Total synthesis of the marine sesquiterpene quinones hyatellaquinone and spongiaquinone

Article abstract of DOI:10.1002/hlca.200390158

The synthesis of the marine sesquiterpene quinone (+)-hyatellaquinone (1) was achieved starting from the sesquiterpene aldehyde (+)-albicanal ((+)-3) (Schemes 3 and 4). Coupling of (+)-albicanal with 2,3,5,6-tetramethoxyphenyllithium led to the aryl-sesqu

Full text of DOI:10.1002/hlca.200390158

Helvetica Chimica Acta Vol. 86 (2003)
2009
Total Synthesis of the Marine Sesquiterpene Quinones Hyatellaquinone
and Spongiaquinone
by Andreas Bernet, Jˆrg Schrˆder, and Karlheinz Seifert*
Lehrstuhl f¸r Organische Chemie, NW II, Universit‰t Bayreuth, D-95440 Bayreuth
The synthesis of the marine sesquiterpene quinone (‡)-hyatellaquinone (1) was achieved starting from the
sesquiterpene aldehyde (‡)-albicanal ((‡)-3) (Schemes 3 and 4). Coupling of (‡)-albicanal with 2,3,5,6-
tetramethoxyphenyllithium led to the aryl-sesquiterpene system, which was modified to the target molecule.
Furthermore, the first total synthesis of the marine compound spongiaquinone (2) was carried out starting from
((À)-albicanal (À)-3) in a reaction sequence encompassing a stereoselective CˆC bond hydrogenation and a
one-pot AcOH elimination/demethylation reaction (Schemes 7 and 10). The occurrence of 1,2- and 1,4-
benzoquinone forms of 1 and 2 depends on the pH of the solvent system.
Introduction. The sesquiterpene quinone hyatellaquinone has been isolated from
the alga Peyssonnelia sp. and the marine sponges Hyatella intestinalis [1] and Spongia
sp. [2]. Spongiaquinone has been obtained from the sponges Spongia sp. [2] and
Stelospongia conulata [3]. Sesquiterpene quinones with a 6-hydroxy-3-methoxy-1,4-
benzoquinone moiety like ilimaquinone or mamanuthaquinone show antitumor
activity, inhibition of the HIV1 reverse transcriptase, and immunomodulation [4 7].
Thus, hyatellaquinone and spongiaquinone are attractive candidates for pharmaco-
logical testing. Therefore, we intended to develop an effective synthesis for these
compounds. The absolute configuration of naturally occurring (‡)-(5R,9R,10R)-
hyatellaquinone1) (1) was recently established: a synthesis starting from the
commercially available synthon (‡)-sclareolide led to (À)-(5S,9S,10S)-hyatellaquinone
[8]. Herein we describe the synthesis of (‡)-hyatellaquinone (1) via (‡)-albicanal
(ˆ(‡)-albicanaldehyde; (‡)-3) (Scheme 1). Moreover, the first total synthesis of
spongiaquinone (2) was achieved starting from (À)-albicanal ((À)-3) (Scheme 2). The
Scheme 1. retroSynthesis of 1 Led to (‡)-Albicanal ((‡)-3)
1
)
Sesquiterpene numbering; for systematic names, see Exper. Part.

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Scheme 2. retro-Synthesis of 2 Led to ( À )-Albicanal ((À)-3)
necessary aldehydes (‡)- and (À)-albicanal ((‡)- and (À)-3, resp.) were obtained from
(‡)- and (À)-albicanic acid, which were prepared starting from b-ionone via a known
route [9 11]. Several steps of this procedure were improved [12].
Results and Discussion. Synthesis of Hyatellaquinone (1). (‡)-Albicanal ((‡)-3)
was coupled with 2,3,5,6-tetramethoxyphenyllithium (Scheme 3) to give the benzylic
alcohols 4a,b as a mixture of diastereoisomers, which were deoxygenated to (‡)-6 [12].
Oxidation of (‡)-6 with Ce(NH4)2(NO3)6 in MeCN/H2O under various standard
conditions [8][13] gave erratic results. However, (‡)-6 was oxidized with Ce(N-
Scheme 3
a) 2,3,5,6-Tetramethoxyphenyllithium (1.2 equiv.), THF, À788 (85%). b) 1. Li (25 equiv.), NH3/THF, À788; 2.
NH4Cl (80%). c) Ce(NH4)2(NO3)6 (5 equiv.) in H2O/MeCN, MeCN/DMF (24% of (‡)-7; 34% of (‡)-8).

Helvetica Chimica Acta Vol. 86 (2003)
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Scheme 4
a) HClO4, MeCN/H2O (99%). b) pH 5.2. c) pH 5.6.
H4)(NO3)6 in MeCN/DMF/H2O to the 1,4-benzoquinone (‡)-7 (24%) and the 1,2-
benzoquinone (‡)-8 (34%). Demethylation of the red 1,2-benzoquinone (‡)-8 with
HClO4 in MeCN/H2O yielded the yellow title compound 1a (ˆ1; Scheme 4). The
increase of the pH above 5.2 led to a color change to intense red, corresponding to the
structure 1b. Increasing the pH to above 5.6 resulted in a dark purple solution
containing the corresponding anion 1c and its mesomeric forms. The interconversion of
these three substances is reversible. A similar isomerization of the sesquiterpene
quinone ilimaquinone with the same 1,4-benzoquinone moiety has already been
reported [14]. A comparison of optical rotation and spectroscopic data (MS, NMR) of
1a with the published data of the natural (‡)-hyatellaquinone (1) [1][2] showed good
agreement.
Synthesis of Spongiaquinone (2). The coupling reaction of drimanal ((Æ)-10) with
2,3,4,5-tetramethoxyphenyllithium was not successful due to the instability of (Æ)-10
(Scheme 5). Thus, we looked for another method to synthesize the benzyl alcohols (Æ)-
5a,b.
Scheme 5. Unsuccessful Coupling of Drimanal ((Æ)-10) with 2,3,4,5-Tetramethoxyphenyllithium
Coupling of (Æ)-drimanic acid methyl ester ((Æ)-11) with 2,3,4,5-tetramethoxy-
phenyllithium (Scheme 6) yielded ketone (Æ)-12 (33%). Ester (Æ)-11 could be
reisolated (57%). Varying the reaction conditions did not improve the yield of (Æ)-12.
Reduction of the exocyclic carbonyl group with DIBAL (diisobutylaluminium hydride)

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 6
a) [RhCl(PPh3)3], H2, C6H6/MeOH 2 :1 (84%). b) 2,3,5,6-Tetramethoxyphenyllithium (2 equiv.), THF, 08 (33%
of (Æ)-12, 57% of (Æ)-11. c) DIBAL (5 equiv.), CH2Cl2, 08 (95%).
led to the diastereoisomeric benzyl alcohols (Æ)-5a,b in a very good yield (95%).
Unfortunately, the overall yield of (Æ)-5a,b starting from albicanic acid methyl ester
((Æ)-9) was only 26%.
A successful strategy for the synthesis of 5a,b based on the coupling of (À)-
albicanal ((À)-3) with 2,3,5,6-tetramethoxyphenyllithium to 13a,b under the conditions
described above (Scheme 7). The exocyclic CH2(12)ˆC(8) bond of the benzyl alcohols
13a,b should be stereoselectively hydrogenated to 5a,b with (8S) configuration1). Since
the first attempt of hydrogenation with [RhCl(PPh3)3] as catalyst failed, we tried the
hydrogenation in presence of Pd/C. Stirring a solution of 13a,b under H2 in MeOH/
AcOEt 5 :2 over Pd/C for 1 h at room temperature yielded the benzyl alcohols 5a,b
(94%). The axial configuration of MeÀC(8) of 5a,b was established by NOESY (cross-
peak Me(12)/Me(15)).
Scheme 7
a) 2,3,5,6-Tetramethoxyphenyllithium (1.2 equiv.), THF, À788 (85%). b) Pd/C, H2, MeOH/AcOEt 5 :2 (94%).
The exocyclic (E)-C(9)ˆCH(11)1) bond in (Æ)-14 was introduced by an acid-
catalyzed elimination of H2O from (Æ)-5a,b in the presence of 1,1,1-trichloro-3,3,3-
trifluoropropan-2-one [15] (Scheme 8). To our surprise, a second compound (Æ)-15 was
obtained, which was formed by an unusual drimane-skeleton rearrangement. The
skeleton rearrangement of (Æ)-5a,b could be explained as follows: The benzylic OH
group of (Æ)-5a,b reacts with 1,1,1-trichloro-3,3,3-trifluoropropan-2-one to a hemiketal
that generates, during its acid-catalyzed transformation, a benzylic carbocation. The

Helvetica Chimica Acta Vol. 86 (2003)
2013
latter can react in two different ways: proton elimination from position 9leads to the
desired elimination product (Æ)-14, whereas hydride shift from position 9to the cation
center C(11) followed by the shift of Me(15) to position 9and elimination of H ÀC(5)
results in compound (Æ)-15 (Scheme 8). It is known that aryl-sesquiterpenes bearing a
Me group in the a-position to a CˆC bond can undergo acid-catalyzed rearrangement
including Me-group shifts [14]. Efforts to suppress rearrangement (Æ)-5a,b ! (Æ)-15
by replacing TsOH with pyridinium tosylate did not have the desired effect; only the
reaction time was increased.
Scheme 8
a) 1,1,1-Trichloro-3,3,3-trifluoropropan-2-one (3 equiv.). TsOH, C6H6 (30% of (Æ)-14, 38% of (Æ-15).
Before optimizing the elimination process from 5a,b, we checked the next reaction
step, the oxidation of (Æ)-14 (Scheme 9). Ce(NH4)2(NO3)6 Oxidation of (Æ)-14,
carried out as described above for the synthesis of (‡)-hyatellaquinone (1), did not
result in the desired dimethoxy-1,2-benzoquinone; only the isomeric dimethoxy-1,4-
benzoquinone (Æ)-16 could be isolated in 30% yield. Unexpectedly, we were able to
isolate 4% of (Æ)-spongiaquinone ((Æ)-2). As the C(9)ˆC(11)1) bond seemed to
disturb the oxidation process, we used another strategy: protection of the benzylic OH
group of 5a,b by acetylation followed by oxidation of 17a,b with Ce(NH4)2(NO3)6
(Scheme 10). Acetylation under various standard conditions (N,N-dimethylpyridin-4-
amine (DMAP), pyridine, Ac2O, 24 h, room temperature) gave no turnover. Finally,
acetylation could be achieved under more-vigorous reaction conditions (DMAP,
pyridine, Ac2O, 4 h, reflux) in 78% yield. Oxidation of the benzylic alcohols 17a,b gave,
besides the desired dimethoxybenzoquinones 18a,b and 19a,b (yields 5 and 50%
respectively), also 4% of spongiaquinone (2). Treatment of the dimethoxy-1,2-
benzoquinone 19a,b with acid (HClO4, TsOH) led to elimination of AcOH and
demethylation at position 6'. The use of TsOH gave a higher yield (74%) in comparison
with HClO4 (48%). As described before [2], optical-rotation measurement of
spongiaquinone (2) is impossible. Thus, 2 was transformed into spongiaquinone methyl
ether ((À)-16). A comparison of the spectroscopic data (NMR, MS) of 2 and optical

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 9
a) Ce(NH4)2(NO3)4 in (5 equiv.) H2O/MeCN, MeCN/DMF 1 :1, HClO4/H2O (30% of (Æ)-16, 4% of (Æ)-2).
Scheme 10
a) DMAP (0.2 equiv.), Py, Ac2O (10 equiv.), 4 h, reflux (78% of 17a,b). b) Ce(NH4)2(NO3)6 (5 equiv.) in H2O/
MeCN, MeCN/DMF 2 :1 (5% of 18a,b, 50% of 19a,b. c) HClO4/H2O, MeCN (48%). d) TsOH ¥ H2O (2 equiv.),
benzene (74%). e) Mel (excess), Me2CO, K2CO3.
rotation of (À)-16 with natural spongiaquinone and its methyl ether [2][3] showed
good agreement. The pH-depending isomerization of the benzoquinone moiety of 2 is
the same as that described above for (‡)-hyatellaquinone (1) (see Scheme 4).
Support of this research by a grant of the Deutsche Forschungsgemeinschaft (Se 595/9-1) is gratefully
acknowledged.

Helvetica Chimica Acta Vol. 86 (2003)
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Experimental Part
General. MPLC: Labomatic Laboprep-MPLC unit MD-50/80/100. Flash chromatography (FC): silica gel
Si 60 (40 63 m; Merck). TLC: Merck precoated plates silica gel 60 F254, detection by 5% molybdophosphoric
acid in EtOH (Aldrich Chemicals Ltd). M.p.: Reichert thermomicroscope. Optical rotation: Jasco P-1020
polarimeter. IR: Bruker IFS-48; in cmÀ1 NMR1). Bruker Avance-360, DRX-500; d in ppm, J in Hz; CDCl3 as
solvent and internal standard. MS: Finnigan MAT 8500, 70 eV; in m/z (rel. %).
1. Hyatellaquinone. (11R)/(11S)-11-(2',3',5',6'-Tetramethoxyphenyl)drim-8(12)-en-11-ol (ˆ(aR,1R,4aR,8-
aR)/(aS,1R,4aR,8aR)-Decahydro-5,5,8a-trimethyl-2-methylene-a-(2,3,5,6-tetramethoxyphenyl)naphthalene-1-
methanol; 4a,b). A mixture of 0.96 g (4.9 mmol) of dried 1,2,4,5-tetramethoxybenzene and 0.81 ml (5.3 mmol)
of tetramethylethylenediamine in 60 ml of abs. THF is cooled to À788, and 2.67 ml (5.34 mmol) of 2m BuLi in
hexane is slowly added. After 30 min, a soln. of 0.73 g (3.3 mmol) of (‡)-albicanal ((‡)-3) in 25 ml of THF is
added. Thirty minutes later, 1 ml of sat. NH4Cl soln. is added, and the solvent is evaporated. The residue is
dissolved in MeOH/H2O 80 :20 and the mixture filtered. Further purification is carried out by MPLC (RP-8
column, MeOH/H2O 80 :20): 1.17 g (85%) of 4a,b. White solid. TLC (hexane/AcOEt 7:1): Rf 0.21. As the
product consists of two diastereoisomers, no further spectroscopic characterization was carried out.
(‡)-11-(2',3',5',6'-Tetramethoxyphenyl)drim-8(12)-ene (ˆ(4aR,5R,8aR)-Decahydro-1,1,4a-trimethyl-6-
methylene-5-[(2,3,5,6-tetramethoxyphenyl)methyl]naphthalene; (‡)-6). A soln. of 0.40 g (0.96 mmol) of 4a,b
in 25 ml of dry THF is dropwise added to a stirred soln. of 0.16 g (23 mmol) of Li in liquid ammonia at À788. The
mixture is stirred for 15 min at À 788, 1.5 g of solid NH4Cl is added, NH3 is allowed to evaporate, and AcOEt is
added. After addition of sat. NH4Cl soln. and stirring for 20 min, the org. layer is separated, washed with brine,
and filtered through silica gel. Further purification by MPLC (hexane/AcOEt 9:1) gives 0.31 g (80%) of ( ‡)-6.
White solid. TLC (hexane/AcOEt 4 :1): Rf 0.60. [a]2D4 ˆ ‡34 (c ˆ 1.0, CHCl3). IR: 2930s, 2860m, 2850m, 1645w,
1590m, 1485s, 1460s, 1440m, 1425m, 1380w, 1360w, 1340m, 1240s, 1215s, 1180w, 1125w, 1085s, 1075s, 1060s,
.
‡
1010m. 1H- and 13C-NMR: Table 1. MS: 402 (M , 84), 387 (5), 370 (65), 355 (31), 340 (5), 246 (11), 233 (32),
211 (100), 196 (81), 181 (29), 153 (15), 137 (15), 109 (12), 95 (17), 81 (12), 69 (20), 55 (15), 41 (15).
Ammonium Cerium Nitrate Solution. To a soln. of 4.3 ml of 1.19m Ce(NH4)2(NO3)6 in H2O, 21 ml of H2O
and 25 ml of MeCN are added (ca. 0.1 mol Ce(NH4)2(NO3)6/l).
(‡)-3-(Drim-8'(12')-en-11'-yl)-2,5-dimethoxy-1,4-benzoquinone (ˆ 3-{[(1R,4aR,8aR)-Decahydro-5,5,8a-
trimethyl-2-methylenenaphthalen-1-yl]methyl}-2,5-dimethoxycyclohexa-2,5-diene-1,4-dione; (‡)-7) and (‡)-3-
(Drim-8'(12')-en-11'-yl)-4,5-dimethoxy-1,2-benzoquinone (ˆ 3-{[(1R,4aR,8aR)-Decahydro-5,5,8a-trimethyl-2-
methylenenaphthalen-1-yl]methyl}-4,5-dimethoxycyclohexa-3,5-diene-1,2-dione; (‡)-8). To a soln. of (‡)-6
(0.41 g, 1.02 mmol) in 100 ml of MeCN/DMF 1:1, a soln. of Ce(NH4)2(NO3)6 (50.3 ml, 5.10 mmol) is slowly
added at r.t. The mixture is stirred for 30 min, 100 ml of H2O is added, and the mixture is diluted with Et2O. The
org. layer is washed with H2O and brine, dried (Na2SO4), and evaporated. Further purification by FC (hexane/
AcOEt 2 :1) leads to 92 mg (24%) of (‡)-7 and 131 mg (34%) of (‡)-8.
Data of (‡)-7: Yellow solid. TLC (hexane/AcOEt 7:3): Rf 0.24. M.p. 628. [a]2D4 ˆ ‡40 (c ˆ 0.5, CHCl3). IR:
3022m, 2917w, 2252vw, 1650vw, 1596vw, 1224w, 1203w, 9 05s, 726s, 668m, 645w. 1H- and 13C-NMR: Table 1. MS:
.
‡
372 (100, M ), 357 (20), 340 (39), 255 (20), 241 (21), 216 (33), 203 (32), 189 (41), 182 (29), 69 (26). HR-MS:
‡
372.2301 (C23H32O4 ; calc. 372.2301).
Data of (‡)-8: TLC (hexane/AcOEt 1:1): Rf 0.43. [a]2D5 ˆ ‡103 (c ˆ 1.0, CHCl3). M.p. 1228. 1H- and
13C-NMR: Table 1. IR: 3025m, 3015m, 2972m, 1652w, 1580w, 1365m, 1260w, 1228w, 9 05s, 725s, 651m. MS: 372
.
‡
(92, M ), 190 (17), 189 (100), 182 (78), 167 (20), 154 (17), 153 (20), 119 (14), 69 (21), 41 (14). HR-MS:
‡
372.2301 (C23H32O4 ; calc. 372.2301).
(‡)-Hyatellaquinone (ˆ 3-{[(1R,4aR,8aR)-Decahydro-5,5,8a-trimethyl-2-methylenenaphthalen-1-yl]meth-
yl}-2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione; 1). A soln. of 44 mg (0.118 mmol) of (‡)-8 in 50 ml of
MeCN is treated with 15 ml of 10% HClO4 in H2O. Within 15 20 min, the color of the soln. is changing from
orange red to light yellow. To this mixture, 50 ml of H2O and 40 ml of Et2O are added. The org. layer is washed
with H2O and brine, dried (Na2SO4), and evaporated. The residue is purified by chromatography (silica gel,
AcOEt): 42 mg (99%) of 1. Yellow solid. M.p. 1458. TLC (hexane/AcOEt 1 :1): Rf 0.80. [a]2D4 ˆ ‡15 (c ˆ 0.5,
CHCl3) ([1]: [a]2D4 ˆ ‡15.6 (c ˆ 0.5, CHCl3). IR: 3390 (br.), 3022m, 2927w, 2360w, 1652m, 1647m, 1615m, 1264w,
.
‡
1227m, 1204w, 674w. 1H- and 13C-NMR: Table 1. MS: 358 (44, M ), 207 (17), 190 (17), 189 (100), 169 (23), 168
‡
(49), 137 (17), 95 (17), 69 (20), 41 (12). HR-MS: 358.2144 (C22H30O4 ; calc. 358.2144).
2. Spongiaquinone. ( Æ )-Drimanic Acid Methyl Ester (ˆ(1RS,2RS,4aRS,8aRS)-Decahydro-2,5,5,8a-
tetramethylnaphthalene-1-carboxylic Acid Methyl Ester; (Æ)-11). A soln. of 2.95 g (11.8 mmol) of (Æ)-albicanic
acid methyl ester ((Æ)-9) and 257 mg (0.72 mmol) of [RhCl(Ph3P)3] in 60 ml of benzene and 30 ml of MeOH is

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Table 1. 1H- and 13C-NMR Data of Compounds (‡)-6, (‡)-7, (‡)-8, and 11). Coupling constants J in Hz.
(‡)-6a)
(‡)-7b)
(‡)-8b)
1b)
d(C) d(H)
d(C) d(H)
d(C) d(H)
d(C) d(H)
CH2(1)
CH2(2)
CH2(3)
C(4)
38.5 1.2938.7 1.3938.7 1.36
1.85
38.8 1.36
1.78
1.75
1.76
19.4 1.51
19.6 1.49
1.591.57
19.2 1.52
19.4 1.52
1.57
1.57
42.2 1.18
1.37
42.2 1.22
1.40
42.1 1.21
1.38
33.6
42.1 1.19
1.37
33.6
33.3
33.6
HÀC(5) 55.5 1.17
55.6 1.15
24.5 1.31
1.70
55.5 1.12
24.4 1.2924.5 1.28
1.691.68
38.3 1.90
2.28
148.6
55.5 1.14
CH2(6)
CH2(7)
C(8)
24.5 1.31
1.66
38.5 1.89
2.23
148.8
38.4 1.91
38.4 1.90
2.292.27
148.9
148.8
HÀC(9) 55.7 2.55
55.0 2.26
40.2
54.7 2.27
40.1
54.2 2.35
40.1
C(10)
40.1
CH2(11)
20.1 2.72
19.5 2.47
19.5 2.47
18.8 2.51
(dd, J ˆ 13.4, 2.9),
(dd, J ˆ 13.6, 2.9),
(dd, J ˆ 13.8, 2.9),
(dd, J ˆ 14.0, 3.0),
2.77
2.67
2.60
2.62
(dd, J ˆ 13.4, 10.1)
(dd, J ˆ 13.6, 10.7)
(dd, J ˆ 13.8, 10.8)
(dd, J ˆ 14.0, 10.8)
CH2(12) 106.94.65, 5.00
106.7 4.64, 4.66
106.94.62, 4.65
106.5 4.65 (
s), 4.67 (s)
Me(13)
Me(14)
Me(15)
C(1')
33.6 0.84 (s)
21.7 0.80 (s)
14.1 0.80 (s)
130.6
33.6 0.84 (s)
21.7 0.79( s)
14.1 0.74 (s)
130.9
33.5 0.84 (s)
21.6 0.78 (s)
14.1 0.72 (s)
33.6 0.84 (s)
21.7 0.79( s)
14.0 0.74 (s)
131.4
11.49
C(2')
141.2
182.8
178.8
182.0
C(3')
148.7
158.8
181.0
161.2
HÀC(4') 96.3 6.37 (s)
105.3 5.67 (s)
183.3
101.3 5.63 (s)
166.3
102.1 5.78 (s)
182.5
C(5')
148.7
C(6')
141.2
156.1
158.8
151.5
Me(7')
Me(8')
Me(9')
Me(10')
OH
60.7 3.73 (s)
56.0 3.80 (s)
56.0 3.80 (s)
60.7 3.73 (s)
61.2 4.04 (s)
56.4 3.76 (s)
56.7 3.85 (s)
61.8 3.87 (s)
56.7 3.81 (s)
7.39(br. s)
a) DRX-500 spectrometer. b) Avance-360 spectrometer.
stirred at r.t. for 4 h under H2 at 1 atm. After evaporation, the residue is dissolved in petroleum ether, the soln.
filtrated through silica gel, and the solvent evaporated: 2.20 g (84%) of (Æ)-11. Colorless oil. TLC (hexane/
AcOEt 17:1): Rf 0.45. IR: 2930s, 2870m, 2850m, 1725s, 1460w, 1435w, 1390w, 1265w, 1205m, 1190m, 1175m,
1150m, 1110w. 1H-NMR (500 MHz, CDCl3): 0.90 (HÀC(1)); 1.60 (HÀC(1)); 1.31 (HÀC(2)); 1.38 (HÀC(2));

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1.11 (HÀC(3)); 1.33 (HÀC(3)); 0.74 (HÀC(5)); 1.40 (HÀC(6)); 1.43 (HÀC(6)); 1.55 (HÀC(7)); 1.59
(HÀC(7)); 2.17 (HÀC(8)); 2.20 (HÀC(9)); 1.01 (d, J ˆ 7.3, Me(12)); 0.80 (s, Me(13)); 0.78 (s, Me(14)); 1.18
(s, Me(15)); 3.56 (s, MeO). 13C-NMR (125 MHz, CDCl3): 39.5 (C(1)); 18.1 (C(2)); 42.0 (C(3)); 33.1 (C(4)); 55.9
(C(5)); 17.2 (C(6)); 33.9(C(7)); 31.4 (C(8)); 59.3 (C(9)); 37.3 (C(10)); 174.3 (C(11)); 17.1 (Me(12)); 33.3
.
‡
(Me(13)); 21.5 (Me(14)); 16.1 (Me(15)); 50.7 (MeO). MS: 252 (49, M ), 237 (73), 221 (5), 205 (11), 196 (37),
177 (18), 163 (8), 137 (11), 123 (100), 109(27), 101 (51), 95 (30), 81 (22), 69(22), 55 (14). HR-MS: 252.2089
‡
(C16H28O2 ; calc. 252.2089).
( Æ )-11-(2',3',5',6'-Tetramethoxyphenyl)driman-11-one (ˆ [(1RS,2RS,4aRS,8aRS)-Decahydro-2,5,5,8a-tet-
ramethylnaphthalen-1-yl](2,3,5,6-tetramethoxyphenyl)methanone; (Æ)-12). To a mixture of 1.37 g (6.91 mmol)
of dry 1,2,4,5-tetramethoxybenzene and 1.14 ml (7.61 mmol) of tetramethylethylenediamine in 25 ml of dry
THF, 3.04 ml (7.61 mmol) of 2m BuLi in hexane is dropwise added at 08. After stirring for 30 min, a soln. of
0.92 g (3.45 mmol) of (Æ)-drimanic acid methyl ester ((Æ)-11) in 40 ml of dry THF is added. The mixture is
stirred at 08 for 1 h. Then 2 ml of sat. NH4Cl soln. is added. The org. layer is dried (Na2SO4) and adsorbed on
silica gel. FC (silica gel; hexane/AcOEt 4 :1) gives 0.48 g (33%) of (Æ)-12 and 0.50 g (57%) of educt (Æ)-11. (Æ)-
12: Light yellow oil. TLC (hexane/AcOEt 1:1): Rf 0.54. IR: 3020s, 2938m, 2848w, 2400vw, 2252vw, 1697m,
.
‡
1
1590vw, 1482m, 1252m, 9 08s. H- and 13C-NMR: Table 2. MS: 418 (17, M ), 267 (4), 226 (8), 225 (100), 210
‡
(7),196 (6). HR-MS: 418.2719 (C25H38O5 ; calc. 418.2719).
( Æ )-(11R)/(11S)-11-(2',3',5',6'-Tetramethoxyphenyl)driman-11-ol
(ˆ(aRS,1RS,2RS,4aRS,8aRS)/
(aRS,1SR,2SR,4aSR,8aSR)-Decahydro-2,5,5,8a-tetramethyl-a-(2,3,5,6-tetramethoxyphenyl)naphthalene-1-
methanol; (Æ)-5a,b) by Reduction of ( Æ )-12. Ketone (Æ)-12 (0.37 g, 0.88 mmol) is dissolved in 50 ml of dry
CH2Cl2. The mixture is cooled to 08, and 4.42 ml (4.42 mmol) of 1m diisobutylaluminium hydride (DIBAL) in
CH2Cl2 is added. After stirring for 20 min, the soln. is poured into a mixture of 15 g of ice and 5 ml of conc. HCl
soln. and stirred for additional 5 min. The aq. layer is extracted with AcOEt, and the combined org. layers are
filtered through Na2SO4 and silica gel. The filtrate is evaporated and the residue purified by FC (silica gel,
hexane/AcOEt 4 :1): 0.35 g (95%) of (Æ)-5a,b. Colorless resin. TLC (hexane/Me2CO 4 :1): Rf 0.36. MS: 420 (3,
.
‡
‡
M
), 228 (11), 227 (100), 212 (15), 197 (8). HR-MS: 420.2876 (C25H40O5 ; calc. 420.2876).
(11R)/(11S)-11-(2',3',5',6'-Tetramethoxyphenyl)drim-8(12)-en-11-ol (ˆ(aR,1S,4aS,8aS)/(aS,1S,4aS,8aS)-
Decahydro-5,5,8a-trimethyl-2-methylene-a-(2,3,5,6-tetramethoxyphenyl)naphthalene-1-methanol; 13a,b). As de-
scribed for 4a,b, with (À)-albicanal ((À)-3).
(8S,11R)/(8S,11S)-11-(2',3',5',6'-Tetramethoxyphenyl)driman-11-ol (ˆ(aR,1S,2S,4aS,8aS)/(aS,1S,2S,4aS,8a
S)-Decahydro-2,5,5,8a-tetramethyl-a-(2,3,5,6-tetramethoxyphenyl)naphthalene-1-methanol; 5a,b) by Hydroge-
nation of 13a,b. To a soln. of 1.35 g (3.23 mmol) of 13a,b in 100 ml of MeOH and 40 ml of AcOEt, 0.50 g of 10%
Pd/C is added. The reaction vessel is evacuated and then filled with N2. This procedure is repeated once. The
mixture is stirred for 2 h under H2 (detection of turnover by reversed-phase TLC). After filtration through silica
gel, the solvent is evaporated: 1.27 g (94%) of 5a,b. Colorless resin. Data of 5a,b: see above.
( Æ )-11-(2',3',5',6'-Tetramethoxyphenyl)drim-9(11)-ene (ˆ(2RS,4aRS,8aRS)-Decahydro-2,5,5,8a-tetra-
methyl-1-[(2,3,5,6-tetramethoxyphenyl)methylene]naphthalene; (Æ)-14) and ( Æ )-(1R,2S)/(1S,2R)-
1,2,3,4,5,6,7,8-Octahydro-1,2,5,5-tetramethyl-1-[(2,3,5,6-tetramethoxyphenyl)methyl]-naphthalene ((Æ)-15). A
soln. of 0.44 g (1.04 mmol) of (Æ)-5a,b in 15 ml of benzene is dropwise added to a mixture of 5 mg of
TsOH ¥ H2O and 0.6 ml (2.92 mmol) of 1,1,1-trichloro-3,3,3-trifluoropropan-2-one in 15 ml of benzene. After
heating under reflux for 1 h and cooling to r.t., 40 ml of Et2O and 40 ml of sat. Na2CO3 soln. are added. The org.
layer is separated and filtered through Na2SO4. The filtrate is evaporated and the residue purified by FC (silica
gel, hexane/Me2CO 15 :1): 0.13 g (30%) of (Æ)-14 and 0.16 g (38%) of (Æ)-15 as colorless solids.
Data of (Æ)-14: TLC (hexane/Me2CO 4 :1): Rf 0.60. IR: 3427 (br.), 3018s, 2968w, 2914w, 2846w, 2398w,
.
‡
2360w, 2330w, 1654w, 1261w, 1222m, 1204m, 1095w, 1041w, 669s. 1H- and 13C-NMR: Table 2. MS: 402 (100, M ),
‡
264 (25), 211 (14), 95 (8). HR-MS: 402.2770 (C25H38O4 ; calc. 402.2770).
Data of (Æ)-15: TLC (hexane/Me2CO 4 :1): Rf 0.70. IR: 3103s, 2973w, 2918w, 2844w, 2396w, 2360w, 2336w,
.
‡
1226m, 1200m, 1034w, 663m. 1H- and 13C-NMR: Table 2. MS: 402 (14, M ), 233 (64), 212 (62), 191 (100), 135
‡
(8). HR-MS: 402.2770 (C25H38O4 ; calc. 402.2770).
Ammonium Cerium Nitrate Solution. An 1.19m aq. soln. of Ce(NH4)2(NO3)6 (1.15 ml) is mixed with 5 ml of
H2O and 5 ml of MeCN.
( Æ )-3-(Drim-9'(11')-enyl)-2,5-dimethoxy-1,4-benzoquinone (ˆ2,4-Dimethoxy-3-[(2RS,4aRS,8aRS)-octa-
hydro-2,5,5,8a-tetramethylnaphthalen-1(2H)-ylidene)methyl]cyclohexa-2,5-diene-1,4-dione; (Æ)-16) and ( Æ )-
Spongiaquinone (ˆ2-Hydroxy-4-methoxy-3-{[(2RS,4aRS,8aRS)-octahydro-2,5,5,8a-tetramethylnaphthalen-
1(2H)-ylidene]methyl}cyclohexa-2,5-diene-1,4-dione; (Æ)-2). To a soln. of 0.11 g (0.27 mmol) of (Æ)-14 in
75 ml of MeCN/DMF 2 :1, 11.2 ml of Ce(NH4)2(NO3)6 soln. (1.37 mmol) is dropwise added. After

2018
Helvetica Chimica Acta Vol. 86 (2003)
Table 2. 1H- and 13C-NMR Data of Compounds of (Æ)-12, (Æ)-14, (Æ)-15, (Æ)-16, and (Æ)-21). Coupling constants J in Hz.
(Æ)-12a)
(Æ)-14b)
(Æ)-15a)
(Æ)-16b)
(Æ)-2b)
d(C) d(H)
d(C) d(H)
d(C) d(H)
d(C) d(H)
d(C) d(H)
CH2(1)
CH2(2)
CH2(3)
38.4 1.17
1.99
18.3 1.37
1.67
42.2 1.14
1.33
38.91.51
1.68
18.91.53
1.70
25.8 1.38
2.05
20.1 1.61 (2 H)
38.5 1.41
1.82
18.7 1.53
1.67
38.5 1.48
1.79
18.91.51
1.67
42.1 1.17
40.1 1.37
41.91.14
41.91.18
1.391.43
1.38
1.36
C(4)
33.2
56.0 0.79
33.9
54.9 0.97
32.9
134.0
33.9
54.3 0.95
34.0
HÀC(5)
or C(5)
CH2(6)
54.4 1.02
17.5 1.45 (2 H)
17.8 1.53
1.56
26.3 1.8917.6 1.53 (2 H) 17.6 1.55 (2 H)
2.12
CH2(7)
34.5 1.46
1.58
33.91.33
1.52
20.6 1.87
2.01
33.6 1.53 (2 H) 33.7 1.55 (2 H)
HÀC(8)
HÀC(9)
or C(9)
C(10)
30.0 2.25
67.1 2.80
(d, J ˆ 3.92)
29.7
32.2 2.74
158.1
33.1 1.80
44.4
32.8 2.48
161.7
33.4 2.52
163.1
40.9
132.4
41.1
41.3
C(11), HÀC(11), 206.0
110.2 5.91 (s)
32.92.64
108.8 5.64 (s)
106.95.53 ( s)
or CH2(11)
(d, J ˆ 12.8),
2.77
(d, J ˆ 12.8)
Me(12)
17.2 1.05
(d, J ˆ 7.4)
33.6 0.80 (s)
21.8 0.82 (s)
17.5 1.33 (s)
149.0
21.3 1.06
20.2 0.74 (s)
21.5 1.03
21.91.08
(d, J ˆ 7.5)
(d, J ˆ 7.5)
(d, J ˆ 7.5)
Me(13)
Me(14)
Me(15)
C(1')
33.4 0.87 (s)
21.8 0.87 (s)
22.4 1.19( s)
128.9
15.1 0.68 (d, J ˆ 6.9) 33.3 0.85 (s)
33.5 0.86 (s)
21.90.87 ( s)
22.4 1.17 (s)
125.5
28.905.9(
s)
21.8 0.85 (s)
22.3 1.16 (s)
124.0
27.8 1.02 (s)
128.3
C(2')
133.3
140.2
142.2
182.3
181.3
C(3')
138.6
148.7
148.6
159.0
161.3
HÀC(4')
98.7 6.49 (s)
96.5 6.42 (s)
96.7 6.42 (s)
105.2 5.78 (s)
102.3 5.84 (s)
C(5')
138.6
133.3
À
148.7
140.2
À
148.6
142.2
À
183.2
154.5
À
182.7
150.2
À
C(6')
À
À
À
À
Me(7')
Me(8')
Me(9')
Me(10')
OH
62.1 3.71 (s)
56.3 3.83 (s)
56.3 3.83 (s)
62.1 3.71 (s)
60.5 3.62 (s)
56.2 3.83 (s)
56.2 3.83 (s)
60.5 3.62 (s)
60.1 3.70 (s)
55.93.83 ( s)
55.93.83 ( s)
60.1 3.70 (s)
61.0 3.95 (s)
56.4 3.79( s)
56.8 3.84 (s)
7.28 (br. s)
a) Avance-360 spectrometer. b) DRX-500 spectrometer.

Helvetica Chimica Acta Vol. 86 (2003)
2019
disappearance of (Æ)-14 (TLC control), 15 ml of 10% HClO4 soln. is added, and the soln. is stirred for 15 min.
To the mixture, 100 ml of H2O and 50 ml of Et2O are added, the org. layer is washed with H2O and brine, dried
(Na2SO4), and evaporated, and the residue purified by FC (hexane/AcOEt 4 :1): 30 mg (30%) of (Æ)-16 and
4 mg (4%) of (Æ)-2.
Data of ( Æ )-16: Yellow oil. TLC (hexane/AcOEt 1:1): Rf 0.87. IR: 3019s, 2967w, 2916w, 2852w, 2403w,
2361m, 2335w, 2254w, 1652m, 1263w, 1228m, 1205m, 9 08s, 665s. 1H- and 13C-NMR: Table 2. MS: 373 (46), 372
.
‡
(100, M ), 290 (13), 275 (11), 234 (75), 222 (57), 220 (54), 202 (15), 189 (17), 69 (14). HR-MS: 372.2300
‡
(C23H32O4 ; calc. 372.2301).
Data of ( Æ )-2: Red solid. TLC (hexane/AcOEt 1:1): Rf 0.44. IR: 3687w, 3616w, 3017s, 2976w, 2916w,
2848w, 2401w, 2361w, 2335w, 1653w, 1521w, 1227m, 1205m, 1046w, 9 30w, 669m. 1H- and 13C-NMR: Table 2. MS:
.
‡
359(32), 358 (100, M ), 342 (93), 220 (71), 208 (53), 207 (74), 191 (21), 168 (31), 69 (21). HR-MS: 358.2144
‡
(C22H30O4 ; calc. 358.2144).
(8S,11R)/(8S,11S)-11-(2',3',5',6'-Tetramethoxyphenyl)driman-11-ol Acetate (ˆ(aR,1S,2S,4aS,8aS)/
(aS,1S,2S,4aS,8aS)-Decahydro-2,5,5,8a-tetramethyl-a-(2,3,5,6-tetramethoxyphenyl)naphthalene-1-methanol
Acetate; 17a,b). To a soln. of 0.70 g (1.66 mmol) of 5a,b and 41 mg (0.33 mmol) of DMAP in 15 ml of dry
pyridine, 1.60 ml (16.60 mmol) of Ac2O is added, and the mixture is heated for 4 h under reflux. The cold
mixture is slowly poured into a AcOEt/ice/sat. aq. NaCl soln. 1:1:1 (ca. 60 ml). The aq. layer is extracted twice
with AcOEt and the combined org. phase washed with 0.5m HCl, sat. NaHCO3 soln., and brine, filtered through
Na2SO4, and evaporated. FC (hexane/AcOEt 3 :1) gives 0.60 g (78%) of 17a,b. Colorless glue-like solid. TLC
.
‡
‡
(hexane/Me2CO 4 :1): Rf 0.42. MS: 462 (55, M ), 227 (100), 43 (37), 212 (11). HR-MS: 462.2981 (C27H42 O6
;
calc. 462.2981).
Ammonium Cerium Nitrate Solution. To 1.3 ml of 1.19m Ce(NH4)2(NO3)6 in H2O, 7 ml of H2O and 7 ml of
MeCN are added (ca. 0.1m Ce(NH4)2(NO3)6/l).
(8'S,11'R)/(8'S,11'S)-3-(11'-Acetoxydriman-11'-yl)-2,5-dimethoxy-1,4-benzoquinone (ˆ 3-{(1R)/(1S)-(Acet-
yloxy)[(1S,2S,4aS,8aS)-decahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]methyl}-2,5-dimethoxycyclohexa-2,4-di-
ene-1,4-dione; 18a,b) and (8'S,11'R)/(8'S,11'S)-3-(11'-Acetoxydriman-11'-yl)-4,5-dimethoxy-1,2-benzoquinone
(ˆ 3-{(1R)/(1S)-(Acetyloxy)[(1S,2S,4aS,8aS)-decahydro-2,5,5,8a-tetramethylnaphthalen-1-yl]methyl}-4,5-di-
methoxycyclohexa-3,5-diene-1,2-dione; 19a,b). To a soln. of 0.15 g (0.32 mmol) of 17a,b in 30 ml of MeCN/DMF
2 :1, 15.4 ml of Ce(NH4)2(NO3)6 soln. (1.62 mmol) is dropwise added, and the mixture is stirred for 15 min.
After addition of 50 ml of H2O and 50 ml of Et2O, the org. layer is washed with H2O and brine, dried (Na2SO4),
and evaporated, and the residue purified by FC (hexane/AcOEt 3 :1): 18 mg (5%) of 18a,b, 70 mg (50%) of
19a,b, and 5 mg (4%) of spongiaquinone (2).
.
‡
Data of 18a,b: Yellow oil. TLC (hexane/Me2CO 4 :1): Rf 0.31. MS: 432 (1, M ), 372 (12), 240 (30), 221
‡
(12), 123 (9), 198 (100), 69 (9). HR-MS: 432.2512 (C 25H36O6 ; calc. 432.2512).
Data of 19a,b: Red solid. TLC (hexane/Me2CO 4 :1): Rf 0.22. MS: 432 (5, M ), 372 (90), 234 (26), 212
(27), 210 (34), 198 (81), 170 (100), 168 (34), 69 (27), 43 (27). HR-MS: 432.2512 (C25H36O6 ; calc. 432.2512).
.
‡
‡
Spongiaquinone (ˆ2-Hydroxy-4-methoxy-3-{[(2S,4aS,8aS)-octahydro-2,5,5,8a-tetramethylnaphthalen-
1(2H)-ylidene]methyl}cyclohexa-2,5-diene-1,4-dione; 2). Method A: Demethylation of 19a,b by Perchloric
Acid. To a soln. of 30 mg (0.07 mmol) of 19a,b in 15 ml of MeCN, 10 ml of 10% HClO4 soln. is added. The color
of the soln. is changing from orange red to yellow. After stirring for 1 h, the mixture is diluted with 60 ml of
brine/H2O/Et2O 1:1:1 and the org. layer filtered through Na2SO4. Further purification by FC (hexane/AcOEt
1:1) yields 12 mg (48%) of 2. Red solid. Data of (Æ)-2, see above.
Method B: Demethylation of 19a,b by TsOH ¥ H2O. A soln. of 26 mg (0.06 mmol) of 19a,b and 24 mg
(0.13 mmol) of TsOH ¥ H2O in 20 ml of dry benzene is stirred for 2 h at 358. For purification, the mixture is
adsorbed on silica gel and submitted to FC (hexane/AcOEt 1:1): 16 mg (74%) of 2. Red solid. M.p. 1588 ([3]:
M.p. 159 160 8). Data for (Æ)-2, see above.
Spongiaquinone Methyl Ether ((ˆ(2,4-Dimethoxy-3-{[(2S,4aS,8aS)-octahydro-2,5,5,8a-tetramethylnaph-
thalen-1(2H)-ylidene]methyl}cyclohexa-2,5-diene-1,4-dione; (À)-16). To a mixture of 20 mg (0.06 mmol) of 2 in
20 ml of Me2CO saturated with K2CO3, 0.03 ml (0.56 mmol) of MeI is added, and the mixture is stirred for 24 h
at r.t. After addition of 1 ml of 1m NaOH in H2O and stirring for 30 min, the mixture is adsorbed on silica gel and
submitted to FC (hexane/AcOEt 1:1): 20 mg (95%) of (À)-16. Yellow oil. For optical-rotation measurements
the compound is purified by MPLC (hexane/AcOEt 4 :1) and dried under high vacuum. [a]2D3 ˆ À82 (c ˆ 1.0,
CHCl3) ([2]: [a]D ˆ À82 (c ˆ 0.5, CHCl3). Data for (Æ)-16, see above.

2020
Helvetica Chimica Acta Vol. 86 (2003)
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Received September 30, 2002