 4.74 (1H, s, H-12), 4.28 (1H, s, H-12),
2.55 (2H, m, H-11), 2.33 (1H, m, H-7), 1.97 (1H, m, H-9),
1.73 (1H, m, H-1), 1.71 (1H, m, H-7), 1.70 (1H, m, H-6),
1.55 (1H, m, H-2), 1.48 (1H, m, H-2), 1.37 (1H, m, H-3),
1.31 (1H, m, H-6), 1.19 (1H, m, H-3), 1.10 (1H, m, H-5),
1.06 (1H, m, H-1), 0.85 (3H, s, H-13), 0.78 (3H, s, H-14),
0.74 (3H, s, H-15). 13C NMR (CDCl3): d 187.8 (C-20, C-50),
149.3 (C-10), 147.1 (C-8), 136.8 (C-30), 136.0 (C-40), 132.8
(C-60), 108.0 (C-12), 55.4 (C-5), 53.9 (C-9), 41.9 (C-3), 39.7
(C-10), 39.1 (C-1), 37.8 (C-7), 33.6 (C-4, C-13), 24.1 (C-6),
23.0 (C-11), 21.1 (C-14), 19.3 (C-2), 14.5 (C-15).
All solvents were dried and puri®ed prior to use. THF and
diethyl ether were dried by distillation from Na/K under Ar.
Flash chromatography: Merck silica gel 60, 0.040±
0.063 mm (230±400 mesh).
IR: Perkin±Elmer 1420 Ratio Recording Spectrometer;
solvent CHCl3. Optical rotation values: JASCO Polarimeter
P-1020 (589 nm). MS: Finnigan MAT 8500 and Finnigan
MAT SS 300;70 eV. NMR: Bruker Avance 360 and Bruker
DRX 500, CDCl3/CHCl3, acetone-d6/acetone, C6D6/C6H6 as
internal standard. MPLC: BuÈchi B688 pump and BuÈchi
B687 gradient former. For TLC runs, precoated silica-gel
foils 60 F254 (5£10 cm2) from Merck were used. Spots were
visualised by irradiation under an UV lamp or by treatment
with phosphomolybdic acid test spray.
3.2.3. Zonarol &3) via deprotection of 13. Zonarol di-THP-
ether (13) (278 mg, 0.57 mmol) was dissolved in 200 ml of
MeOH/ethyl acetate (3:2) and mixed with 60 ml of 2%
oxalic acid. The mixture was stirred until the deprotection
was complete (checked by TLC, 3 h). For workup 50 ml of
saturated NaCl-solution and 50 ml of H2O were added. The
organic layer was separated and the aqueous layer extracted
three times with 50 ml of t-butyl methyl ether. The
combined organic layers were washed with brine, dried
with Na2SO4 and ®ltered through silica gel. After evapora-
tion of the solvent the residue was puri®ed using the
LOBARw-system (column type A, LiChroprepw RP-18
(40±63 mm);MeOH/H 2O 75:25) to obtain 3 (145 mg,
0.46 mmol, 80%). Colourless crystals (MeCN);mp 154 8C
3.2. Preparation, physical and spectroscopic data of the
compounds
3.2.1. Yahazunol &1). To yahazunol dibenzyl ether ((1)-23)
(150 mg, 0.29 mmol) in 50 ml of EtOH 5 mg of Pd/C (10%)
was added. The solution was stirred for 2 h under H2-
atmosphere. After ®ltration through RP-material and
removement of the solvent the residue was puri®ed using
MPLC (LiChrospherw 100 RP-18 (12 mm);MeCN/H 2O 3:1,
20 bar, 30 ml/min) to get 1 (52 mg, 0.16 mmol, 54%).
24
Colourless crystals (CHCl3);mp 126±128 8C, [a]D ˆ211
23
27
(sub.), [a]D ˆ117 (c 1.7, CHCl3). Ref. 9: [a]Dˆ118
(c 0.1, CHCl3). Ref. 9: [a]D ˆ212 (c 0.1, CHCl3). IR
(CHCl3). IR (cm21): 3590 (m), 3350 (w), 2930 (s), 2860
(m), 2840 (m), 1640 (w), 1595 (w), 1495 (s), 1450 (m),
1435 (m), 1385 (w), 1360 (m), 1315 (w), 1285 (w), 1255
(w), 1165 (s), 1140 (m), 1070 (w). MS m/z (%): 314 (68,
M1z), 299 (8), 229 (6), 217 (6), 201 (6), 191 (100), 178 (23),
163 (24), 161 (28), 149 (17), 137 (20), 109 (19), 95 (29), 81
(17). HRMS: Calcd for C21H30O2 314.2246. Found
314.2246. 1H NMR (C6D6): d 6.63 (1H, d, Jˆ2.5 Hz,
H-60), 6.31 (1H, dd, Jˆ8.5, 2.5 Hz, H-40), 6.24 (1H, d,
Jˆ8.5 Hz, H-30), 4.87 (2H, s, H-12), 2.81 (1H, dd,
Jˆ15.5, 10.2 Hz, H-11), 2.73 (1H, dd, Jˆ15.5, 1.9 Hz,
H-11), 2.29 (1H, m, H-7), 2.17 (1H, d, Jˆ10.2 Hz, H-9),
1.91 (1H, dd, Jˆ12.8, 4.6 Hz, H-7), 1.74 (1H, d, Jˆ12.6 Hz,
H-1), 1.57 (1H, m, H-6), 1.52 (1H, m, H-2), 1.40 (1H, m,
H-2), 1.34 (1H, d, Jˆ13.2 Hz, H-3), 1.26 (1H, dd, Jˆ12.8,
4.1 Hz, H-6), 1.14 (1H, m, H-3), 1.04 (1H, m, H-1), 1.02
(cm21): 3560 (w), 3022 (m), 2923 (w), 1710 (m), 1500
(w), 1364 (w), 1216 (s). MS m/z (%): 332 (2, M1z), 314
(70), 191 (100), 178 (16), 161 (50), 123 (83), 95 (39) 69
(17). HRMS: Calcd for C21H32O3 332.2351. Found
1
332.2351. H NMR (360 MHz, acetone-d6): d 6.64 (1H, d,
Jˆ2.7 Hz, H-60), 6.53 (1H, d, Jˆ8.5 Hz, H-30), 6.49 (1H,
dd, Jˆ8.5, 2.7 Hz, H-40), 2.85 (1H, dd, Jˆ20.7, 2.7 Hz,
H-11), 2.40 (1H, dd, Jˆ20.7, 8.5 Hz, H-11), 1.92 (1H,
ddd, Jˆ16.9, 4.0 Hz, H-7), 1.84 (1H, m, H-1), 1.66 (1H,
m, H-6), 1.62 (1H, m, H-2), 1.57 (2H, m, H-7, H-9), 1.34
(2H, m, H-2, H-6), 1.33 (1H, m, H-3), 1.30 (3H, s, H-12),
1.11 (1H, m, H-3), 0.97 (3H, s, H-15), 0.94 (1H, d,
Jˆ3.1 Hz, H-5), 0.86 (3H, s, H-13), 0.83 (3H, s, H-14),
0.72 (1H, ddd, Jˆ4.4, 17.9 Hz, H-1). 13C NMR (90 MHz,
acetone-d6): d 150.4 (C-50), 149.7 (C-20), 131.2 (C-10),
118.9 (C-60), 117.4 (C-30), 114.3 (C-40), 75.1 (C-8), 62.4

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T. Laube et al. / Tetrahedron 58 -2002) 4299±4309
(1H, m, H-5), 0.84 (3H, s, H-13), 0.80 (3H, s, H-15), 0.78
(3H, s, H-14). 13C NMR (C6D6): d 150.0 (C-50), 148.6 (C-8),
147.8 (C-20), 130.1 (C-10), 116.9 (C-60), 115.8 (C-30), 112.7
(C-40), 108.2 (C-12), 56.3 (C-9), 55.6 (C-5), 42.4 (C-3), 40.2
(C-10), 39.2 (C-1), 38.5 (C-7), 33.7 (C-4, C-13), 24.6 (C-6),
23.9 (C-11), 21.7 (C-14), 19.8 (C-2), 14.7 (C-15).
(s), 1095 (w), 1040 (w). MS m/z (%): 314 (96, M1z), 191
(100), 175 (18), 161 (13), 135 (17), 123 (36), 109 (37), 95
(27), 69 (13), 55 (14).). HRMS: Calcd for C21H30O2
314.2246. Found 314.2246. 1H NMR (CDCl3): d 6.72
(1H, d, Jˆ2.7 Hz, H-60), 6.58 (1H, d, Jˆ8.5 Hz, H-30),
6.49 (1H, dd, Jˆ8.5, 2.7 Hz, H-40), 5.37 (1H, bs, H-7),
2.56 (2H, m, H-11), 2.32 (1H, bs, H-9), 1.97 (1H, m,
H-6), 1.88 (1H, m, H-1), 1.87 (1H, m, H-6), 1.54 (1H, m,
H-2), 1.45 (3H, s, H-12), 1.41 (2H, m, H-2, H-3), 1.26 (1H,
m, H-5), 1.17 (1H, m, H-3), 1.08 (1H, m, H-1), 0.89 (3H, s,
H-14), 0.86 (6H, s, H-13, H-15). 13C NMR (CDCl3): d 149.2
(C-50), 147.0 (C-20), 135.3 (C-8), 131.3 (C-10), 122.3 (C-7),
116.5 (C-60), 116.1 (C-30), 112.8 (C-40), 54.2 (C-9), 50.3
(C-5), 42.2 (C-3), 39.5 (C-1), 36.8 (C-10), 33.3 (C-13), 33.0
(C-4), 26.2 (C-11), 23.7 (C-6), 22.2 (C-12), 21.9 (C-14),
18.9 (C-2), 13.9 (C-15).
3.2.4. &^)-Zonarol &&^)-3) via &^)-12 and &^)-2. (^)-
Zonarol dimethyl ether ((^)-12) (150 mg, 0.44 mmol) was
dissolved in 42 ml of MeCN/DMF (1:1). To this solution
500 mg of pyridine-2,6-dicarboxylic acid N-oxide, 16.5 ml
of H2O, and 4.5 ml of an aqueous 1.2 M CAN-solution
(5.4 mmol) were added under stirring. After 8 min 100 ml
of H2O was added and the solution extracted three times
with t-butyl methyl ether. The solvent of the combined
organic phases was removed and the residual oil dissolved
in 50 ml of THF/H2O (3:2), 762 mg Na2S2O4 was added and
the mixture heated under re¯ux for 30 min. The mixture was
extracted three times with ethyl acetate. The combined
organic layers were washed with saturated NaCl-solution
and dried with Na2SO4. After ®ltration through silica gel
and removing the solvent the residue was puri®ed using
MPLC (LiChrospherw Si-60 (15 mm);hexane/ethyl acetate
6:1, 20 bar, 30 ml/min) to give (^)-3 (76 mg, 0.24 mmol,
55%).
3.2.7. &1)-Albicanal &&1)-6). Pyridinium chlorochromate
(19.4 g, 90 mmol) was stirred for 15 min in 250 ml of
CH2Cl2. A solution of (2)-albicanol ((2)-29) (1.91 g,
8.6 mmol) in 20 ml of CH2Cl2 was slowly added. The reac-
tion was monitored, until the educt had completely disap-
peared (15±40 min). The mixture was ®ltered through a
short silica gel column (12 cm) to separate the chromium
salts. Removing the solvent in vacuo at room temperature
gave (1)-6 (1.85 g, 8.4 mmol, 98%) as a colourless oil.
26
3.2.5. Isozonarone &4). Isozonarone (4) was prepared as 2
(91%), but 3.5 equiv. CAN, DMF/MeCN/H2O (1:1:1) were
used. Yellow crystals (MeOH);mp 130±132 8C;
[a]D ˆ177 (c 1.0, CHCl3). Ref. 28: (2)-6 [a]Dˆ267.3
(c 1.83, CHCl3). IR (cm21): 3025 (m), 2950 (s), 2860 (m),
1720 (s), 1470 (m), 1365 (m), 1100 (w). MS m/z (%): 220 (6,
M1z), 207 (11), 193 (18), 177 (32), 137 (100), 123 (63), 109
(43), 95 (58), 81 (64), 69 (64), 55 (38). 1H NMR (CDCl3): d
9.84 (1H, d, Jˆ2.5 Hz, H-11), 4.88 (1H, s, H-12), 4.42 (1H,
s, H-12), 2.41 (1H, m, H-9), 2.39 (1H, m, H-7), 2.02 (1H, m,
H-7), 1.67 (1H, m, H-6), 1.54 (2H, m, H-1, H-2), 1.42 (1H,
m, H-2), 1.40 (2H, m, H-3, H-6), 1.16 (1H, m, H-3), 1.15
(1H, m, H-1), 1.12 (3H, s, H-15), 0.99 (1H, m, H-5), 0.85
(3H, s, H-13), 0.83 (3H, s, H-14). 13C NMR (CDCl3): d
206.6 (C-11), 145.0 (C-8), 109.2 (C-12), 67.8 (C-9), 53.9
(C-5), 41.8 (C-3), 39.8 (C-1), 39.0 (C-10), 36.7 (C-7), 33.5
(C-13), 33.4 (C-4), 23.0 (C-6), 21.9 (C-14), 18.7 (C-2), 16.0
(C-15).
21
30
[a]D ˆ189 (c 0.1, MeOH). Ref. 10: [a]D ˆ195
(MeOH). IR (cm21): 2925 (s), 1660 (s), 1600 (m), 1445
(m), 1385 (w), 1365 (w), 1300 (m), 1080 (w), 1065 (w),
910 (m). MS m/z (%): 314 (4), 312 (2, M1z), 189 (33),
124 (38), 119 (100), 109 (40), 95 (18), 91 (21), 81 (19),
69 (25). HRMS: Calcd for C21H28O2 312.2089. Found
312.2089. 1H NMR (C6D6): d 6.46 (1H, d, Jˆ2.3 Hz,
H-60), 6.15 (1H, d, Jˆ10.0 Hz, H-30), 6.11 (1H, dd,
Jˆ10.0, 2.3 Hz, H-40), 5.33 (1H, s, H-7), 2.48 (1H, m,
H-11), 2.13 (1H, m, H-11), 1.94 (1H, m, H-9), 1.86 (1H,
m, H-6), 1.77 (1H, m, H-6), 1.56 (1H, m, H-1), 1.43 (1H, m,
H-2), 1.40 (3H, s, H-12), 1.34 (2H, m, H-2, H-3), 1.10 (2H,
m, H-3, H-5), 0.84 (3H, s, H-13), 0.83 (3H, s, H-14), 0.80
(1H, m, H-1), 0.75 (3H, s, H-15). 13C NMR (C6D6): d 187.1
(C-50), 187.0 (C-20), 151.1 (C-10), 136.5 (C-30), 135.7
(C-40), 133.8 (C-8), 132.8 (C-60), 123.4 (C-7), 53.2 (C-9),
50.0 (C-5), 42.3 (C-3), 39.6 (C-1), 36.9 (C-10), 33.3 (C-13),
33.1 (C-4), 25.9 (C-11), 24.0 (C-6), 22.8 (C-12), 22.0
(C-14), 19.1 (C-2), 13.9 (C-15).
3.2.8. &2)-Drim-7-en-11-al &&2)-7). (2)-Drim-7-en-11-al
((2)-7) was prepared starting from (1)-drim-7-en-11-ol
((1)-31) using the same procedure as described for (1)-6
(97%). [a]Dˆ221 (c 1.0, CHCl3). Ref. 29: [a]Dˆ219.2 (c
3.7, CHCl3). IR (cm21): 2950 (s), 1725 (s), 1680 (w), 1465
(m), 1450 (m), 1400 (m), 1380 (w), 1280 (w), 1130 (w). MS
m/z (%): 220 (39, M1z), 191 (57), 135 (20), 124 (47), 123
(38), 121 (23), 109 (100), 107 (20), 97 (29), 95 (38), 81 (21),
69 (24). 1H NMR (CDCl3): d 9.65 (1H, d, Jˆ5.2 Hz, H-11),
5.67 (1H, s, H-7), 2.55 (1H, bs, H-9), 2.04 (1H, m, H-6),
1.94 (1H, m, H-6), 1.64 (1H, m, H-1), 1.59 (3H, s, H-12),
1.50 (1H, m, H-2), 1.42 (2H, m, H-2, H-3), 1.25 (1H, m,
H-1), 1.18 (1H, m, H-3), 1.11 (1H, m, H-5), 1.04 (3H, s, H-
15), 0.89 (3H, s, H-14), 0.84 (3H, s, H-13). 13C NMR
(CDCl3): d 206.9 (C-11), 127.7 (C-8), 125.4 (C-7), 67.5
(C-9), 48.9 (C-5), 41.9 (C-3), 40.3 (C-1), 37.0 (C-10),
33.3 (C-13), 33.0 (C-4), 23.6 (C-6), 22.0 (C-14), 21.6
(C-12), 18.2 (C-2), 15.7 (C-15).
3.2.6. Isozonarol &5). Isozonarol di-THP-ether (14)
(235 mg, 0.49 mmol) was dissolved in 140 ml of ethyl
acetate/MeOH (1:1). To this mixture 25 ml of 2.8% oxalic
acid was added. The mixture was stirred for 5 h at 408C,
diluted with saturated NaCl-solution and extracted four
times with hexane/ethyl acetate (1:1). The combined
organic layers were washed with saturated NaCl-solution
and ®ltered through silica gel. After removing the solvent
the residue was puri®ed using MPLC (LiChrospherw Si-60
(15 mm);hexane/ethyl acetate 3:1, 20 bar, 30 ml/min) to
give 5 (129 mg, 0.41 mmol, 84%). Colourless crystals;mp
22
150±1528C (CHCl3), [a]D ˆ128 (c 1.0, CHCl3). Ref. 9:
[a]Dˆ130 (CHCl3). IR (cm21): 3610 (m), 3350 (m), 2925
3.2.9. &^)-Albicanic acid &&^)-8). A mixture of (^)-
albicanic acid methyl ester ((^)-28) (20 g, 79.9 mmol),
(s), 1500 (s), 1455 (s), 1385 (m), 1365 (m), 1290 (m), 1170

T. Laube et al. / Tetrahedron 58 -2002) 4299±4309
4305
NaSEt (60 g, 72 mmol) and 250 ml of DMF was heated for
1 h at 1508C. After cooling the reaction mixture was poured
into 0.5 l of conc. HCl and 1 kg of crushed ice. Saturated
NaCl-solution (600 ml) was added and the solution was
extracted three times with ethyl acetate. The solvent was
removed and 60 g of a yellow oil was obtained, which
was dissolved in 200 ml of MeOH. H2O (800 ml) was
slowly added. The precipitate was ®ltered off and washed
with cold hexane to obtain 18 g of (^)-8. Recrystallization
from MeOH gave (^)-8 (14.9 g, 63.1 mmol, 79%);mp
129±1308C. IR (cm21): 3500 (w), 3020 (s), 2990 (s), 2940
(s), 2850 (s), 1720 (s), 1650 (m), 1460 (m), 1440 (m), 1390
(m), 1365 (m), 1225 (m), 1210, (s). MS m/z (%): 236 (22,
M1z), 221 (20), 176 (15), 137 (100), 123 (42), 121 (25), 109
(33), 95 (45), 81 (40), 41 (56). HRMS: Calcd for C15H24O2
236.1780. Found 236.1780. 1H NMR (CDCl3): d 4.87 (1H,
s, H-12), 4.77 (1H, s, H-12), 2.63 (1H, s, H-9), 2.28 (1H, m,
H-7), 1.93 (1H, m, H-7), 1.58 (1H, m, H-6), 1.49 (1H, m,
H-1), 1.46 (1H, m, H-2), 1.31 (1H, m, H-2), 1.30 (1H, m,
H-3), 1.28 (1H, m, H-6), 1.10 (1H, m, H-1), 1.09 (1H, m,
H-3), 0.99 (1H, dd, Jˆ12.5, 2.5 Hz, H-5), 0.91 (3H, s,
H-15), 0.75 (3H, s, H-13), 0.72 (3H, s, H-14). 13C NMR
(CDCl3): d 175.2 (C-11), 145.5 (C-8), 108.7 (C-12), 64.5
(C-9), 55.8 (C-5), 43.2 (C-3), 40.3 (C-1), 40.0 (C-10), 37.4
(C-7), 34.4 (C-4), 34.0 (C-13), 24.5 (C-6), 22.2 (C-14), 20.0
(C-2), 14.7 (C-15).
3.2.13.
&11R,S)-11-&20,50-Di-tetrahydropyranyloxy-10-
phenyl)-drim-7-en-11-ol &11a, b). The drimenols 11a, b
were prepared in the same way as described for 10a, b,
but the hydroquinone di-THP-ether in abs. THF was not
cooled to 08C. Yield for 11a, b: 80%.
3.2.14. &1)-Zonarol dimethyl ether &&1)-12). To a stirred
mixture of 35 ml of liquid NH3 and 18 ml of THF at 2788C
Li (103 mg, 14.8 mmol, granulate, Merck) was added. After
15 min 9a, b (1.00 g, 2.79 mmol), dissolved in 10 ml of
THF, was added dropwise. After stirring for 15 min 2 g of
NH4Cl was added in portions (colour changed from dark
blue to colourless). The NH3 was allowed to evaporate
(2 h). The residue was distributed in 150 ml of ethyl acetate
and 100 ml of H2O. The organic layer was dried with
Na2SO4 and ®ltered through silica gel. Removing the
solvent yielded (1)-12 (927 mg, 2.71 mmol, 97%) as a
colourless solid. Very pure (1)-12 was obtained by
MPLC (LiChrospherw Si-60 (15 mm);hexane/ t-butyl
methyl ether 10:1, 16 bar, 15 ml/min);mp 74±75 8C.
21
26
[a]D ˆ125 (c 1.0, CHCl3). Ref. 30: [a]D ˆ127.9
(CHCl3). IR (cm21): 3000 (m), 2940 (s), 2860 (m), 2830
(m), 1640 (w), 1605 (w), 1585 (w), 1495 (s), 1460 (m), 1440
(m), 1385 (w), 1365 (w), 1280 (w), 1210 (s), 1180 (w), 1160
(w), 1050 (m). MS m/z (%): 342 (100, M1z), 327 (10), 310
(14), 257 (1), 245 (2), 218 (1), 206 (9), 191 (15), 164 (16),
151 (77), 137 (23), 121 (32), 109 (11), 95 (16), 81 (11), 55
(8). HRMS: Calcd for C23H34O2 342.2559. Found 342.2558.
1H NMR (CDCl3): d 6.72 (1H, d, Jˆ9.0 Hz, H-30), 6.71
(1H, d, Jˆ2.8 Hz, H-60), 6.63 (1H, dd, Jˆ9.0, 2.8 Hz,
H-40), 4.74 (1H, s, H-12), 4.61 (1H, s, H-12), 3.78 (3H, s,
MeO-20), 3.72 (3H, s, MeO-50), 2.74 (2H, m, H-11), 2.34
(1H, m, H-7), 2,20 (1H, m, H-7), 2.19 (1H, m, H-9), 1.87
(1H, m, H-1), 1.73 (1H, m, H-6), 1.62 (1H, m, H-2), 1.49
(1H, m, H-2), 1.41 (1H, m, H-3), 1.32 (1H, m, H-6), 1.24
(1H, m, H-5), 1.22 (1H, m, H-3), 1.15 (1H, m, H-1), 0.89
(3H, s, H-13), 0.83 (3H, s, H-14), 0.81 (3H, s, H-15). 13C
NMR (CDCl3): d 153.2 (C-50), 151.7 (C-20), 148.3 (C-8),
132.1 (C-10), 116,2 (C-60), 110.8 (C-30), 109.6 (C-40), 107.6
(C-12), 55.9 (C-9), 55.8 (MeO-20, 55.7 (C-5), 55.5 (MeO-
50), 42.2 (C-3), 39.9 (C-10), 39.1 (C-1), 38.3 (C-7), 33.6
(C-4, C-13), 24.4 (C-6), 23.2 (C-11), 21.8 (C-14), 19.5
(C-2), 14.6 (C-15).
3.2.10. &1)-Albicanic acid) &&1)-8). Racemic albicanic
acid ((^)-8) was separated into the two enantiomers (1)-
and (2)-albicanic acid, as described in the literature.13 We
obtained (1)-8 as colourless crystals;mp 130±132 8C.
23
25
[a]D ˆ127 (c 1.0, CHCl3) Ref. 13: [a]D ˆ129 (CHCl3).
3.2.11.
&11R,S)-11-&20,50-Dimethoxy-10-phenyl)-drim-
8,12-en-11-ol &9a, b). Hydroquinone dimethyl ether
(1.66 g, 12.0 mmol) dissolved in 25 ml of abs. Et2O was
mixed with 6.2 ml of 1.3 M sec-BuLi in cyclohexane
(8.0 mmol) at 08C. The ice bath was removed and the
mixture was stirred for 3 h at room temperature. (1)-Albi-
canal ((1)-6) (880 mg, 4.0 mmol) in 5 ml of Et2O was
added and after stirring for 5 min 0.5 ml of saturated
NH4Cl-solution was dropped. Saturated NaCl-solution
(5 ml) was added, the organic phase separated and dried
with Na2SO4. The solvent was evaporated and the product
was puri®ed by MPLC (LiChroprepw RP-8 (15±25 mm);
MeOH/H2O 80:20, 4±6 bar, 25 ml/min) to obtain 9a, b
(1.39 g, 3.9 mmol, 97%).
3.2.15. Zonarol di-THP-ether &13). The diastereomers
10a, b were converted into 13 in the same way as described
for preparation of 12. Puri®cation of 13 was possible by
chromatography using the LOBARw-system (column type
A, LiChroprepw RP-18 (40±63 mm), MeCN/H2O 9:1).
Yield of 13: 95%.
3.2.12.
&11R,S)-11-&20,50-Di-tetrahydropyranyloxy-10-
phenyl)-drim-8,12-en-11-ol &10a, b). Hydroquinone di-
THP-ether (1.52 g, 5.4 mmol) was dissolved in 110 ml of
abs. THF, cooled to 08C, mixed with 3.4 ml of 1.3 M sec-
BuLi in cyclohexane (4.4 mmol) and stirred for 2.5 h. (1)-
Albicanal ((1)-6) (481 mg, 2.18 mmol), dissolved in 5 ml
of abs. THF, was dropped to the obtained suspension and
stirred for 15 min. To the reaction mixture 20 ml of satu-
rated NH4Cl-solution and 100 ml of ethyl acetate were
added, the organic phase was separated, dried with
Na2SO4 and evaporated. The product was prepuri®ed by
¯ash chromatography (CH2Cl2). Further puri®cation by
MPLC (LiChroprepw RP-8 (15±25 mm);MeCN/H 2O
3.2.16. Isozonarol di-THP-ether &14). The drimene 14 was
prepared as described for 13. Yield of 14: 98%.
3.2.17. &^)-8-Epiyahazunol dimethyl ether &&^)-17).
Ytterbium(III)
tri¯uoromethanesulfonate
(330 mg,
0.56 mmol) was dissolved in 15 ml of THF and cooled to
2788C. To this solution MeLi (0.35 ml, 0.56 mmol) was
added. After 30 min (^)-11-(20,50-dimethoxyphenyl)-8-
oxo-12-nordrimane ((^)-16) (192 mg, 0.53 mmol) was
added and stirred for 30 min. Saturated NaHCO3-solution
(15 ml) was added, the organic layer was separated and the
aqueous layer extracted two times with 30 ml of ethyl
83:17, 10 bar, 30 ml/min) yielded 10a,
1.74 mmol, 80%).
b (870 mg,

4306
T. Laube et al. / Tetrahedron 58 -2002) 4299±4309
acetate. The combined organic layers were washed with
saturated NaCl-solution and dried with Na2SO4. After ®ltra-
tion through silica gel and removing the solvent further
puri®cation was carried out by MPLC (LiChrospherw Si-
60 (15 mm);hexane/ethyl acetate 15:1, 20 bar, 30 ml/min)
to get (^)-17 (45.2 mg, 0.12 mmol, 21%) and still (^)-16
(135 mg, 0.37 mmol).
combined organic layers were washed with saturated NaCl-
solution and dried with Na2SO4. After ®ltration through
silica gel and removing the solvent we obtained (^)-19
(250 mg, 0.70 mmol, 92%). MS m/z (%): 358 (100, M1z),
340 (14), 220 (61), 204 (39), 203 (43), 189 (85), 159 (37),
152 (58), 151 (98), 121 (57). 1H NMR (CDCl3): d 6.75 (1H),
6.68 (1H), 6.62 (1H), 3.77 (6H, MeO), 2.58 (1H), 2.35 (2H),
2.15 (1H), 2.0±1.85 (3H), 1.75±1.55 (3H), 1.50±1.20 (4H),
1.20±1.05 (2H), 1.02 (3H, s), 0.92 (3H, s), 0.89 (3H, s). 13C
NMR (CDCl3): d 153.4, 151.6, 132.9, 116.1, 110.9, 109.4,
57.9, 55.8, 55.6, 55.3, 51.5, 49.4, 42.1, 40.1, 39.2, 36.1, 33.6
(2 C), 21.8, 20.4, 20.2, 18.7, 14.7.
To a solution of samarium(II) iodide (9.1 ml, 0.91 mmol) in
THF were added a solution of (^)-11-(20,50-dimethoxy-
phenyl)-8-oxo-12-nordrimane
((^)-16)
(164 mg,
0.46 mmol) in 20 ml of THF, methyl iodide (0.02 ml,
0.46 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (0.55 ml, 4.55 mmol). After 30 min 20 ml of
saturated NH4Cl-solution was added, the organic layer was
separated and the aqueous phase extracted two times with
30 ml of ethyl acetate. The combined organic layers were
washed with saturated NaCl-solution and dried with
Na2SO4. After ®ltration through silica gel and removing
the solvent further puri®cation was carried out by MPLC
(LiChrospherw Si-60 (15 mm);hexane/ethyl acetate 15:1,
20 bar, 30 ml/min) to get (^)-17 (15 mg, 0.04 mmol, 7%)
and (^)-16 (120 mg, 0.33 mmol).
3.2.20. &1)-Zonarol dibenzyl ether &&1)-20). Zonarol
((1)-3) (385 mg, 1.22 mmol) was dissolved in 50 ml of
acetone. To this solution 1.3 g of K2CO3 and benzyl
bromide (0.75 ml, 6.24 mmol) were added. The mixture
was heated under re¯ux for 36 h. The solution was ®ltered
through silica gel and puri®ed using MPLC (LiChrospherw
Si-60 (15 mm);pentane/Et 2O 25:1, 20 bar, 30 ml/min) to get
(1)-20 (514 mg, 1.04 mmol, 85%) as colourless crystals.
24
Mp 110±1118C (pentane/Et2O), [a]D ˆ118 (c 1.05,
CHCl3). IR (cm21): 3020 (s), 2930 (m), 1495 (m), 12227
(m), 1205 (w), 1024 (w). MS m/z (%): 494 (72, M1z), 403
(6), 213 (8), 137 (7), 123 (8), 91 (100). HRMS: Calcd for
IR (cm21): 3480 (s), 2950 (s), 2860 (m), 2840 (m), 1440 (s),
1390 (m), 1320 (m), 1270 (w), 1220 (w), 1170 (m), 1050
(w). MS m/z (%): 360 (100 M1z), 342 (1), 204 (70), 151 (73),
121 (13). 1H NMR (CDCl3): d 6.80 (1H, d, Jˆ2.6 Hz, H-60),
6.72 (1H, d, Jˆ8.8 Hz, H-30), 6.62 (1H, dd, Jˆ8.8, 2.6 Hz,
H-40), 3.78 (3H, s, MeO-20), 3.75 (3H, s, MeO-50), 2.93 (1H,
dd, Jˆ15.9, 7.7 Hz, H-11), 2.51 (1H, d, Jˆ15.9 Hz, H-11),
1,78 (1H, m, H-7), 1.75 (1H, m, H-1), 1.56 (1H, m, H-6),
1.49 (1H, m, H-2), 1.46 (1H, m, H-9), 1.41 (2H, m, H-3,
H-7), 1.32 (1H, m, H-6), 1.24 (1H, m, H-2), 1.22 (1H, m,
H-3), 1.05 (3H, s, H-15), 0.95 (1H, m, H-1), 0.91 (1H, m,
H-5), 0.88 (3H, s, H-12), 0.86 (3H, s, H-14), 0.84 (3H, s,
1
C35H42O2 494.3185 Found 494.3184. H NMR (CDCl3): d
7.44±7.30 (10H, m, benzyl), 6.81 (1H, d, Jˆ2.8 Hz, H-60),
6.78 (1H, d, Jˆ8.7 Hz, H-30), 6.68 (1H, dd, Jˆ8.7, 2.8 Hz,
H-40), 5.01 (2H, bs, CH2O-50), 4.97 (2H, bs, CH2O-20), 4.72
(1H, s, H-12), 4.63 (1H. s, H-12), 2.81 (1H, m, H-11), 2.73
(1H, m, H-11), 2.32 (1H, m, H-7), 2.23 (1H, m, H-9), 1.95
(1H, m, H-7), 1.73 (2H, m, H-1, H-6), 1.55 (1H, m, H-2),
1.41 (1H, m, H-2), 1.32 (1H, m, H-3), 1.30 (1H, m, H-6),
1.10 (2H, m, H-3, H-5), 1.01 (1H, m, H-1), 0.86 (3H, s,
H-13), 0.80 (3H, s, H-14), 0.76 (3H, s, H-15). 13C NMR
(CDCl3): d 152.7 (C-20), 151.1 (C-50), 148.4 (C-8), 137.5
(benzyl), 137.4 (benzyl), 132.5 (C-10), 128.5 (benzyl), 128.4
(benzyl), 127.8 (benzyl), 127.7 (benzyl), 127.6 (benzyl),
127.5 (benzyl), 117.6 (C-60), 112.5 (C-30), 111.2 (C-4`),
107.6 (C-12), 70.9 (CH2O-20), 70.5 (CH2O-50), 55.7 (C-9),
55.6 (C-5), 42.1 (C-3), 39.9 (C-10), 38.9 (C-1), 38.3 (C-7),
33.7 (C-13), 33.6 (C-4), 24.4 (C-6), 24.0 (C-11), 21.7
(C-14), 19.4 (C-2), 14.5 (C-15).
13
H-13). C NMR (CDCl3): d 153.5 (C-40), 151.2 (C-20),
134.3 (C-10), 116.2 (C-60), 111.0 (C-30), 109.3 (C-40),
73.3 (C-8), 58.8 (C-9), 56.0 (C-5), 56.0 (MeO-20), 55.6
(MeO-50), 42.6 (C-7), 42.0 (C-3), 39.9 (C-1), 39.0 (C-10),
33.6 (C-13), 33.5 (C-4), 31.2 (C-12), 23.0 (C-11), 21.8
(C-14), 18.4 (C-2, C-6), 15.3 (C-15).
3.2.18. &^)-8-Epiyahazunol dimethyl ether &&^)-17) via
&^)-19. (^)-8-Epiyahazunol dimethyl ether ((^)-17) was
prepared by reduction of (^)-19 with LiAlH4 as described
for (2)-22 and (1)-23, but the reaction time was reduced
from 2 h to 30 min. Yield of (^)-17: 97%.
3.2.21. &8R,S)-8,12-Epoxyzonarol dibenzyl ether &21a, b).
To a solution of (1)-zonarol dibenzyl ether ((1)-20)
(500 mg, 1.01 mmol)) in 50 ml of CH2Cl2 1018 mg
MCPBA (70±75%) was added. The reaction was monitored
until the educt had completely vanished (90±120 min). A
saturated solution of K2CO3 (20 ml) was added, the organic
layer separated and the H2O layer extracted three times with
t-butyl methyl ether. The combined organic layers were
washed with NaCl-solution, dried with Na2SO4 and ®ltered
through silica gel. Further puri®cation was achieved by
MPLC (LiChrospherw 100 RP-18 (12 mm);MeCN/H 2O
4:1, 20 bar, 30 ml/min) to obtain 21a, b (433 mg,
0.85 mmol, 84%) as a colourless oil.
3.2.19. &^)-8,12-Epoxyzonarol dimethyl ether &&^)-19).
Sodium hydride (60%, 43 mg, 1.08 mmol) was dissolved in
15 ml of DMSO and heated for 20 min to 758C (until the
formation of hydrogen has ended). After cooling to room
temperature 20 ml of THF was added and the mixture was
cooled to 2208C. To this solution trimethylsulfonium
iodide (220 mg, 1.08 mmol), dissolved in 2 ml of DMSO,
was added over a period of three min. After 1 min (^)-11-
(20,50-dimethoxyphenyl)-8-oxo-12-nordrimane
((^)-16)
(261 mg, 0.76 mmol), dissolved in 10 ml of THF, was
added. After stirring for 15 min at 2208C and 45 min at
room temperature, 10 ml of saturated NaHCO3-solution
was added. The organic layer was separated and the aqueous
phase extracted two times with 5 ml of ethyl acetate. The
3.2.22. 8-Epiyahazunol dibenzyl ether &&2)-22) and
yahazunol dibenzyl ether &&1)-23). To a solution of 21a,
b (400 mg, 0.78 mmol) in 50 ml of Et2O 950 mg LiAlH4
was added. After heating under re¯ux for 2 h the reaction
mixture was slowly poured into a mixture of 100 ml of conc.

T. Laube et al. / Tetrahedron 58 -2002) 4299±4309
4307
HCl and 250 g of crushed ice. The organic layer was sepa-
rated and the aqueous layer extracted two times with t-butyl
methyl ether. The combined organic layers were washed
with sat. KHCO3-solution, saturated NaCl-solution and
dried with Na2SO4. After ®ltration through silica gel and
removing the solvent further puri®cation was carried out
by MPLC (LiChrospherw Si-60 (15 mm);hexane/ t-butyl
methyl ether 8:1, 20 bar, 30 ml/min) to get (2)-22
(47 mg, 0.092 mmol, 12%) and (1)-23 (226 mg,
1360 (m). MS m/z (%): 194 (9, M1z), 193 (25), 179 (7), 175
(44), 152 (40), 135 (39), 133 (46), 123 (30), 121 (42), 119
(35), 107 (36), 95 (40), 43 (100). 1H NMR (CDCl3): d 2.46
(2H, m, H-8), 2.20 (2H, m, H-7), 2.10 (3H, s, H-10), 1.85
(2H, m, H-4), 1.52 (3H, s, H-11), 1.50 (2H, m, H-3), 1.36
(2H, m, H-2), 0.93 (6H, s, H-12, H-13). 13C NMR (CDCl3):
d 208.9 (C-9), 135.9 (C-6), 127.7 (C-5), 44.5 (C-8), 39.7
(C-2), 35.0 (C-1), 32.7 (C-4), 29.7 (C-10), 28.4 (C-12,
C-13), 22.2 (C-7), 19.6 (C-11), 19.4 (C-3).
23
0.44 mmol, 56%) as colourless oils. (2)-22: [a]D ˆ210
(c 1.0, CHCl3). IR (cm21): 3490 (w), 3019 (m), 2925 (m),
1498 (w), 1460 (w), 1216 (s), 1026 (w). MS m/z (%): 512
(100, M1z), 404 (12), 313 (14), 191 (9), 91 (80). HRMS:
3.2.24.
5-&1,1,5-Trimethylcyclohex-5-en-6-yl)-3-oxo-
pentanoic acid methyl ester &26). To a solution of dihydro-
b-ionone (25) (52.0 g, 268 mmol) in 500 ml of toluene NaH
(7.70 g, 480 mmol) and dimethyl carbonate (40.6 ml,
43.4 g, 480 mmol) were added and the mixture was heated
for 2 h at 1008C. After cooling the solution was slowly
poured into a mixture of 300 ml of conc. HCl and 600 g
of ice. The organic layer was separated and the aqueous
layer extracted two times with ethyl acetate. The combined
organic layers were washed with saturated NaCl-solution
and dried with Na2SO4. After ®ltration through silica gel
and removing the solvent further puri®cation was carried
out by MPLC (LiChrospherw Si-60 (15 mm);hexane/ethyl
acetate 12:1, 20 bar, 30 ml/min) to get 26 (65.5 g,
259.6 mmol, 97%). IR (cm21): 3020 (m), 2960 (s), 2930
(s), 2870 (m), 1740 (s), 1710 (s), 1435 (m), 1405 (w),
1380 (w), 1320 (m). MS m/z (%): 194 (19), 179 (39), 176
1
Calcd for C35H44O3 512.3290. Found 512.3290. H NMR
(CDCl3): d 7.42±7.24 (10H, m, benzyl), 6.84 (1H, d,
Jˆ2.5 Hz, H-60), 6.78 (1H, d, Jˆ8.8 Hz, H-30), 6.70 (1H,
dd, Jˆ8.8, 2.5 Hz, H-40), 5.01 (2H, bs, CH2O-20), 5.00 (2H,
bs, CH2O-50), 2.93 (1H, dd, Jˆ16.2, 2.9 Hz, H-11), 2.56
(1H, d, Jˆ16.2 Hz, H-11), 1.73 (1H, m, H-7), 1.71 (1H,
m, H-1), 1.49 (2H, m, H-2, H-6), 1.42 (1H, m, H-9), 1.41
(1H, m, H-7), 1.39 (1H, m, H-3), 1.30 (2H, m, H-2, H-6),
1.11 (1H, m, H-3), 1.01 (3H, s, H-15), 0.89 (3H, s, H-12),
0.87 (3H, s, H-13), 0.84 (2H, m, H-1, H-5), 0.83 (3H, s,
13
H-14). C NMR (CDCl3): d 152.9 (C-50), 150.5 (C-20),
137.5 (benzyl), 137.4 (benzyl), 134.9 (C-10), 128.6 (benzyl),
128.5 (benzyl), 127.9 (benzyl), 127.8 (benzyl), 127.6
(benzyl), 127.4 (benzyl), 117.2 (C-60), 113.2 (C-30), 111.2
(C-40), 73.3 (C-8), 71.1 (CH2O-20), 70.6 (CH2O-50), 58.8
(C-9), 56.0 (C-5), 42.6 (C-7), 41.9 (C-3), 39.7 (C-1), 39.0
(C-10), 33.6 (C-13), 33.4 (C-4), 31.3 (C-12), 23.2 (C-11),
21.8 (C-14), 18.4 (C-2, C-6), 15.3 (C-15). (1)-23:
1
(55), 161 (73), 136 (56), 123 (51), 121 (100), 43 (28). H
NMR (CDCl3): d 3.71 (3H, s, CH3O), 3.42 (2H, s, H-10),
2.58 (2H, m, H-8), 2.25 (2H, m, H-7), 1.86 (2H, m, H-4),
1.54 (2H, m, H-3), 1.53 (3H, s, H-11), 1.38 (2H, m, H-2),
0.94 (6H, s, H-12, H-13). 13C NMR (CDCl3): d 202.7 (C-9),
167.6 (C-14), 135.5 (C-6), 128.1 (C-5), 52.3 (CH3O), 48.9
(C-10), 43.8 (C-8), 39.7 (C-2), 35.0 (C-1), 32.7 (C-4), 28.4
(C-12, C-13), 22.0 (C-7), 19.7 (C-11), 19.4 (C-3).
23
[a]D ˆ15 (c 1.0, CHCl3). IR (cm21): 3490 (w), 3019
(m), 2925 (m), 1498 (w), 1460 (w), 1216 (s), 1026 (w).
MS m/z (%): 512 (100, M1z), 404 (12), 313 (14), 191 (9),
91 (80). HRMS: Calcd for C35H44O3 512.3290 Found
512.3290. 1H NMR (CDCl3): d 7.42±7.23 (10H, m, benzyl),
6.86 (1H, d, Jˆ2.8 Hz, H-60), 6.80 (1H, d, Jˆ8.8 Hz, H-30),
6.70 (1H, dd, Jˆ8.8, 2.8 Hz, H-40), 5.00 (4H, m, CH2O),
2.78 (1H, dd, Jˆ14.6, 5.8 Hz, H-11), 2.57 (1H, dd, Jˆ14.6,
4.0 Hz, H-11), 1.75 (1H, m, H-7), 1.69 (1H, m, H-1), 1.61
(1H, m, H-9), 1.60 (1H, m, H-6), 1.49 (1H, m, H-2), 1.31
(1H, m, H-7), 1.30 (2H, m, H-2, H-3), 1.25 (1H, m, H-6),
1.15 (3H, s, H-12), 1.04 (1H, m, H-3), 0.84 (3H, s, H-13),
0.81 (3H, s, H-15), 0.80 (1H, m, H-5), 0.76 (3H, s, H-14),
0.74 (1H, m, H-1). 13C NMR (CDCl3): d 153.7 (C-50), 151.2
(C-20), 137.3 (benzyl), 136.8 (benzyl), 134.5 (C-10), 128.6
(benzyl), 128.5 (benzyl), 128.2 (benzyl), 128.1 (benzyl),
127.9 (benzyl), 127.5 (benzyl), 118.2 (C-60), 113.0 (C-30),
111.8 (C-40), 73.8 (C-8), 71.3 (CH2O-20), 70.5 (CH2O-50),
62.4 (C-9), 56.1 (C-5), 43.4 (C-7), 41.8 (C-3), 40.1 (C-1),
39.2 (C-10), 33.5 (C-13), 33.3 (C-4), 24.9 (C-11), 24.2
(C-12), 21.5 (C-14), 20.2 (C-6), 18.6 (C-2), 15.4 (C-15).
3.2.25. &^)-8-Oxo-12-nordriman-11-acid methyl ester
&&^)-27). A solution of 26 (15.7 g, 62.2 mmol) in 0.75 l
CH2Cl2 was cooled to 08C and pure SnCl4 (26.3 g,
100.8 mmol) was slowly added within 15 min. The reaction
was stirred for 2 h at 08C followed by 16 h at 258C. The
mixture was washed three times with 250 ml of 10% HCl
(08C), 50 ml saturated KHCO3-solution (08C), 50 ml satu-
rated NaCl-solution (08C) and ®ltered through silica gel.
Removement of the solvent gave an orange oil which was
diluted with 30 ml of hexane. The mixture was left over
night at 48C to crystallise. After ®ltration and drying we
obtained (^)-27 (11.3 g, 44.8 mmol, 72%) as colourless
needles;mp 85±86 8C. IR (cm21): 3012 (m), 2955 (s),
2935 (s), 2850 (m), 1745 (s), 1710 (s), 1460 (m), 1440
(m), 1375 (m), 1355 (m), 1260 (m), 1200 (m), 1170 (s),
1115 (m). MS m/z (%): 252 (11, M1z), 237 (5), 234 (20),
221 (19), 219 (22), 206 (7), 205 (19), 177 (12), 163 (10), 137
1
3.2.23. Dihydro-b-ionone &25). b-Ionone (24) (40.5 ml,
38.5 g, 20.0 mmol), ethyldimethylsilane (29 ml, 19 g,
(36), 136 (100), 123 (23), 116 (26). H NMR (CDCl3): d
3.64 (3H, s, CH3O), 3.18 (1H, s, H-9), 2.46 (1H, m, H-7),
2.31 (1H, m, H-7), 1.99 (1H, m, H-6), 1.70 (1H, m, H-6),
1.62 (1H, m, H-1), 1.52 (1H, m, H-2), 1.45 (2H, m, H-2,
H-3), 1.39 (1H, dd, Jˆ12.5, 2.7 Hz, H-5), 1.29 (1H, m, H-3),
1.23 (1H, m, H-1), 1.11 (3H, s, H-15), 0.93 (3H, s, H-13),
0.85 (3H, s, H-14). 13C NMR (CDCl3): d 205.5 (C-8), 168.6
(C-11), 69.9 (C-9), 53.1 (C-5), 51.4 (CH3O), 41.9 (C-10),
41.8 (C-3), 41.2 (C-7), 39.1 (C-1), 33.5 (C-4), 33.4 (C-13),
22.9 (C-6), 21.6 (C-14), 18.5 (C-2), 14.7 (C-15).
22.0 mmol)
and
tris(triphenylphosphane)rhodium(I)
chloride (0.20 mmol) were stirred for 2 h at 50±558C.
After cooling to room temperature 200 ml of 0.1% K2CO3
in MeOH was added. The mixture was stirred for 3 h,
®ltered through silica gel and the solvent was evaporated.
The residue was dried for 2 h at 508C and 20 mbar to obtain
25 (38.5 g, 19.8 mmol, 99%) as a pale yellow oil. IR (cm21):
3000 (m), 2950 (s), 2930 (s), 2870 (m), 1710 (s), 1475 (w),

4308
T. Laube et al. / Tetrahedron 58 -2002) 4299±4309
3.2.26. &^)-Albicanic acid methyl ester &&^)-28). The
Wittig reagent was prepared by heating of methyltriphenyl-
phosphonium bromide (35.7 g, 100 mmol) and NaNH2
(4.88 g, 125 mmol) in 300 ml of toluene for 2.5 h. The
mixture was allowed to cool to room temperature. After
6 h without any disturbance, the clear orange solution
over the white solid was used for the described reaction.
(m), 1020 (s). MS m/z (%): 222 (12, M1z), 207 (8), 204 (9),
191 (6), 189 (13), 137 (100), 123 (25), 109 (21), 95 (41). 1H
NMR (CDCl3): d 4.92 (1H, s, H-12), 4.62 (1H, s, H-12),
3.81 (1H, dd, Jˆ11.0, 9.5 Hz, H-11), 3.74 (1H, dd, Jˆ11.0,
3.8 Hz, H-11), 2.40 (1H, m, H-7), 2.00 (1H, m, H-7), 1.95
(1H, m, H-9), 1.72 (1H, m, H-6), 1.64 (1H, m, H-1), 1.52
(1H, m, H-2), 1.47 (1H, m, H-2), 1.38 (1H, m, H-3), 1.32
(1H, m, H-6), 1.19 (1H, m, H-1), 1.17 (1H, m, H-3), 1.10
(1H, dd, Jˆ12.6, 2.9 Hz, H-5), 0.85 (3H, s, H-13), 0.78 (3H,
s, H-14), 0.69 (3H, s, H-15). 13C NMR (CDCl3): d 147.8
(C-8), 106.3 (C-12), 59.2 (C-9), 58.7 (C-11), 55.2 (C-5),
42.0 (C-3), 39.0 (C-1), 38.9 (C-10), 37.9 (C-7), 33.6 (C-13),
33.4 (C-4), 24.1 (C-6), 21.7 (C-14), 19.2 (C-2), 15.3 (C-15).
A solution of (^)-27 was dissolved in 50 ml of toluene and
mixed slowly with the clear orange solution of the Wittig
reagent. After 1 h the reaction mixture was ®ltered through
silica gel. The solvent was removed and the obtained oil was
taken up in 200 ml of hexane. The mixture is heated for
15 min under re¯ux and then left to cool to 208C. The
white precipitate of triphenylphosphine oxide was ®ltered
off. Removing the solvent gave (^)-28 (9.59 g, 38.3 mmol,
99%) as a colourless oil. IR (cm21): 3000 (m), 2940 (s),
2870 (m), 2850 (m), 1730 (s), 1650 (m), 1460 (m), 1440
(m), 1390 (m), 1375 (m), 1200 (m), 1170 (s). MS m/z (%):
251 (25), 250 (89, M1z), 235 (68), 219 (11), 191 (29), 179
3.2.29. &2)-Drim-7-en-11-acid methyl ester &2)-30). A
mixture of (1)-28 (614 mg, 2.45 mmol), Pd/CaCO3 (5%
Pd, 313 mg, 0.15 mmol) and Ph3P (36 mg, 0.14 mmol) in
30 ml of ethyl acetate was stirred for 24 h under a H2-
atmosphere. After ®ltration through silica gel and remove-
ment of the solvents the residual oil is further puri®ed by
MPLC (LiChrospherw Si-60 (15 mm);hexane/toluene 3:2,
10 bar, 30 ml/min) to get (2)-30 (437 mg, 1.75 mmol, 71%)
1
(24), 176 (56), 161 (40), 137 (100), 123 (72), 121 (69). H
NMR (CDCl3): d 4.80 (1H, s, H-12), 4.64 (1H, s, H-12),
3.62 (3H, s, CH3O), 2.78 (1H, s, H-9), 2.40 (1H, m, H-7),
2.04 (1H, m, H-7), 1.67 (1H, m, H-6), 1.54 (1H, m, H-1),
1.45 (1H, m, H-2), 1.41 (1H, m, H-2), 1.40 (1H, m, H-6),
1.39 (1H, m, H-3), 1.18 (1H, m, H-3), 1.16 (1H, m, H-1),
1.05 (1H, dd, Jˆ12.7, 2.8 Hz, H-5), 1.03 (3H, s, H-15), 0.85
(3H, s, H-13), 0.81 (3H, s, H-14). 13C NMR (CDCl3): d 172.0
(C-11), 143.8 (C-8), 108.3 (C-12), 63.1 (C-9), 54.6 (C-5),
50.8 (CH3O), 42.2 (C-3), 39.1 (C-1, C-10), 36.3 (C-7), 33.5
(C-13), 33.4 (C-4), 23.3 (C-6), 21.7 (C-14), 18.9 (C-2), 14.2
(C-15).
24
as a colourless liquid. [a]D ˆ225 (c 1.2, CHCl3). IR
(cm21): 2940 (s), 1725 (s) 1465 (m), 1440 (m), 1395 (w),
1330 (w), 1220 (s), 1165 (m), 1040 (w). MS m/z (%): 250
(33, M1z), 127 (38), 124 (56), 109 (100), 105 (19), 95 (20),
91 (19), 81 (18). 1H NMR (CDCl3): d 5.52 (1H, s, H-7), 3.63
(3H, s, CH3O), 2.87 (1H, s, H-9), 1.98 (1H, m, H-6), 1.87
(1H, m, H-6), 1.58 (1H, m, H-1), 1.57 (3H, s, H-12), 1.49
(1H, m, H-2), 1.42 (1H, m, H-3), 1.40 (1H, m, H-2), 1.22
(1H, m, H-1), 1.16 (1H, m, H-5), 1.15 (1H, m, H-3), 0.91
(3H, s, H-15), 0.87 (3H, s, H-14), 0.84 (3H, s, H-13). 13C
NMR (CDCl3): d 173.3 (C-11), 129.1 (C-8), 124.2 (C-7),
62.1 (C-9), 51.0 (CH3O), 49.3 (C-5), 42.0 (C-3), 40.3 (C-1),
36.1 (C-10), 33.3 (C-13), 32.9 (C-4), 23.6 (C-6), 21.9
(C-14), 21.3 (C-12), 18.6 (C-2), 14.8 (C-15).
3.2.27. &1)-Albicanic acid methyl ester &&1)-28). To a
solution of (1)-8 (2.00 g, 8.46 mmol) in 50 ml of MeOH
tetraethylammonium hydroxide (20% in H2O, 7.5 ml,
10.3 mmol) was added. The solvent was removed and the
residue was dissolved in 40 ml of THF. To this solution
dimethyl sulfate (2.4 ml, 26.4 mmol) (CAUTION: Cancer
hazard!) and after 10 min 10 ml of 25% NH3 in H2O was
added and the mixture was stirred for further 15 min. After
addition of 100 ml of H2O the mixture was extracted three
times with Et2O. The combined organic phases were dried
with MgSO4 and ®ltered through silica gel. Removing
the solvent yielded (1)-28 (2.09 g, 8.37 mmol, 99%) as a
3.2.30. &1)-Drim-7-en-11-ol &&1)-31). Compound (1)-31
was prepared as described for (2)-29. After MPLC
(LiChrospherw Si-60 (15 mm);hexane/ethyl acetate 7:1,
14 bar, 15 ml/min) we obtained (1)-31 as waxlike solid
24
(95%). [a]D ˆ120 (c 1.0, CHCl3) Ref. 31: (2)-31:
20
[a]D ˆ220 (c 1.0, CHCl3). IR (cm21): 3640 (m), 3475
(w), 2940 (s), 1475 (m), 1460 (m), 1405 (w), 1380 (w),
1255 (s), 1065 (w). MS m/z (%): 222 (14, M1z), 124 (32),
123 (9), 109 (100), 95 (11). 91 (9), 81 (10), 69 (12), 55 (9).
24
colourless oil;[ a]D ˆ122 (c 1.00, CHCl3).
1
HRMS: Calcd for C15H26O 222.1984. Found 222.1984. H
NMR (CDCl3): d 5.50 (1H, s, H-7), 3.82 (1H, dd, Jˆ11.1,
2.4 Hz, H-11), 3.69 (1H, dd, Jˆ11.1, 4.7 Hz, H-11), 1.94
(2H, m, H-1, H-6), 1.81 (2H, m, H-6, H-9), 1.52 (1H, m,
H-2), 1.42 (1H, m, H-2), 1.38 (1H, m, H-3), 1.15 (2H, m,
H-3, H-5), 1.03 (1H, m, H-1), 0.85 (3H, s, H-14), 0.83 (3H,
s, H-13), 0.81 (3H, s, H-15). 13C NMR (CDCl3): d 132.9
(C-8), 124.0 (C-7), 60.8 (C-11), 57.1 (C-9), 49.7 (C-5), 42.0
(C-3), 39.8 (C-1), 35.9 (C-10), 33.3 (C-13), 32.8 (C-4), 23.5
(C-6), 22.0 (C-14), 21.9 (C-12), 18.7 (C-2), 14.8 (C-15).
3.2.28. &2)-Albicanol) &&2)-29). A solution of (1)-28
(5.14 g, 20.5 mmol) in 100 ml of abs. CH2Cl2 was cooled
to 08C, DIBAH (Aldrich, 1.0 M in abs. CH2Cl2, 50 ml,
50 mmol) was added dropwise. After 30 min the solution
was slowly poured into a mixture of 100 ml of conc. HCl
and 250 g of ice. The organic layer was separated and the
aqueous layer extracted two times with ethyl acetate. The
combined organic layers were washed with sat. KHCO3-
solution, sat. NaCl-solution and dried with Na2SO4. Filtra-
tion through silica gel and removing the solvent yielded
(2)-29 (4.44 g, 20.0 mmol, 98%) as a colourless oil,
which became a waxlike solid after several hours. Crystal-
line (2)-29 was obtained using MeOH for crystallization;
Acknowledgements
24
mp 68±708C [a]D ˆ214 (c 1.0, CHCl3). IR (cm21): 3600
Support of this research by a grant of the Deutsche
Forschungsgemeinschaft (Se-595/9-1) is gratefully
acknowledged.
(w), 3500±3300 (w), 3010 (s), 2930 (s), 2870 (s), 2850 (s),
1640 (m), 1460 (m), 1440 (m), 1390 (w), 1365 (w), 1260

T. Laube et al. / Tetrahedron 58 -2002) 4299±4309
4309
15. Small, G. H.;Engman Minnella, A.;Hall, S. S. J. Org. Chem.
1975, 40, 3151±3152.
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