Synthesis of geranyl phenyl ethers based on the cytotoxic monoterpenoids from the liverwort genus Trichocolea

Article abstract of DOI:10.1021/np980031w

The synthesis of three geranyl ethers, methyl 4-[{(2E)-3,7-dimethyl-5- oxo-2,6-octadienyl}oxy]3-methoxybenzoate (1), methyl 4-[{(2E)-3,7- dimethyl-2,6-octadienyl}oxy]-3-methoxybenzoate (2), and methyl 4-[{(2E)- 3,7-dimethyl-2,6-octadienyl}oxy]-3-hydroxybenzoate (3), previously isolated from New Zealand Trichocolea liverworts, is described. Differing reactivity of the hydroxy groups of methyl protocatachuate toward alkylation and the ability of alkyl groups to migrate from oxygen to an ortho-oxygen in these benzene derivatives are noted.

Full text of DOI:10.1021/np980031w

J . Nat. Prod. 1998, 61, 1143-1145
1143
Syn th esis of Ger a n yl P h en yl Eth er s Ba sed on th e Cytotoxic Mon oter p en oid s
fr om th e Liver w or t Gen u s Tr ich ocolea
Seung-Hwa Baek,† Nigel B. Perry,‡ and Rex T. Weavers*,‡
Plant Extracts Research Unit, New Zealand Institute for Crop & Food Research Limited, Department of Chemistry, University
of Otago, Box 56, Dunedin, New Zealand, and Department of Chemistry, Wonkwang University, Iksan 570-749, Korea
Received J anuary 30, 1998
The synthesis of three geranyl ethers, methyl 4-[{(2E)-3,7-dimethyl-5-oxo-2,6-octadienyl}oxy]-
3-methoxybenzoate (1), methyl 4-[{(2E)-3,7-dimethyl-2,6-octadienyl}oxy]-3-methoxybenzoate
(2), and methyl 4-[{(2E)-3,7-dimethyl-2,6-octadienyl}oxy]-3-hydroxybenzoate (3), previously
isolated from New Zealand Trichocolea liverworts, is described. Differing reactivity of the
hydroxy groups of methyl protocatachuate toward alkylation and the ability of alkyl groups to
migrate from oxygen to an ortho-oxygen in these benzene derivatives are noted.
Sch em e 1. Proposed Alkyl Migrations
Liverworts of the genus Trichocolea (family Trichoco-
laceae) are a treasury of isoprenyl phenyl ethers. We
have reported1 that the main cytotoxic component of T.
mollissima (Hook. F. and Tayl.) Gott. is the 5-oxogeranyl
ether 1. This compound has shown cytotoxic activity
in the U.S. National Cancer Institute’s AIDS-related
lymphoma screens.2
Here we describe the preparation of 1, along with
syntheses of two less-oxidized geranyl ethers, 2 and 3,
which we have isolated from T. tomentella (Ehrh.)
Dum.1 and T. hatcheri Hodgs.,3 respectively. These
compounds have not been synthesized previously.
The key intermediate in the synthesis of 1 is a geranyl
halide that has appropriate functionality at C-5 and is
suitable for alkylating methyl vanillate. The inexpen-
sive and commercially available 3-methyl-2-butenoic
acid is readily converted into its acid chloride by reaction
with excess thionyl chloride.4 This compound has been
converted previously into 8-chloro-2,6-dimethyl-2,6-oc-
tadien-4-one (4) by treatment with isoprene in the
presence of tin (IV) chloride.5 Both 4 and the corre-
sponding bromide were able to be stored for short
periods at low temperature, but decomposed rapidly and
spontaneously, presumably when concentrations of HBr
or HCl had built up to a critical level. When freshly
prepared 4 or the bromide was used in an attempted
alkylation of methyl vanillate, the only products identi-
fied were ocimenones (5). To avoid loss of halide from
the alkylating agent, via either enolic or enolate species,
4 was reduced to alcohol 6. This compound could be
reacted satisfactorily with methyl vanillate to yield the
5-hydroxygeranyl ether (7), which, upon oxidation by
pyridinium chlorochromate-alumina,6 formed the de-
sired natural product 1 in about 30% yield. Synthetic
however, uncovered some interesting chemistry. Reac-
tion of methyl 3,4-dihydroxybenzoate (methyl protocat-
echuate) with geranyl bromide and sodium hydride in
DMF at 0° gave a monogeranyl ether, which proved to
be identical to the natural product 3 from T. hatcheri.3
Also obtained was the double alkylation product 8.
When the reaction was conducted at room temperature,
however, compound 8 and a new monogeranyl ether 9
were obtained. Compound 9 had very similar 1H and
13C NMR spectra to those of 3 but differed significantly
in the pattern of the two overlapping signals for the
protons ortho to the carboxymethyl group (δ 7.5-7.7)
in the 1H NMR spectrum. The phenolic OH signals also
differed considerably (δ 5.7 in 3 and δ 6.1 in 9). As 3
had already been established as having the 4-gerany-
loxy-3-hydroxy substitution pattern by NOE studies,3
the new compound was deemed to be the 3-geranyloxy-
3-hydroxy isomer 9. It appears that 3 is the kinetically
favored product, corresponding to alkylation of the more
acidic 4-hydroxyl group. Compound 9 might arise
through the intermediacy of the dialkyl compound 8 or
through an alkyl migration. Equilibrium should favor
formation of the more stabilized 4-oxyanion (Scheme 1),
and this would lead to the 3-geranyloxy compound. This
latter proposal was supported by the surprising obser-
vation that methylation of either 3 or 9 (with methyl
iodide and potassium carbonate in DMF) led to the same
4-geranyl-3-methoxy product, 2. It appears that, under
these reaction conditions, migration of the geranyl group
does indeed occur, with the reaction being completed
by preferential alkylation of the less stabilized and more
nucleophilic 3-oxyanion. In a similar fashion, alkylation
of methyl 3-hydroxy-4-methoxybenzoate with geranyl
bromide gave a mixture consisting of mainly the 3-gera-
nyloxy-4-methoxy compound 10, along with a small
percentage of its isomer 2, the result of methyl migra-
1
1 proved to be identical (TLC, IR, H and 13C NMR) to
the natural product isolated from T. mollissima.1
Geranyl phenyl ether 2, identical to that isolated from
T. tomentella,1 was readily obtained in good yield by
reaction of methyl vanillate with geranyl bromide. The
synthesis of the corresponding phenolic compound 3,
* To whom correspondence should be addressed. Tel.: +64-3-
4797925. Fax: +64-3-4797906. E-mail: rweavers@alkali.otago.ac.nz.
† Department of Chemistry, Wonkwang University.
‡ Department of Chemistry, University of Otago.
S0163-3864(98)00031-7 CCC: $15.00
© 1998 American Chemical Society and American Society of Pharmacognosy
Published on Web 07/25/1998

1144 J ournal of Natural Products, 1998, Vol. 61, No. 9
Notes
tion. Such migrations of alkyl groupings between ortho-
positioned oxygens on a benzene ring are unusual and
are probably facilitated by the electron-withdrawing
carboxymethyl grouping.
4.10 (2H, d, 8 Hz, H-8), 4.50 (1H, m, H-4), 5.17 (1H, br
d, 8 Hz, H-3), 5.55 (1H, br t, 8 Hz, H-7); 13C NMR
(CDCl3, 50 MHz) δ 18.2/22.6 (each q, 2-Me, 6-Me), 25.7
(q, C-1), 40.6 (t, C-8), 47.6 (t, C-5), 66.5 (d, C-4), 123.5/
127.3 (each d, C-3, 7), 127.3 (C-2), 135.3/139.2 (each s,
C-2,6).
Gen er a l P r oced u r e for P r ep a r a tion of Ger a n yl
P h en yl Eth er s. A solution of the alkyl halide in dry
DMF was added dropwise with stirring to a flame-dried
flask containing the phenolic esters and NaH under N2.
The mixture was stirred at the specified temperature
for the specified time, following which the reaction
mixture was partitioned between H2O and CH2Cl2. The
H2O fraction was re-extracted with CH2Cl2, the organic
fractions combined, dried with anhydrous MgSO4, and
the solvent removed under reduced pressure. Flash
chromatography afforded the geranyl phenyl ethers.
Conditions are summarized as: product, phenolic ester
(mass, mmol); alkyl halide (mass, mmol); NaH (mass,
mmol); DMF (vol); reaction temperature; reaction time;
data.
Meth yl 4-[{(2E)-3,7-d im eth yl-5-h yd r oxy-2,6-octa -
d ien yl}oxy]-3-m eth oxyben zoa te (7): methyl vanil-
late (88 mg, 0.48 mmol); 8-chloro-2,6-dimethyl-2,6-
octadien-4-ol (110 mg, 0.58 mmol); NaH (60%, 19.2 mg,
0.48 mmol) in dry DMF (0.5 mL); 20 °C; 26 h. Flash
chromatography (5% EtOAc-hexane) gave 7 (125 mg,
78%); colorless oil; TLC Rf 0.13 (blue with anisalde-
hyde-H2SO4); anal. C 68.26%, H 7.64%, calcd for
C19H26O5, C 68.26%, H 7.78%; IR (film) 3426, 2924,
1714, 1599, 1513, 1435, 1271, 1219, 1135, 990, 764 cm-1
;
Exp er im en ta l Section
1H NMR (CDCl3, 300 MHz) δ 1.69 (3H, d, J ) 2 Hz,
7′-Me), 1.71 (3H, d, J ) 1 Hz, H-8′), 1.80 (3H, d, J ) 1
Hz, 3′-Me), 2.23 (2H, m, H-4′), 3.89 (3H, s, 1-COOMe),
3.92 (3H, s, 3-OMe), 4.51 (1H, dt, J ) 5, 8 Hz, H-5′),
4.70 (2H, d, J ) 6 Hz, H-1′), 5.16 (1H, br d, J ) 8 Hz,
H-6′), 5.60 (1H, br d, J ) 7 Hz, H-2′), 6.87 (1H, d, J )
8 Hz, H-5), 7.55 (1H, d, J ) 2 Hz, H-2), 7.65 (1H, dd, J
) 2, 8 Hz, H-6); 13C NMR (CDCl3, 75 MHz) δ 17.1 (q,
3′-Me), 18.2 (q, 7′-Me), 25.7 (q, C-8′), 47.8 (t, C-4′), 51.9
(q, 1-COOMe), 56.0 (q, 3-OMe), 65.6 (t, C-1′), 66.4 (d,
C-5′), 111.8 (d, C-5), 112.2 (d, C-2), 122.4 (d, C-2′), 122.6
(s, C-1), 123.4 (d, C-6), 127.4 (d, C-6′), 135.2 (s, C-7′),
138.0 (s, C-3′), 149.0 (s, C-3), 152.1 (s, C-4), 166.8 (s,
1-COOMe).
Gen er al Exper im en tal P r ocedu r es. Melting points
were determined on a Kofler hot stage and are uncor-
rected. 1H and 13C NMR spectra were recorded using
Varian Gemini-200 and Varian VXR-300 spectrometers
for CDCl3 solutions referenced to either CHCl3 (1H, δH,
7.27) or CDCl3 (13C, δc 77.08). Multiplicities of the 13C
NMR signals were determined from the DEPT spectra,
and spectral assignments were based on those for
compounds already reported in this series.1,3 Elemental
analyses were performed by the Campbell Microana-
lytical Laboratory, Otago University. IR spectra were
recorded on a Perkin-Elmer 1600 FTIR spectropho-
tometer. TLC was carried out on Si gel 60 F254 pre-
coated 0.2-mm aluminum sheet (Merck 5562). Devel-
oped plates were visualized by UV light and by staining
with solution of either 1% anisaldehyde + 2% H2SO4 in
AcOH or 1% vanillin + 1% H2SO4 in EtOH. Flash
chromatography was carried out with Si gel 230-400
mesh.
8-Ch lor o-2,6-d im eth yl-2,6-octa d ien -4-ol (6). A so-
lution of 8-chloro-2,6-dimethyl-2,6-octadien-4-one (4)5
(140 mg, 0.75 mmol) in dry THF (0.25 mL) was added
to absolute EtOH (2.5 mL). The mixture was cooled to
-40 °C and NaBH4 (56.5 mg, 1.5 mmol) was added. The
reaction mixture was stirred for 15 min at -40 °C,
allowed to warm to -10 °C, and quenched by the
addition of H2O (50 mL). Et2O (25 mL) was added, the
layers were separated, and the organic layer was
evaporated to dryness. Separation by flash chromatog-
raphy (elution with EtOAc-hexane 25:75) yielded 6 (45
mg, 32%): colorless oil; TLC Rf 0.22 (blue with anisal-
dehyde-H2SO4); 1H NMR (CDCl3, 200 MHz) δ 1.70/1.73/
1.79 (each 3H, s, H-1, 2-Me, 6-Me), 2.23 (2H, m, H-5),
Meth yl 4-[{(2E)-3,7-dim eth yl-2,6-octa dien yl}oxy]-
3-m eth oxyben zoa te (2): methyl vanillate (300 mg,
1.65 mmol); geranyl bromide (295 mg, 1.36 mmol); NaH
(60%, 66 mg, 1.65 mmol) in dry DMF (2 mL); 20 °C; 26
h; flash chromatography (5% EtOAc-hexane) gave 2
(380 mg, 60%); mp 39-40 °C; TLC (25% EtOAc-hexane)
Rf 0.31 (grey with vanillin-H2SO4); anal. C 71.79%, H
8.31%, calcd for C19H26O4, C 71.70%, H 8.18%; identical
1
to the natural product (TLC, IR H and 13C NMR).1
Meth yl 4-[{(2E)-3,7-dim eth yl-2,6-octa dien yl}oxy]-
3-h yd r oxyben zoa te (3): methyl 3,4-dihydroxybenzoate
(278 mg, 1.65 mmol); geranyl bromide (434 mg, 2.00
mmol); NaH (60%, 66 mg, 1.65 mmol) in dry DMF (2
mL); 0 °C; 17 h; flash chromatography (5% EtOAc-
hexane) gave 3 (220 mg, 44%): mp 32-34 °C; TLC (40%
EtOAc-hexane) Rf 0.58 (dark green with vanillin-H2-
SO4); anal. C 71.92%, H 8.61%, calcd for C18H24O4, C
71.05%, H 7.89%; identical to the natural product (TLC,
1
IR, H and 13C NMR).3 Also isolated was methyl 3,4-

Notes
J ournal of Natural Products, 1998, Vol. 61, No. 9 1145
di-[{(2E)-3,7-dimethyl-2,6-octadienyl}oxy]-benzoate (8)
(130 mg, 18%): TLC (40% EtOAc-hexane) Rf 0.47 (dark
green with vanillin-H2SO4); anal. C 76.27%, H 9.35%,
calcd for C28H40O4, C 76.36%, H 9.09%; IR (film) 2920,
1720, 1596, 1514, 1438, 1267, 1208, 1132, 1009, 762
(3H, br s, H-8′), 1.77 (3H, d, J ) 1 Hz, 3′-Me), 2.09 (4H,
m, H-4′,5′), 3.89 (3H, s, 1-COOMe), 3.92 (3H, s, 4-OMe),
4.67 (2H, d, J ) 7 Hz, H-1′), 5.08 (1H, m, H-6′), 5.52
(1H, br t, J ) 7 Hz, H-2′), 6.88 (1H, d, J ) 8 Hz, H-5),
7.56 (1H, d, J ) 2 Hz, H-2), 7.67 (1H, dd, J ) 2, 8 Hz,
H-6); 13C NMR (CDCl3, 50 MHz) δ 16.7 (q, 3′-Me), 17.7
(q, 7′-Me), 25.7 (q, C-8′), 26.3 (t, C-5′), 39.7 (t, C-4′), 52.0
(q, 1-COOMe), 56.0 (q, 4-OMe), 65.9 (t, C-1′), 110.4 (d,
C-5), 113.8 (d, C-2), 119.3 (d, C-2′), 122.6 (s, C-1), 123.5
(d, C-6), 123.9 (d, C-6′), 131.8 (s, C-7′), 141.4 (s, C-3′),
147.9 (s, C-4), 153.4 (s, C-3), 167.0 (s, 1-COOMe).
Meth yl 4-[{(2E)-3,7-d im eth yl-5-oxo-2,6-octa d ien -
yl}oxy]-3-m eth oxyben zoa te (1). Pyridinium chloro-
chromate-alumina6 (1402 mg, 1.14 mmol) was added
to solution of 7 (127 mg, 0.38 mmol) in dry hexane (10
mL). After stirring for 24 h, the mixture was filtered
and washed with Et2O (3 × 10 mL). The combined Et2O
solutions were evaporated. Flash chromatography (elu-
tion with EtOAc-hexane 5:95) yielded 1 (37.8 mg, 30%),
1
cm-1; H NMR (CDCl3, 200 MHz) δ 1.59 (6H, br s, 7′-
Me), 1.66 (6H, br s, H-8′), 1.73/1.76 (each 3H, br s, 3′-
Me), 2.08 (8H, m, H-4′,5′), 3.87 (3H, s, 1-COOMe), 4.66/
4.69 (each 2H, d, J ) 8 Hz, H-1′), 5.08 (2H, m, H-6′),
5.50 (2H, br t, J ) 7 Hz, H-2′), 6.87 (1H, d, J ) 8 Hz,
H-5), 7.56 (1H, d, J ) 2 Hz, H-2), 7.63 (1H, dd, J ) 2, 9
Hz, H 6); 13C NMR (CDCl3, 50 MHz) δ 16.7 (2 × q, 3′-
Me), 17.7 (2 × q, 7′-Me), 25.6/26.2 (each q, C-8′), 26.2/
26.3 (each t, C-5′), 39.5/39.6 (each t, C-4′), 52.0, (q,
1-COOMe), 66.1 (2 x t, C-1′), 112.3 (d, C-5), 114.5 (d,
C-2), 119.5/119.6 (each d, C-2′), 122.4 (s, C-1), 123.5 (d,
C-6), 123.8/123.9 (each d, C-6′), 131.7/131.8 (each s,
C-7′), 140.7/140.8 (each s, C-3′), 148.2 (s, C-3), 152.9 (s,
C-4), 167.0 (s, 1-COOMe).
1
identical to the natural product (TLC, IR, H and 13C
Meth yl 3-[{(2E)-3,7-dim eth yl-2,6-octa dien yl}oxy]-
4-h yd r oxyben zoa te (9): methyl 3,4-dihydroxybenzoate
(278 mg, 1.65 mmol); geranyl bromide (358 mg, 1.65
mmol); NaH (60%, 66 mg, 1.65 mmol) in dry DMF (2
mL); 20 °C; 48 h; flash chromatography (5% EtOAc-
hexane) gave (8) (196 mg, 27%) and 9 (245 mg, 49%);
mp 34-37 °C; TLC (30% EtOAc-hexane) Rf 0.45 (dark
green with vanillin-H2SO4); anal. C 71.05%, H 7.89%,
calcd for C18H24O4, C 71.05%, H 7.89%; IR (film), 3388,
2921, 1709, 1595, 1512, 1438, 1286, 1211, 1126, 988,
NMR).1
Meth yla tion of 3 a n d 9. A mixture of K2CO3 (48.4
mg, 0.35 mmol), CH3I (26.0 mg, 0.18 mmol), and 3 (35.6
mg, 0.12 mmol) in DMF (1.0 mL) was stirred at 20 °C
for 17 h. The reaction mixture was diluted with H2O
and extracted with Et2O. The Et2O layer was washed
with H2O and saturated aqueous NaCl and the H2O
before drying over MgSO4 and evaporation. Preparative
TLC gave 2 (20 mg, 54%). Likewise, reaction of 9 (90
mg) gave 2 (50 mg, 50.4%).
1
764 cm-1; H NMR (CDCl3, 200 MHz) δ 1.62 (3H, br s,
7′-Me), 1.68 (3H, br s, H-8′), 1.77 (3H, br s, 3′-Me), 2.11
(4H, m, H-4′,5′), 3.89 (3H, s, COOMe), 4.66 (2H, d, J )
7 Hz, H-1′), 5.09 (1H, m, H-6′), 5.49 (1H, br t, J ) 7 Hz,
H-2′), 6.12 (1H, s, 4-OH), 6.94 (1H, d, J ) 8 Hz, H-5),
7.57 (1H, d, J ) 2 Hz, H-2), 7.63 (1H, dd, J ) 2, 8 Hz,
H-6); 13C NMR (CDCl3, 50 MHz) δ 16.7 (q, 3′-Me), 17.8
(q, 7′-Me), 25.7 (q, C-8′), 26.3 (t, C-5′), 39.6 (t, C-4′), 52.0
(q, 1-COOMe), 66.0 (t, C-1′), 113.1 (d, C-5), 114.1 (d, C-2),
118.6 (d, C-2′), 122.8 (s, C-1), 123.7 (d, C-6), 124.1 (d,
C-6′), 132.0 (s C-7′), 142.7 (s, C-3′), 145.5 (s, C-4), 150.4
(s, C-3), 167.0 (s, 1-COOMe).
Ack n ow led gm en t. We thank B. May for prelimi-
nary work; E. Sausville, U.S. National Cancer Institute
for AIDS-related lymphoma results; M. Thomas for
NMR spectra; and R. Cunninghame and associates for
microanalyses. This research was supported in part by
both the New Zealand Foundation for Research, Science
and Technology and Wonkwang University.
Refer en ces a n d Notes
(1) Perry, N. B.; Foster, L. M.; Lorimer, S. D.; May, B. C. H.;
Weavers, R. T.; Toyota, M.; Nakaishi, E.; Asakawa, Y. J . Nat.
Prod. 1996, 59, 729-733.
Meth yl 3-[{(2E)-3,7-dim eth yl-2,6-octa dien yl}oxy]-
4-m eth yoxyben zoa te (10): methyl 3-hydroxy-4-meth-
oxybenzoate (1230 mg, 6.76 mmol); geranyl bromide
(1779 mg, 8.19 mmol); NaH (60%, 295 mg, 7.37 mmol)
in dry DMF (8.2 mL); 20 °C; 26 h; flash chromatography
(3% EtOAc-hexane) gave 10 (1503 mg, 70%) (14); mp
40-42 °C; TLC (30% EtOAc-hexane) Rf 0.36 (green
with vanillin-H2SO4); anal. C 71.43%, H 8.17%, calcd
for C19H26O4, C 71.70%, H 8.18%; IR (Nujol) 1720, 1594,
(2) 50% growth inhibition values range from 9.7 × 10-9 to 2.5 ×
10-5 M.; see Skehan, P.; Williamson, K.; Giavazzi, R.; Malspeis,
L.; Camalier, R.; Grever, M. Proc. Annu. Meet. Am. Assoc. Cancer
Res. 1993, 34 (4), A2600.
(3) Baek, S.-H.; Perry, N. B.; Weavers, R. T.; Tangney, R. S. J . Nat.
Prod. 1998, 61, 126-129.
(4) Bergman, J .; Venemalm, L. Tetrahedron Lett. 1987, 28, 3741-
3744.
(5) Adams, D. R.; Bhatnagar, S. P.; Cookson, R. C.; Tuddenham, R.
M. J . Chem. Soc., Perkin Trans. 1 1975, 1741-1743.
(6) Cheng, Y.-S.; Liu, W.-L.; Chen, S.-H. Synthesis 1980, 223-224.
1513, 1463, 1376, 1267, 1218, 1131, 1011, 835, 726 cm-1
1H NMR (CDCl3, 300 MHz) δ 1.60 (3H, br s, 7′-Me), 1.66
;
NP980031W