Synthesis from geraniol of (2E,6E,10E,14E)-16-hydroxygeranylgeraniol and some of its derivatives

Article abstract of DOI:10.1007/s10600-007-0104-3

Several α,ω-bifunctional derivatives of E,E,E-geranylgeraniol were prepared via convergent synthesis starting with geraniol (8), which was converted in three steps into the tetrahydropyranyl ether of 8-chlorogeraniol (9) and 8-hydroxygeranylphenylsulfone (10). Combination of synthons 9 and 10 with subsequent reductive removal of the phenylsulfonyl group produced the tetrahydropyranyl ether of ω-hydroxygeranylgeraniol (5), hydrolysis of which gave exclusively trans-ω-hydroxygeranylgeraniol (1). Derivatives 5-7 of geranylgeraniol were synthesized using standard methods.

Full text of DOI:10.1007/s10600-007-0104-3

Chemistry of Natural Compounds, Vol. 43, No. 3, 2007
SYNTHESIS FROM GERANIOL OF
(2 ,6 ,10 ,14 )-16- HYDROXYGERANYLGERANIOL
E E
E
E
AND SOME OF ITS DERIVATIVES
M. Grin′ko,1 V. Kulcitki,1 N. Ungur,1
A. Barba,1 K. Delyanu,2 and P. F. Vlad1
UDC 547.569/599
α,ω
E E E
-bifunctional derivatives of , , -geranylgeraniol were prepared via convergent synthesis
Several
starting with geraniol (8), which was converted in three steps into the tetrahydropyranyl ether of
8-chlorogeraniol (9) and 8-hydroxygeranylphenylsulfone (10). Combination of synthons 9 and 10
with subsequent reductive removal of the phenylsulfonyl group produced the tetrahydropyranyl ether of
ω
5
ω
1
-hydroxygeranylgeraniol ( ), hydrolysis of which gave exclusively trans- -hydroxygeranylgeraniol ( ).
Derivatives 5-7 of geranylgeraniol were synthesized using standard methods.
Key words: aliphatic diterpenoids, natural compounds, synthesis, combination reaction, alcohols.
Diterpenoids have been isolated from plants, fungi, and marine organisms [1]. Natural aliphatic diterpenoids are
usually monofunctional compounds although certain α,ω-bifunctional representatives are also known. For example, the
biologically active α,ω-bifunctional diterpenoids 1-4 were isolated from the fungus Boletinus cavipes [2]. These compounds
turned out to be inhibitors of peroxide formation in macrophagous cells and can be used to prevent illnesses caused by such
compounds.
OR
1
O
HO C
O
OR
1 - 4
2
2
fumaryloxy group
1: R1 = R2 = H
2: R1 = R2 = fumaryloxy
3: R1 = H, R2 = fumaryloxy
4: R1 = fumaryloxy, R2 = H
Herein we report the synthesis of exclusively trans-16-hydroxygeranylgeraniol (1) and its α,ω-bifunctional
analogs 5-7 (Scheme 1) starting from the commercially available monoterpenol geraniol (8). The synthetic approach to the
α,ω-bifunctional aliphatic diterpenoids 1 and 5-7 consisted of combination of synthons 9 and 10, which were prepared from
the single precursor 8 (Scheme 1). Compound 9 was synthesized in three steps. Protection of the hydroxyl in 8 with
dihydropyran gave tetrahydropyranyl ether 11. The terminal methyl in 11 was selectively oxidized by selenium dioxide to give
hydroxyether 12. Replacement of the hydroxyl in 12 by Cl gave bifunctional derivative 9.
1)InstituteofChemistry, AcademyofSciences ofMoldova, ul. Akademii, 3, MD 2028, Kishinev, RepublicofMoldova,
fax:373-22-73-97-75, e-mail:vlad_p@mail.md;2)InstituteofOrganicChemistry, Romanian Academy, SplayulIndependentsei
202B, Bucharest, Romania. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 231-234, May-June, 2007. Original
article submitted March 9, 2007.
0009-3130/07/4303-0277 ©2007 Springer Science+Business Media, Inc.
277

i
OH
OT HP
8
11
iv
ii
10
5
8
3
R
OTHP
1
7
1
R
R
2
9, 12
10, 13, 14
13: R = Br; R = H
12: R = OH
9: R = Cl
1
2
v
iii
14: R = SO Ph, R = H
1
2
2
vi
10: R = SO Ph, R = OH
1
2
2
vii
20
3
18
5
12
OT HP
OT HP
OH
7
ix
viii
11
1
10
10
17
14
16
9
HO
SO Ph
2
OH
OH
10(11)
9(10)
15
5 ∆
(73%)
(7%)
1
+
x
16 ∆
OTHP
3'
OH
ix
(18%)
1
+
1'
THP =
5'
O
H
OAc
6
7 (59%)
OAc
i. DHP, CH2Cl2, PyTs, 94%; ii. SeO2, EtOH/Py, 58; iii. TsCl, DMAP, Et3N, CH2Cl2, LiCl 93%; iv. PBr3, Et2O, Py, 0° C; v. NaSO2Ph, DMF,
84%, after two steps; vi. SeO2, EtOH, 54%; vii. n-BuLi, THF, -78C to 0°C, 1.5 h, 91%; viii. Na/Hg (6%), Na2HPO4, MeOH, 73%;
ix. p-TsOH, MeOH; x. Ac2O, Py, 99%
Scheme 1.
10
8
8
The second synthon
13
was synthesized from also in three steps. Geraniol ( ) was brominated by phosphorus
14
tribromide to , which was used without further purification to give geranylphenylsulfone ( ) in ~84% yield [3-5]. The
10
10
sulfone was selectivelyoxidized byselenium dioxide in 54% yield into hydroxysulfone . The PMR spectrum of contained
signals for two methyls on double bonds, two vinyl protons, >C–CH O– and –CH – groups next to a –SO Ph group, a vinyl
2
2
2
proton, and signals characteristic of five aromatic protons. These spectral data agreed with those published [5].
10
9
15
The combination of structural fragments and under mild conditions [6] formed racemic diterpene derivative
(91% overall yield). The PMR spectrum of the combination product had signals for four methyls on double bonds, four vinyl
and five aromatic protons, and two hydroxymethylene groups, one of which was isolated and the other, next to a vinyl proton.
15
The spectral data confirmed the structure of
.
15
Reduction of the phenylsulfone in by sodium amalgam as before [6] produced target α,ω-bifunctional diterpenoid
5
16
and a small (~10%) quantity of its isomer in which the double bond migrated from the C10–C11 position to the C9–C10
5
position. Compound was purified by semi-preparative HPLC.
5
5
The structure of reduction product was established using spectral data. The PMR spectrum of contained signals
for four methyls on double bonds, four vinyl protons, two –CH O– groups, and the tetrahydropyranyl protons. The spectral data
2
5
5
and elemental analysis confirmed the structure of . The tetrahydropyranyl group of was removed byacid hydrolysis as before
13
1
[7] to produce 16-hydroxygeranylgeraniol ( ). Its spectral data (PMR and C NMR) agreed with those published [8] and
confirmed its structure.
278

Acetylation of 5 under standard conditions with acetic anhydride in pyridine gave in quantitative yield 6, the structure
of which was confirmed by spectral data and elemental analysis. The THP protection in 6 was removed as before [7] to give
monoacetate 7 (59%) and a small (18%) amount of diol 1.
Thus, we developed for the first time a nine-step original method for synthesizing the natural product exclusively
trans-16-hydroxygeranylgeraniol (1). This α,ω-bifunctionalized diterpenoid 1 was prepared from commercially available
geraniol (8) in 12% overall yield.
α,ω-Bifunctionalized derivatives 5-7 were synthesized under standard conditions. They were suitable synthons for
preparing difficultly accessible biologically active natural aliphatic diterpenoids.
EXPERIMENTAL
13
IR spectra were recorded on a Bio-Rad FTS 7 spectrometer; PMR and C NMR spectra in CDCl , on Bruker AC 80
3
(80 MHz), Bruker WM 300 (300 MHz), and Bruker AM 400 (400 MHz) spectrometers. Chemical shifts are given in ppm.
Assignments were made relative to CHCl as an internal standard (δ 7.26 and δ 77.0). Semi-preparative HPLC was
3
H
C
performed on a Gilson liquid chromatograph. Column chromatography used Merck 60 silica gel (70-230 mesh, ASTM) and
neutral aluminum oxide (activitylevel II). TLC used Merck plates. Chromatograms were developed byspraying with Ce(SO )
4 2
solution (0.1%) in H SO (2 N) and heating for 5 min at 80°C. Reaction mixtures in organic solvents were worked up by
2
4
extracting with diethylether, washing the extract with water until the rinsings were neutral, drying over anhydrous Na SO ,
2
4
filtering, and removing solvent in vacuo.
Geraniol Tetrahydropyranyl Ether (11). A solution of geraniol (8, 4.393 g, 28.53 mmol) in CH Cl (59 mL) was
2
2
treated with dihydropyran (4.2 mL, 45.65 mmol) and pyridinium p-toluenesulfonate (PyTs, 0.325 g, 1.29 mmol). The mixture
was stirred for 12 h at room temperature. The usual work up gave crude product (6.431 g), which was chromatographed over
a column of Al O (40 g) with gradient elution bypetroleum ether:AcOEt to afford 11 (6.395 g, 94%) as a colorless liquid. The
2
3
spectral data (IR and PMR) were identical with those published [6].
8-Hydroxygeraniol Tetrahydropyranyl Ether (12). Selenium dioxide (415 mg, 3.74 mmol) was added to a solution
of 11 (1.802 g, 8.04 mmol) in ethanol (15 mL) and pyridine (0.4 ml, 4.82 mmol). The mixture was stirred for 20 h at room
temperature, diluted with water (100 mL), and extracted with AcOEt (3 × 50 mL). The extract was washed with NaCl solution
(2 × 50 mL) and concentrated in vacuo to give a yellow oil (1.908 g). The product was chromatographed over a column of
Al O (54 g) with gradient elution by petroleum ether:AcOEt to afford starting 11 (502 mg, 28%) and 8-hydroxygeraniol
2
3
tetrahydropyranyl ether (12, 810 mg, 58% counting returned 11) as a colorless oil. Spectral data of 12 were identical with those
published [6].
8-Chlorogeraniol Tetrahydropyranyl Ether (9). A solution of 12 (437 mg, 1.71 mmol) in dryCH Cl (4.3 mL) was
2
2
treated under Ar at ambient temperature with 4-dimethylaminopyridine (DMAP, 131 mg, 1.07 mmol), tosylchloride (408 mg,
2.14 mmol), and triethylamine (0.24 mL, 1.71 mmol). The mixture was stirred for 3 h at room temperature, treated with LiCl
(145 mg, 3.40 mmol), and stirred for another 2 h at the same temperature. CH Cl was removed in vacuo. The residue was
2
2
treated with water (10 mL) and extracted with ether (3 × 5 mL). The combined ether extract was washed with NaCl solution
(2 × 5 mL) and evaporated in vacuo to afford 8-chlorogeraniol tetrahydropyranyl ether (9, 411 mg) as a yellow oil that was used
without further purification. Spectral data of 9 were identical with those published [6].
Geranylphenylsulfone (14). Phosphorus tribromide (4.3 mL, 12.255 g, 45.29 mmol) was dissolved in dry ether
(16 mL) and added dropwise to a stirred solution of 8 (5.120 g, 33.25 mmol) in dry ether (47 mL) with cooling on an ice bath.
The mixture was stirred for 12 h at room temperature and treated with saturated NaHCO solution. The ether layer was
3
separated, washed with NaCl solution, dried, and concentrated in vacuo. The resulting liquid product was added to a solution
of sodium benzenesulfonate (6.55 g, 39.90 mmol) in dry DMF (46 mL). The mixture was stirred at room temperature under
Ar in the dark for 3 h, treated with NaCl solution, and extracted with ether. The extract was worked up as usual to afford a
liquid product that was chromatographed over a column of SiO (260 g) with gradient elution by petroleum ether:AcOEt to
2
afford a colorless oil (7.39 g, 84% yield in two steps). Spectral data of 14 were identical with those published [3-5].
8-Hydroxygeranylphenylsulfone (10). A suspension of selenium dioxide (1.84 g, 16.55 mmol) in ethanol (15 mL)
was added to a solution of 14 (9.20 g, 33.09 mmol) in ethanol (25 mL). The mixture was stirred at 40°C for 4 h, cooled to 0°C,
treated with NaBH (670 mg, 16.50 mmol), stirred at the same temperature for 30 min, diluted with water (100 mL), and
4
279

extracted with AcOEt (3 × 50 mL). The extract was washed with saturated NaCl solution (2 × 50 mL) and evaporated in vacuo.
The resulting liquid product (9.5 g) was chromatographed over a column of SiO (200 g) with gradient elution by petroleum
2
ether:AcOEt to afford starting 14 (1.7 g, 18%) and liquid 8-hydroxygeranylphenylsulfone (10, 4.03 g, 54% counting returned
14). IR spectra and PMR spectra were identical with those published [5].
16-Hydroxy-9-phenylsulfonylgeranylgeraniol Tetrahydropyranyl Ether (15). A stirred solution of 10 (611 mg,
2.08 mmol) in dry THF (9 mL) and hexamethylphosphortriamide (HMPA, 1 mL) was treated at -78°C under Ar with n-BuLi
(4.16 mmol) in hexane. The temperature of the mixture was gradually increased to 0°C over 1 h and then again reduced to
-78°C. The mixture was treated dropwise with 9 (471 mg, 1.73 mmol) in dry THF (8 mL) and HMPA (0.8 mL). The
temperature was gradually increased to room temperature. The mixture was stirred at this temperature overnight and worked
up as usual. The product was chromatographed over a column of SiO (46 g) with gradient elution by petroleum ether:AcOEt
2
to afford 16-hydroxy-9-phenylsulfonylgeranylgeraniol tetrahydropyran ether (15, 834 mg, 91%) as a colorless oil, C H SO .
31 46
5
IR spectrum (liquid film, ν, cm−1): 3450, 1665, 1582, 1310, 1140.
PMR spectrum (80 MHz, δ , ppm): 1.50 (3H, s, H -19), 1.52 (3H, s, H -18), 1.64 (3H, s, H -17), 1.66 (3H, s, H -20),
H
3
3
3
3
3.58-3.75 (3H, m, H-9 and H -5′), 4.87 (1H, m, H-1′), 5.00 (2H, m, H-6 and H-10), 5.33 (2H, m, H-2 and H-14), 7.40-7.90 (5H,
2
m, Ar–H).
16-Hydroxygeranylgeraniol Tetrahydropyranyl Ether (5). A mixture of 15 (530 mg, 1.0 mmol) and Na HPO
2
4
(568 mg, 4 mmol) in dry methanol (11 mL) was treated at 0°C with an excess of freshly prepared sodium amalgam (4 g) and
stirred at the same temperature overnight. The excess of the amalgam was decomposed with cold water. The mixture was
extracted with ether. The extract was worked up as usual. The product (378 mg) was chromatographed over a column of SiO
2
(4 g) with gradient elution bypetroleum ether:AcOEt to afford a product (357 mg) containing traces of other compounds. Then
this product was purified by semi-preparative HPLC over a Nova-Pack C-18 column (MeOH:H O, 95:5, elution flow rate
2
1.5 mL/min) to afford 16-hydroxygeranylgeraniol THP ether (5, 284 mg, 73%) as a colorless oil, C H O .
25 42
3
IR spectrum (liquid film, ν, cm−1): 3423, 2920, 2850, 1450, 1370, 1210, 1020, 838.
PMRspectrum (80 MHz, δ , ppm): 1.52 (6H, s, H -18 and H -19), 1.59 (6H, s, H -17 and H -20), 2.57 (1H, br.s, OH),
H
3
3
3
3
3.49-3.82 (2H, m, H -5′), 3.90 (2H, br.s, H -16), 4.09 (2H, d, J = 7, H -2), 4.54 (1H, m, H-1′), 5.04 (2H, m, H-6 and H-10), 5.23
2
2
2
(2H, m, H-2 and H-14).
16-Hydroxygeranylgeraniol (1). A solution of 5 (105 mg, 0.269 mmol) in methanol (1.6 mL) was treated at room
temperature under Ar with p-toluenesulfonic acid (1.5 mg, 0.0087 mmol). The mixture was stirred for 12 h and worked up as
usual. The product (79 mg) was chromatographed over a column of SiO (3 g) with gradient elution by petroleum ether:AcOEt
2
to afford 1 (68 mg, 83%) as a colorless oil. Spectra data (IR and PMR) were identical to those published [8].
16-Acetoxygeranylgeraniol Tetrahydropyranyl ether (6). Asolution of5(480 mg, 1.23 mmol) in pyridine (2.5 mL)
was treated at room temperature with acetic anhydride (0.24 mL, 2.55 mmol). The mixture was held overnight at the same
temperature, poured onto ice, and extracted with ether. The extract was worked up as usual. The product (564 mg)
was chromatographed over a column of SiO (16 g) with gradient elution by petroleum ether:AcOEt to afford
2
16-acetoxygeranylgeraniol THP ether (6, 530 mg, 99%) as a colorless oil, C H O .
27 44
4
IR spectrum (liquid film, ν, cm−1): 1725, 1660, 1440, 1360, 1230, 1020, 845.
PMR spectrum (400 MHz, δ , ppm, J/Hz): 1.59 (6H, s, H -18 and H -19), 1.64 (3H, s, H -17), 1.67 (3H, s, H -20),
H
3
3
3
3
2.06 (3H, s, OAc), 2.62 (1H, br.s, OH), 3.50 (1H, m, H -5′), 3.89 (1H, m, H -5′), 4.02 (1H, dd, J = 7.3, J = 12.0, H -2), 4.23
A
B
1
2
A
(1H, dd, J = 6.4, J = 12.0, H -2), 4.44 (1H, s, H -16), 4.62 (1H, dd, J = 3.1, J = 3.9, H-1′), 5.11 (1H, m, H-6), 5.28 (1H, m,
1
2
B
2
1
2
H-10), 5.35 (1H, t, J = 7, H-2), 5.44 (1H, t, J = 7, H-14).
16-Acetoxygeranylgeraniol (7). A solution of 6 (509 mg, 1.18 mmol) in methanol (7 mL) was treated at room
temperature under Ar with p-toluenesulfonic acid (7 mg, 0.041 mmol), stirred for 12 h, and worked up as usual. The residue
(440 mg) was chromatographed over a column of SiO (15 g) with gradient elution by petroleum ether:AcOEt to afford
2
16-acetoxygeranylgeraniol (7, 240.7 mg, 59%) and 16-hydroxygeranylgeraniol (1, 64 mg, 18%).
Compound 7, C H O , colorless oil. IRspectrum (liquid film, ν, cm−1): 3423, 2920, 2850, 2360, 1730, 1670, 1445,
22 26
3
1380, 1235, 1023, 840.
PMR spectrum (300 MHz, δ , ppm, J/Hz): 1.60 (6H, s), 1.65 (3H, s), 1.68 (3H, s), 2.07 (3H, s), 4.15 (2H, d, J = 6.6),
H
4.44 (2H, s), 5.11 (1H, m), 5.42 (2H, m).
13
C NMR spectrum (75.5 MHz, δ , ppm): 170.0 (s, OCOCH ), 140.2 (s, C-3), 135.7 (s, C-15), 134.8 (s, C-11), 128.4
C
3
(s, C-7), 128.0 (d, C-14), 125.1 (d, C-2), 124.2 (d, C-10), 123.7 (d, C-6), 69.8 (t, C-16), 62.4 (t, C-1), 40.1 (t, C-4), 39.5 (t, C-8
280

and C-12), 27.0 (t, C-5), 26.8 (t, C-13), 26.7 (t, C-9), 21.5 (q, OCOCH ), 16.7 (q, C-17), 16.4 (q, C-18 and C-20), 14.4 (q,
3
C-19).
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