First total synthesis of the mastigophorenes C and D and of simplified unnatural analogs

Article abstract of DOI:10.1016/S0040-4020(00)01131-5

The first total synthesis of the mastigophorenes C (2) and D (3), natural 'dimeric' sesquiterpenes isolated from the liverwort Mastigophora diclados with interesting biological activities, is described. As previously for mastigophorenes A (1) and B, the divergent synthetic approach was first optimized on a simplified model system with a tert-butyl group instead of the chiral cyclopentyl residue, also in order to find more easily available compounds with similar or even improved biological activity.

Full text of DOI:10.1016/S0040-4020(00)01131-5

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1269±1275
First total synthesis of the mastigophorenes C and D and of
simpli®ed unnatural analogs
Gerhard Bringmann,p Thomas Pabst, Petra Henschel and Manuela Michel
È È È È
Institut fur Organische Chemie, Universitat Wurzburg, Am Hubland, D-97074 Wurzburg, Germany
Received 17 November 2000; accepted 4 December 2000
AbstractÐThe ®rst total synthesis of the mastigophorenes C (2) and D (3), natural `dimeric' sesquiterpenes isolated from the liverwort
Mastigophora diclados with interesting biological activities, is described. As previously for mastigophorenes A (1) and B, the divergent
synthetic approach was ®rst optimized on a simpli®ed model system with a tert-butyl group instead of the chiral cyclopentyl residue, also in
order to ®nd more easily available compounds with similar or even improved biological activity. q 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
C2-symmetric sidechain±sidechain coupled analog mastigo-
phorene D (3). All mastigophorenes are biosynthetically
formed from a joint monomeric precursor, herbertenediol
(4), by oxidative phenolic coupling.2,3,5 The mastigo-
phorenes A (1), B, and D (3) exhibit neurotrophic activity
and are therefore interesting structures for new therapeutic
agents against neurodegenerative diseases.2,6,7 Mastigo-
phorene C (2) and herbertenediol (4), by contrast, have
negative effects on the growth of nerve cells.2 Stimulated
The mastigophorenes are novel `dimeric' sesquiterpenes
from the liverwort Mastigophora diclados (Mastigo-
phoraceae).1±4 Besides the core±core coupled, axially chiral
natural biaryl product mastigophorene A (1) and its atropo-
diastereomer mastigophorene B (not shown), the constitu-
tionally asymmetric core±sidechain linked isomer mastigo-
phorene C (2) was isolated, as well as the again
Figure 1. Natural sesquiterpenes 1±5 from liverworts and simpli®ed unnatural analogs thereof.
Keywords: mastigophorene C; mastigophorene D; natural products; sesquiterpenes.
Corresponding author. Tel.: 149-931-888-5323; fax: 149-931-888-4755; e-mail: bringman@chemie.uni-wuerzburg.de
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01131-5

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G. Bringmann et al. / Tetrahedron 57 (2001) 1269±1275
Scheme 1. Synthesis of 7 and 8, as analogs of mastigophorenes C (2) and D (3). Reaction conditions: (a) NBS, CHCl3, 83%; (b) CaCO3, H2O/dioxan; (c) MnO2,
CH2Cl2, 94% from 11; (d) n-BuLi, THF, 60%; (e) TiCl4, Zn, THF, 58%; (f) H2, Pd/C, 95%; (g) BBr3, CH2Cl2, 91%; (h) NaBH4, CF3COOH, 89%; (i) BBr3,
CH2Cl2, 73%.
by these bioactivities, we have recently developed methods
for the stereoselective total synthesis of herbertenediol (4)8
and for the atropisomer-selective synthesis of mastigo-
phorenes A (1) and B.8,9 In order to ®nd simpli®ed and
more easily available structures with similar or even better
activities, we have, starting from the achiral herbertenediol
analog 9, prepared the novel model mastigophorene 6 and
some derivatives,10 which were found to be active, too.11 In
these simpli®ed compounds, the chiral cyclopentyl residue
is replaced by a tert-butyl group. Here we present a short
synthesis of the achiral simpli®ed analogs 7 and 8 of the
mastigophorenes C (2) and D (3) and the ®rst total synthesis
of the natural products 2 and 3 themselves. In this context,
the naturally occurring12 aldehyde 5 has been prepared for
the ®rst time, too (Fig. 1).
synthesis and, simultaneously, getting simpli®ed analogs
with perhaps even better bioactivities. For a short and
rational synthesis of both target molecules, 7 and 8, from
a joint synthetic precursor, aldehyde 13 was chosen as the
starting material.
Compound 13 was synthesized in three smooth reaction
steps from the O,O-dimethylated herbertenediol analog
10,8 by sidechain bromination with NBS, hydrolysis and
subsequent oxidation with MnO2. Transformation of the
known10 building block 14 to the corresponding aryl lithium
reagent and reaction with 13 gave the (racemic) diaryl-
carbinol 15 as the main product, despite the high steric
hindrance in 14. As side products, 13 (unreacted starting
material) and 10 (formed from 14 by hydrodehalogenation)
were isolated and could be recycled, thus increasing the
overall yield. Reductive deoxygenation of 15 with NaBH4/
CF3COOH13 smoothly led to the still tetra-O-methylated
analog 17. Ultimate deprotection with BBr3 gave the simpli-
®ed analog 7 of mastigophorene C (2).
2. Results and discussion
Suitable synthetic strategies for the preparation of 2 and 3
were ®rst developed on the model system, thus saving the
more precious authentic chiral material for the ultimate
`Dimerization' of the same aldehyde 13 under the conditions

G. Bringmann et al. / Tetrahedron 57 (2001) 1269±1275
1271
Scheme 2. First total synthesis of mastigophorenes C (2) and D (3) and of the aldehyde 5. Reaction conditions: (a) NBS, CHCl3; (b) CaCO3, H2O/dioxan;
(c) MnO2, CH2Cl2, 55% from 18; (d) n-BuLi, THF, 58%; (e) TiCl4, Zn, THF; (f) H2, Pd/C, 67% from 19; (g) BBr3, CH2Cl2, 95%; (h) NaBH4, CF3COOH, 83%;
(i) BBr3, CH2Cl2, 94%; (j) BBr3, CH2Cl2, 92%.
of a McMurry coupling,14 with subsequent catalytic hydro-
genation of the resulting stilbene, led to the sidechain±side-
chain coupled product 16 in an overall 55% yield.
Subsequent O-demethylation with BBr3 gave the mastigo-
phorene D analog 8 (Scheme 1).
worked out for the simpli®ed analog 8, McMurry coupling
of 19 and hydrogenation led to 22, whose O-demethylation
completed the straightforward synthesis of mastigophorene
D (3). The spectroscopic data of 3 were again in full
accordance with those reported in the literature.1,2
The application of this synthetic strategy to the preparation
of the authentic natural target molecules, 2 and 3, is shown
in Scheme 2. In full analogy to the model system above, the
joint synthetic precursor to both natural products, compound
19, was prepared from herbertenediol dimethylether (18),
which was available from previous total syntheses.8,15
Arylation of 19 with lithiated 208 gave 21 as a diastereo-
meric mixture, which, in analogy to the reaction sequence
described above, was deoxygenated to 23 and O-demethyl-
ated to mastigophorene C (2). The product obtained was
found to be in full agreement with the data published for
the natural product.1,2 Likewise according to the protocol
From the key aldehyde 19 even a third synthetically as yet
unattained natural product could be prepared (Scheme 2):
simple deprotection of 19 with BBr3 gave 5, a natural
`monomeric' sesquiterpene from the liverwort Herbertus
aduncus.12
The presented total synthesis of mastigophorenes C (2) and
D (3) and the preparation of their simpli®ed analogs 7 and 8
provides suf®cient quantities for extended biological tests,
which are now under investigation. In addition, the syn-
theses rigorously con®rm the structures and absolute con-
®gurations of the natural products.

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G. Bringmann et al. / Tetrahedron 57 (2001) 1269±1275
3. Experimental
5-tert-butyl-3,4-dimethoxybenzyl alcohol (12): mp 738C;
IR (®lm): n~ 3300, 3260 (OH), 2960, 2940, 2820 (C±H),
1
1140, 1070, 1010; H NMR (250 MHz, CDCl3): dˆ1.38
3.1. General
[s, 9H, C(CH3)3], 3.87 (s, 6H, OCH3), 4.62 (s, 2H,
CH2OH), 6.87±6.89 (m, 2H, Ar±H); 13C NMR (63 MHz,
CDCl3): dˆ30.49 [C(CH3)3], 35.07 [C(CH3)3], 55.70, 60.36
(OCH3), 65.74 (CH2OH), 109.5, 117.5, 135.33, 143.3,
148.0, 153.3 (Ar±C); MS: m/z (%)ˆ224 (49) [M1], 209
(100) [M12CH3], 194 (37) [2092CH3]; Anal. calcd for
C13H20O3 (224.3): C, 69.61; H, 8.99. Found C, 69.25; H,
8.88.
Melting points were measured on
a Reichert-Jung
Thermovar hot-plate and are uncorrected. IR spectra were
taken on a Perkin±Elmer 1420 infrared spectrophotometer
and are reported in wave numbers (cm21). NMR spectra
were recorded with a Bruker AC 200, AC 250, or AMX
400 spectrometer. The chemical shifts d are given in parts
per million (ppm) with the proton signals in the deuterated
solvent as the internal reference for H and 13C NMR.
1
3.1.3. (rac)-4,50-Di-tert-butyl-6-methyl-2,3,30,40-tetrameth-
oxy-diphenylmethanol (15). To a cooled (08C) solution of
116 mg (403 mmol) 14 and 73 ml (806 mmol) TMEDA
(N,N,N0,N0-tetramethylethylenediamine) in dry THF
(3 ml), 177 ml (443 mmol) of n-BuLi (2.5 M in n-hexane)
were added. After 20 min of stirring a solution of 98.5 mg
(443 mmol) 13 in 3 ml dry THF was added dropwise. The
obtained solution was stirred for 1 h at 08C and then at room
temperature overnight. The reaction mixture was quenched
with water and 2N HCl and extracted with Et2O. The extract
was dried (Na2SO4), the solvent was evaporated, and the
obtained residue was fractionated by column chromato-
graphy on silica gel (petroleum ether/Et2O 10:1!1:1) to
yield 104 mg (60% relative to 14) of 15 as an oil, besides
29.2 mg (30%) of 13 and 26.0 mg (31% relative to 14) of 10.
IR (®lm): n~ 3420 (OH), 2920, 2840, 2800 (C±H), 1560,
1440, 1290, 1220, 1060; 1H NMR (250 MHz, CDCl3):
dˆ1.29 [s, 9H, C(CH3)3], 1.37 [s, 9H, C(CH3)3], 2.32 (s,
3H, CH3), 3.34 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.82 (s,
3H, OCH3), 3.85 (s, 3H, OCH3), 4.20 (d, Jˆ10.7 Hz, 1H,
CHOH), 6.72 (dd, Jˆ2.1 Hz, Jˆ0.9 Hz, 1H, 20-H or
60-H), 6.87 (d, Jˆ0.6 Hz, 1H, 5-H), 6.90 (dd, Jˆ2.0 Hz,
Jˆ0.8 Hz, 1H, 20-H or 60-H); 13C NMR (63 MHz, CDCl3):
dˆ19.61 (ArCH3), 30.48, 30.49 [C(CH3)3], 34.88, 35.06
[C(CH3)3], 55.73, 59.35, 59.51, 60.33 (OCH3), 71.65
(CHOH), 108.3, 116.0, 123.6 (Ar±CH), 130.0,
134.0,139.3, 142.5, 143.0, 147.2, 151.0, 151.8, 153.0
(Ar±C); MS: m/z (%)ˆ430 (38) [M1], 373 (17)
[M12C3H9], 235 (100) [CH3C6H(C4H9)(OCH3)2CO1],
207 (19) [CH3C6H(C4H9)(OCH3)21], 57 (19) [C3H91];
Anal. calcd for C26H38O5 (430.6): C, 72.53; H, 8.90.
Found: C, 72.25; H, 9.00.
Coupling constants, J, are reported in Hertz. The mass
spectra were obtained on Finnigan MAT 8200 and MAT
90 mass spectrometers at 70 eV in the EI mode.
3.1.1. 5-Bromomethyl-3-tert-butyl-1,2-dimethoxybenzene
(11). To a solution of 1.00 g (4.80 mmol) 10 in 50 ml
CCl4, 850 mg (4.80 mmol) NBS and 250 mg (1.03 mmol)
(PhCOO)2 were added. After re¯uxing overnight the
reaction mixture was cooled, ®ltered, and washed with
water. The extract was dried (Na2SO4) and the residue
obtained after evaporation of the solvent was puri®ed by
column chromatography on silica gel (petroleum ether/
Et2O 10:1), to give 1.15 g (83%) of 11 as an oil: IR (®lm):
n~ 2970, 2920, 2840, 2800 (C±H), 1300, 1130, 1050, 1000;
1H NMR (250 MHz, CDCl3): dˆ1.38 [s, 9H, C(CH3)3], 3.87
(s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.49 (s, 2H, CH2Br),
6.87 (d, Jˆ2.1 Hz, 1H, Ar±H), 6.93 (d, Jˆ2.1 Hz, 1H,
Ar±H); 13C NMR (63 MHz, CDCl3): dˆ30.39 [C(CH3)3],
34.76 (CH2Br) 35.05 [C(CH3)3], 55.71, 60.34 (OCH3),
111.3, 119.7, 132.0, 143.4, 148.7, 153.2 (Ar±C); MS: m/z
(%)ˆ288/286 (3/3) [M1], 207 (100) [M12Br], 193 (70)
[2072CH2], 178 (46) [1932CH3]; Anal. calcd for
C13H19BrO2 (287.2): C, 54.37; H, 6.67. Found: C, 54.73;
H 6.78.
3.1.2. 5-tert-Butyl-3,4-dimethoxybenzaldehyde (13). To a
solution of 1.00 g (3.48 mmol) 11 in a mixture of 25 ml
water and 25 ml dioxan, 1.74 g (17.4 mmol) CaCO3 were
added. The solution was re¯uxed overnight, then acidi®ed
with 2N HCl and extracted with CH2Cl2. The dried
(Na2SO4) extract was concentrated to ca. 150 ml and, after
addition of 3.10 g (35.7 mmol) MnO2, the reaction mixture
was warmed to 308C with ultrasonic irradiations. After
complete reaction the mixture was ®ltered and puri®ed by
column chromatography on silica gel (petroleum ether/Et2O
4:3) to yield 13 (726 mg, 97%) as colorless oil. IR (KBr): n~
3050, 2940, 2850 (C±H), 1680 (CvO), 1375, 1302, 1225,
1000; 1H NMR (250 MHz, CDCl3): dˆ1.41 [s, 9H,
C(CH3)3], 3.92 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 7.35
(d, Jˆ1.8 Hz, 1H, 2-H or 6-H), 7.46 (d, Jˆ1.8 Hz, 1H,
2-H or 6-H), 9.88 (s, 1H, CHO); 13C NMR (63 MHz,
CDCl3): dˆ30.23 [C(CH3)3], 35.27 [C(CH3)3], 55.84,
60.60 (OCH3), 109.1, 123.8, 131.3, 143.2, 153.8, 154.3
(Ar±C), 191.7 (CvO); MS: m/z (%)ˆ222 (54) [M1], 207
(100) [M12CH3], 192 (23) [2072CH3], 179 (36)
[2072CO]; Anal. calcd for C13H18O3 (222.3): C, 70.24;
H, 8.16. Found: C, 69.96; H, 7.93.
3.1.4. 4,50-Di-tert-butyl-6-methyl-2,3,30,40-tetramethoxy-
diphenylmethane (17).
A
suspension of 22.0 mg
(576 mmol) NaBH4 in 1 ml tri¯uoroacetic acid was stirred
for 15 min. Then a solution of 62.0 mg (144 mmol) 15 in
tri¯uoroacetic acid (5 ml) was added dropwise at room
temperature. After stirring for 2 h the mixture was cooled,
diluted with water, and NaOH was added. The mixture was
extracted with Et2O, the extract was washed with brine,
dried over Na2SO4, and the solvent was removed under
reduced pressure. Column chromatography on silica gel
(petroleum ether/Et2O 5:1) gave 17 (53.2 mg, 89%) as
colorless oil. IR (KBr): n~ 2930, 2840, 2810 (C±H), 1560,
1440, 1290, 1230, 1060, 1040; 1H NMR (250 MHz, CDCl3):
dˆ1.32 [s, 9H, C(CH3)3], 1.38 [s, 9H, C(CH3)3], 2.22 (s, 3H,
CH3), 3.71 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.82 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 3.93 (s, 2H, CH2), 6.63 (d,
Jˆ2.0 Hz, 1H, 20-H or 60-H), 6.72 (d, Jˆ2.0 Hz, 1H, 20-H
or 60-H), 6.85 (s, 1H, 5-H); 13C NMR (50 MHz, CDCl3):
Optional workup after hydrolysis and column chroma-
tography on silica gel (petroleum ether/Et2O 1:1) and
subsequent crystallization from petroleum ether gave

G. Bringmann et al. / Tetrahedron 57 (2001) 1269±1275
1273
dˆ19.75 (ArCH3), 30.60, 30.63 [C(CH3)3], 32.45 (CH2),
34.82, 34.98 [C(CH3)3], 55.66, 59.79, 59.91, 60.39
(OCH3), 110.9, 118.9, 123.4 (Ar±CH), 131.3, 131.5,135.5,
141.3, 142.7, 146.2, 150.7, 151.9, 153.0 (Ar±C); MS: m/z
(%)ˆ414 (100) [M1], 399 (14) [M12CH3], 353 (14)
[M12C4H9], 221 (42) [CH3C6H(C4H9)(OCH3)2CH21], 207
(40) [CH3C6H(C4H9)(OCH3)21], 57 (48) [C4H91]; Anal.
calcd for C26H38O4 (414.6): C, 75.32; H, 9.24. Found: C,
74.68; H, 8.95.
tert-butyl-30,40-dimethoxyphenyl)ethene in 10 ml EtOH
and 10 ml ethyl acetate, 50 mg Pd/C (10%) were added
and the mixture was hydrogenated with H2 at atmospheric
pressure. After complete reaction (TLC) the solvent was
removed in vacuo and the obtained residue was submitted
to column chromatography on silica gel (petroleum ether/
Et2O 5:1) and to crystallization from n-hexane, to yield
pure 16 (296 mg, 95%): mp 1188C; IR (KBr): n~ 3040,
2980, 2920, 2840, 2800 (C±H), 1560, 1400, 1310, 1240,
1055, 1000; 1H NMR (250 MHz, CDCl3): dˆ1.35 [s,
18H, C(CH3)3], 2.84 (s, 4H, CH2), 3.82 (s, 6H, OCH3),
3.85 (s, 6H, OCH3), 6.59 (d, Jˆ1.8 Hz, 2H, 20-H or 60-H),
6.67 (d, Jˆ2.1 Hz, 2H, 20-H or 60-H); 13C NMR (63 MHz,
CDCl3): dˆ30.61 [C(CH3)3], 35.01 [C(CH3)3], 38.16 (CH2),
55.68, 60.35 (OCH3), 110.9, 118.8 (Ar±CH), 136.3, 142.8,
146.5, 152.9 (Ar±C); MS: m/z (%)ˆ414 (16) [M1], 207
(100) [(C6H2(OCH3)2C(CH3)3CH21]; Anal. calcd for
C26H38O4 (414.6): C, 75.32; H, 9.24. Found: C, 75.07; H,
8.96.
3.1.5. 4,50-Di-tert-butyl-6-methyl-2,3,30,4-tetrahydroxy-
diphenylmethane (7). To a cooled (08C) solution of
35.0 mg (84.5 mmol) 17 in 10 ml dry CH2Cl2, 370 ml
(370 mmol) of a BBr3 solution (1 M in CH2Cl2) was
added. After complete reaction (TLC), the solution was
quenched with MeOH, the solvent was removed under
reduced pressure, and the residue was puri®ed by column
chromatography on silica gel (petroleum ether/Et2O 4:3).
Crystallization from n-hexane gave 22.2 mg (73%) of 7:
mp 1628C; IR (KBr): n~ 3460 (OH), 3010, 2940, 2880,
2840 (C±H), 1580, 1420, 1300, 1220, 1190, 970; 1H
NMR (200 MHz, CDCl3): dˆ1.40 [s, 9H, C(CH3)3], 1.41
[s, 9H, C(CH3)3], 2.26 (s, 3H, CH3), 3.87 (s, 2H, CH2),
6.34 (d, Jˆ2.2 Hz, 1H, 20-H or 60-H), 6.72 (s, 1H, 5-H),
6.72 (d, Jˆ2.1 Hz, 1H, 20-H or 60-H); 13C NMR
(100 MHz, CDCl3): dˆ19.73 (ArCH3), 29.52, 29.63
[C(CH3)3], 32.29 (CH2), 34.36, 34.68 [C(CH3)3], 112.3,
119.3, 120.2 (Ar±CH), 123.5, 126.9, 129.4, 134.1,
137.0, 141.8, 141.9, 142.0, 143.3 (Ar±C); MS: m/z
(%)ˆ358 (60) [M1], 193 (83) [CH3C6H(C4H9)(OH)2CH21],
192 (100) [CH3C6H(C4H9)(OH)2CH1], 177 (52)
[CH3C6H2(C4H9)(OH)21]; exact mass calcd for C22H30O4:
358.2144. Found: 358.2145.
3.1.8. 1,2-Bis-(50-tert-butyl-30,40-dihydroxyphenyl)ethane
(8). To a cooled (08C) solution of 100 mg (241 mmol) 16
in 15 ml dry CH2Cl2, 92.0 ml (968 mmol) BBr3 were
added. After 3 h of stirring the reaction was quenched
with MeOH, the solvent was removed in vacuo and the
obtained residue was puri®ed by column chromatography
on silica gel (Et2O). Crystallization from n-hexane gave
79.0 mg (91%) 8 as a colorless solid: mp 194±1968C; IR
(KBr): n~ 3460, 3410 (OH), 2930, 2880, 2840 (C±H), 1575,
1
1420, 1290; H NMR [250 MHz, (CD3)2CO]: dˆ1.37 [s,
18H, C(CH3)3], 2.67 (s, 4H, CH2), 6.56 (d, Jˆ1.5 Hz, 2H,
20-H or 60-H), 6.60 (d, Jˆ1.8 Hz, 2H, 20-H or 60-H); 13C
NMR [63 MHz, (CD3)2CO]: dˆ29.76 [C(CH3)3], 34.94
[C(CH3)3], 38.55 (CH2), 113.6, 118.5 (Ar±CH), 132.7,
135.9, 142.7, 144.7 (Ar±C); MS: m/z (%)ˆ358 (10) [M1],
179 (100) [C6H2(OH)2C(CH3)3CH21]; Anal. calcd for
C22H30O4 (358.5): C, 73.71; H, 8.44. Found: C, 73.18; H,
8.34.
3.1.6. (E)-1,2-Bis-(50-tert-butyl-30,40-dimethoxyphenyl)-
ethene. To a stirred suspension of 1.10 g (16.9 mmol)
zinc powder in 11 ml dry THF, 780 ml (7.19 mmol) TiCl4
were added dropwise at 2108C. Then this mixture was
heated to re¯ux and a solution of 576 mg (2.59 mmol) 13
in 23 ml dry THF was added slowly. After 24 h of re¯uxing
the reaction was quenched with saturated aqueous NaHCO3
solution, the organic solvent was removed under reduced
pressure and the remaining layer was extracted with Et2O.
The extract was dried (MgSO4), concentrated in vacuo,
and the obtained residue was puri®ed by column chro-
matography on silica gel (petroleum ether/Et2O 5:1).
Crystallization from petroleum ether gave 310 mg (58%)
of (E)-1,2-bis-(50-tert-butyl-30,40-dimethoxyphenyl)ethene
as colorless crystals: mp 157±1608C; IR (KBr): n~ 2980,
2925, 2840, 2800 (C±H), 1560, 1315, 1245, 1060, 1000;
1H NMR (250 MHz, CDCl3): dˆ1.41 [s, 18H, C(CH3)3],
3.89 (s, 6H, OCH3), 3.92 (s, 6H, OCH3), 6.94 (s, 2H,
CvCH), 7.00 (d, Jˆ2.1 Hz, 2H, 20-H or 60-H), 7.03 (d,
Jˆ2.1 Hz, 2H, 20-H or 60-H); 13C NMR (63 MHz, CDCl3):
dˆ30.54 [C(CH3)3], 35.13 [C(CH3)3], 55.77, 60.48
(OCH3), 107.8 (CvC), 118.0, 127.7 (Ar±CH), 132.3,
143.3, 148.3, 153.4 (Ar±C); MS: m/z (%)ˆ412 (100)
[M1], 397 (29) [M12CH3], 57 (35) [C4H91]; Anal. calcd
for C26H36O4 (412.6): C, 75.69; H, 8.80. Found: C, 75.72; H,
8.56.
3.1.9. (10S)-3,4-Dimethoxy-5-(1,2,2-trimethylcyclopentyl)-
benzaldehyde (19). To a solution of 400 mg (1.52 mmol)
18 in 20 ml CCl4, 271 mg (1.52 mmol) NBS and 73.9 mg
(305 mmol) (PhCOO)2 were added. After re¯uxing for 3 h
the reaction mixture was cooled, ®ltered, and washed with
water. The extract was dried (MgSO4) and, after evaporation
of the solvent, the obtained residue was puri®ed by column
chromatography on silica gel (petroleum ether/Et2O 10:1),
to give a light yellow oil of 5-bromomethyl-1,2-dimethoxy-
3-(1,2,2-trimethylcyclopentyl)benzene, which was directly
dissolved in 13 ml dioxan. To this solution, 13 ml water and
763 mg (7.62 mmol) CaCO3 were added and the mixture
was heated to re¯ux overnight. The reaction mixture was
acidi®ed with 2N HCl and extracted with CH2Cl2. The dried
(Na2SO4) extract was concentrated to about 60 ml and, after
addition of 1.32 g (15.2 mmol) MnO2, the reaction mixture
was warmed to 408C with ultrasonic irradiation. After
completion of the reaction (TLC) the mixture was ®ltered
and puri®ed by column chromatography on silica gel (petro-
leum ether/Et2O 4:3) to yield 19 (230 mg, 55%) as a color-
less oil: [a]23 ˆ262.7 (cˆ0.91 in CHCl3); IR (KBr): n~
D
3040, 2930, 2850, 2800, 2700 (C±H), 1675 (CvO), 1130;
1H NMR (200 MHz, CDCl3): dˆ0.68 (s, 3H, CH3), 1.14 (s,
3H, CH3), 1.36 (s, 3H, CH3), 1.39±1.91 (m, 5H, 30-, 40-H,
3.1.7. 1,2-Bis-(50-tert-butyl-30,40-dimethoxyphenyl)ethane
(16). To a solution of 310 mg (751 mmol) (E)-1,2-bis-(50-

1274
G. Bringmann et al. / Tetrahedron 57 (2001) 1269±1275
50-CHH), 2.53±2.67 (m, 1H, 50-CHH), 3.87 (s, 3H, OCH3),
3.90 (s, 3H, OCH3), 7.31 (d, Jˆ1.8 Hz, 1H, Ar±H), 7.49 (d,
Jˆ1.9 Hz, 1H, Ar±H), 9.85 (s, 1H, CHO); 13C NMR
(50 MHz, CDCl3): dˆ20.28 (CH2), 23.79, 25.22, 26.86
(CH3), 39.23, 41.02 (CH2), 44.90, 51.69 (C-10 and C-20),
55.75, 60.48 (OCH3), 108.5, 126.3, 130.9, 141.2, 153.9,
154.7 (Ar±C), 191.6 (CvO); MS: m/z (%)ˆ276 (86)
[M1], 245 (87) [M12OCH3], 206 (57) [M12C5H10], 194
(96) [M12C6H10], 193 (73) [M12C6H11], 191 (100)
[M12C6H13], 165 (54) [1942CHO], 163 (69) [1912CO];
Anal. calcd for C17H24O3 (276.4): C, 72.88; H, 8.75. Found:
C, 73.53; H, 8.48.
as a colorless foam. [a]23 ˆ247.3 (cˆ0.69 in CHCl3)
D
{Lit.2 [a]23 ˆ246.7 (cˆ0.4 in CHCl3)}.
D
3.1.12. (1000,1000S)-1,2-Bis-[50-(1,2,2-trimethylcyclopentyl)-
30,40-dimethoxyphenyl]ethane (22). To a cooled (2108C)
suspension of 155 mg (2.37 mmol) zinc powder in 1.6 ml of
dry THF, 110 ml (1.01 mmol) TiCl4 were added slowly. The
reaction mixture was heated to re¯ux and a solution of
100 mg (362 mmol) 19 in 3 ml dry THF was added drop-
wise. After re¯uxing for 2 h the mixture was cooled and
quenched with saturated aqueous NaHCO3 solution, the
organic solvent was removed under reduced pressure and
the remaining layer was extracted with Et2O. The dried
(MgSO4) extract was puri®ed by column chromatography
on silica gel (petroleum ether/Et2O 5:1) to yield a colorless
solid. This was directly dissolved in a mixture of 2 ml EtOH
and 2 ml ethyl acetate and hydrogenated with H2 and with
Pd/C (10%) as the catalyst under atmospheric pressure.
After complete reaction (TLC) the mixture was puri®ed
by ®ltration through silica gel (petroleum ether/Et2O 5:1)
to yield 22 as a colorless solid (63.0 mg, 67%): mp 1018C
3.1.10. (100,1000S)-4,50-Bis-(1,2,2-trimethylcyclopentyl)-6-
methyl-2,3,30,40-tetramethoxy-diphenylmethane (23). To
a
solution of 89.7 mg (263 mmol) 20 and 48 ml
(532 mmol) TMEDA in dry THF (3 ml), 116 ml
(289 mmol) of an n-BuLi solution (2.5 M in n-hexane)
were added at 08C. After stirring for 20 min, 80.0 mg
(289 mmol) of the aldehyde 19, dissolved in 2 ml of dry
THF, were added dropwise. The reaction mixture was stir-
red for 1 h at 08C and overnight at room temperature, then
quenched with water and 2N HCl, and extracted with Et2O.
The solvent was evaporated and the obtained residue was
fractionated by column chromatography on silica gel (petro-
leum ether/Et2O 10:1) to yield 82.0 mg (58% relative to 20)
of the expected product 21 as an oil, besides 26.7 mg (33%)
of 19 and 29.8 mg (42% relative to 20) of 18. The obtained
oil was dissolved in CF3COOH (2 ml) and added dropwise
to a solution of 22.5 mg (595 mmol) NaBH4 in 2 ml
CF3COOH. After stirring for 3 h, the reaction mixture was
diluted with water, and 2.9 g of solid NaOH were added.
Extraction with Et2O, drying with MgSO4, and puri®cation
by column chromatography on silica gel (petroleum ether/
Et2O 5:1) gave 23 (64.8 mg, 83%) as a colorless oil.
(n-hexane); [a]23 ˆ 222.3 (cˆ1.0 in CHCl3); IR (KBr): n~
D
1
2920, 2840 (C±H), 1560, 1450, 1400, 1050, 1000, 830; H
NMR (250 MHz, CDCl3): dˆ0.67 (s, 6H, CH3), 1.09 (s, 6H,
CH3), 1.34 (s, 6H, CH3), 1.39±1.83 (m, 10H, 30-, 40-H, 50-
CHH), 2.64±2.49 (m, 2H, 50-CHH), 2.84 (s, 4H, CH2) 3.76
(s, 6H, OCH3), 3.78 (s, 6H, OCH3), 6.51 (d, Jˆ2.0 Hz, 2H,
Ar±H), 6.71 (d, Jˆ2.0 Hz, 2H, Ar±H); 13C NMR (63 MHz,
CDCl3): dˆ20.38 (CH2), 24.21, 25.19, 26.75 (CH3), 38.00
(ArCH2), 38.92, 40.80 (CH2), 44.99, 51.59 (C-10 and C-20),
55.62, 60.35 (OCH3), 110.6, 121.2, 135.4, 140.1, 147.0,
153.0 (Ar±C); MS: m/z (%)ˆ522 (65) [M1], 440 (13)
[M12C6H10], 261 (100) [C6H2(OCH3)2(C8H13)CH21], 179
(60) [2612C6H10]; Exact mass calcd for C34H50O4:
522.3709. Found: 522.3714.
[a]23 ˆ228.6 (cˆ0.89 in CHCl3); IR (®lm): n~ 2940,
D
2840 (C±H), 1560, 1440, 1400, 1380, 1050, 1000; 1H
NMR (400 MHz, CDCl3): dˆ0.63 (s, 3H, CH3), 0.72 (s,
3H, CH3), 0.97 (s, 3H, CH3), 1.15 (s, 3H, CH3), 1.30 1.39
(s, 3H, CH3), 1.47±1.84 (m, 10H, 300-, 3000-, 400-, 4000-H, 500-,
5000-CHH), 2.39±2.49 (m, 1H, 500-CHH or 5000-CHH),
2.57±2.70 (m, 1H, 500-CHH or 5000-CHH), 3.63 (s, 3H,
OCH3), 3.76 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.81 (s,
3H, OCH3), 3.93±4.02 (m, 2H, a-CH2) 6.54 (d, Jˆ1.8 Hz,
1H, 20- or 60-H), 6.67 (d, Jˆ1.8 Hz, 1H, 20- or 60-H), 6.92
(s, 1H, 5-H); 13C NMR (100 MHz, CDCl3): dˆ19.67
(ArCH3), 20.23, 20.44 (CH2), 24.07, 24.40, 24.94, 25.24,
26.25, 26.84 (CH3), 32.08 (a-CH2), 38.86, 38.95, 40.59,
40.87 (CH2), 44.88, 45.06, 51.43, 51.60 (Cq), 55.52,
59.76, 59.89, 60.40 (OCH3), 110.3, 120.6, 125.5, 131.0,
134.6, 138.5, 140.0, 146.7, 151.1, 152.1, 153.2 (Ar±C);
MS: m/z (%)ˆ522 (100) [M1], 440 (11) [M12C6H10],
275 (21) [C6H(OCH3)2(C8H13)CH3CH21], 261 (11)
[C6H(OCH3)2(C8H13)CH31]; Exact mass calcd for
C34H50O4: 522.3709. Found: 522.3704.
3.1.13. Mastigophorene D (3). To a cooled (08C) solution
of 31.0 mg (59.4 mmol) 22 in 3 ml dry CH2Cl2, 238 ml
(238 mmol) of a BBr3 solution (1 M in CH2Cl2) were
added. After 1 h of stirring at 08C and 1 h at room tempera-
ture the reaction was quenched with MeOH, the solvent was
removed in vacuo, and the obtained residue was puri®ed by
®ltration through silica gel (Et2O/petroleum ether 1:1).
Crystallization from n-hexane gave 26.2 mg (95%) 3 as a
colorless solid: mp 213±2168C (Lit.2 201±2038C);
[a]23 ˆ248.2 (cˆ0.50 in CHCl3) {Lit.2 [a]23 ˆ246.1
D
D
(cˆ0.5 in CHCl3)}.
3.1.14. (10S)-3,4-Dihydroxy-5-(1,2,2-trimethylcyclopen-
tyl)benzaldehyde (5). To a cooled (08C) solution of
24.7 mg (89.4 mmol) 19 in dry CH2Cl2 (2 ml), 300 ml of a
BBr3 solution (1 M in CH2Cl2) were added. The stirred
solution was allowed to warm up to RT and stirring was
continued overnight. Then MeOH was added, the solvent
was evaporated, and the residue was puri®ed by column
chromatography on silica gel (petroleum ether/Et2O 1:1).
The obtained solid was crystallized from CH2Cl2 to yield
20.3 mg (92%) of 5 as colorless needles: mp 1548C (Lit.12
3.1.11. Mastigophorene C (2). To a cooled (08C) solution
of 26.0 mg (49.8 mmol) of tetramethylether 23 in dry
CH2Cl2 (3 ml), 200 ml of BBr3 (1 M in CH2Cl2) were
added. After 3 h of stirring the reaction was quenched
with MeOH, the solvent was removed under reduced pres-
sure, and the residue was puri®ed by ®ltration through silica
gel (petroleum ether/Et2O 1:1), giving 21.8 mg (94%) of 2
153±1558C); [a]23 ˆ276.6 (cˆ0.56 in CHCl3) {Lit.12
D
[a]23 ˆ211 (cˆ1.5 in CHCl3)}; authentic sample of 5
D
from Herbertus aduncus12,17 [a]23 ˆ276.1 (cˆ0.50 in
D
CHCl3).

G. Bringmann et al. / Tetrahedron 57 (2001) 1269±1275
1275
6. Hefti, F. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 239±267.
7. Skaper, S. D.; Walsh, F. S. Mol. Cell. Neurosci. 1998, 12,
179±193.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
(SFB 347 `Selektive Reaktionen Metall-aktivierter
MolekuÈle') and the Fonds der Chemischen Industrie is
gratefully acknowledged.
8. Bringmann, G.; Pabst, T.; Henschel, P.; Kraus, J.; Peters, K.;
Peters, E.-M.; Rycroft, D. S.; Connolly, J. D. J. Am. Chem.
Soc. 2000, 122, 9127±9133.
9. Bringmann, G.; Hinrichs, J.; Pabst, T.; Henschel, P.; Peters,
K.; Peters, E.-M. Synthesis 2001 155±167.
References
10. Bringmann, G.; Pabst, T.; Busemann, S.; Peters, K.; Peters,
E.-M. Tetrahedron 1998, 54, 1425±1438.
1. Fukuyama, Y.; Toyota, M.; Asakawa, Y. J. Chem. Soc., Chem.
Commun. 1988, 1341±1342.
11. Gille, G.; Pabst, T.; Janetzky, B.; Bringmann, G.; Reichmann,
H.; Rausch, W.-D. Drug Dev. Res. 2000, 50, 153±156.
12. Buchanan, M. S.; Connolly, J. D.; Rycroft, D. S. Phyto-
chemistry 1996, 43, 1245±1248.
2. Fukuyama, Y.; Asakawa, Y. J. Chem. Soc., Perkin Trans. 1
1991, 2737±2741.
3. Asakawa, Y. In Progress in the Chemistry of Organic Natural
Products; Herz, W., Kirby, G. W., Moore, R. E., Steglich, W.,
Tamm, C., Eds.; Springer: Vienna, 1995; Vol. 65.
4. More recently the mastigophorenes A, B, and C were also
isolated from the liverwort Herbertus sakuraii; Irita, H.;
Hashimoto, T.; Fukuyama, Y.; Asakawa, Y. Phytochemistry
2000, 247±253.
13. Gribble, G. W.; Leese, R. M. Synthesis 1977, 172±176.
È
14. Dyker, G.; Korning, J.; Stirner, W. Eur. J. Org. Chem. 1998,
139±148 (and references cited therein).
15. For a partial synthesis of 19 from the natural aldehyde 5 as
isolated from Herbertus aduncus,12 see Ref. 16.
16. Bringmann, G.; Pabst, T.; Rycroft, D. S.; Connolly, J. D.
Tetrahedron Lett. 1999, 40, 483±486.
5. Mechanistically, an intermediate transformation of a phenoxy
radical into a benzyl radical has been postulated in the case of
the side chain couplings.2,3
17. A sample of 5 isolated from Herbertus aduncus was kindly
provided by Professor J. D. Connolly.