A practical synthesis of a hydroxylated sesquiterpene coumarin 10′R-acetoxy-11′-hydroxyumbelliprenin by regioselective dihydroxylation

Article abstract of DOI:10.3987/COM-12-12636

A practical synthesis of 10′R-acetoxy-11′-hydroxyumbelliprenin was achieved using regioselective Sharpless asymmetric dihydroxylation as a key reaction, in which the regioselectivity was achieved by using (DHQD) ₂AQN as a ligand instead of the conventional (DHQD)₂PHAL. 10′R-Acetoxy-11′-hydroxyumbelliprenin was synthesized by the coupling of a coumarin unit (umbelliferone) and sesquiterpene unit in 11% overall yield through 5 steps.

Full text of DOI:10.3987/COM-12-12636

HETEROCYCLES, Vol. 87, No. 2, 2013
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HETEROCYCLES, Vol. 87, No. 2, 2013, pp. 423 - 428. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 24th November, 2012, Accepted, 13th December, 2012, Published online, 21st December, 2012
DOI: 10.3987/COM-12-12636
A PRACTICAL SYNTHESIS OF A HYDROXYLATED SESQUITERPENE
COUMARIN 10’R-ACETOXY-11’-HYDROXYUMBELLIPRENIN BY
REGIOSELECTIVE DIHYDROXYLATION
Yasunao Hattori,a Genki Kinami,a Kenta Teruya,b Kazuto Nosaka,c Kazuya
Kobayashi,a and Kenichi Akajia*
aDepartment of Medicinal Chemistry, Kyoto Pharmaceutical University,
Yamashina-ku, Kyoto 607-8412, Japan; bDepartment of Chemistry, Kyoto
Prefectural University of Medicine, Kita-ku, Kyoto 603-8334, Japan; cDepartment
of Chemistry, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
*E-mail: akaji@mb.kyoto-phu.ac.jp
Abstract – A practical synthesis of 10’R-acetoxy-11’-hydroxyumbelliprenin was
achieved using regioselective Sharpless asymmetric dihydroxylation as a key
reaction, in which the regioselectivity was achieved by using (DHQD)2AQN as a
ligand instead of the conventional (DHQD)2PHAL. 10’R-Acetoxy-11’-
hydroxyumbelliprenin was synthesized by the coupling of a coumarin unit
(umbelliferone) and sesquiterpene unit in 11% overall yield through 5 steps.
Sesquiterpene coumarins isolated from Ferula, Heptaptera, Heraclum, Peucedanum, Angelica (Apiaceae),
Artemisia (Asteraceae), and Haplophyllum (Rutaceae) have attracted attention due to anti-inflammatory,
cytotoxic, cancer chemopreventative, and antibacterial activities.1,2 More than 230 natural products
including over 120 sesquiterpene coumarins have been reported from the genus Ferula.
10’R-Acetoxy-11’-hydroxyumbelliprenin (1, Figure 1) is a new sesquiterpene coumarin isolated from a
CHCl3-soluble extract of Ferula assa-foetida through bioassay-guided fractionation in 2009 by Lee et al.3
Compound 1 has one acetoxy group at C-10’, one hydroxy group at C-11’, and two double bonds at C-2’
and C-6’ of the sesquiterpene part connected to 7-hydroxycoumarin. The absolute configuration of 1 was
established as R by the derivatization to the MTPA ester combined with specific rotation. In an in vitro
anti-influenza A viral (H1N1) assay, 1 showed a similar potency to the positive control, amantadine;3 the
IC50 (g/mL) of 1 is 0.94±0.07 and that of amantadine is 0.92±0.04. Synthesis of 1 has not been reported

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to date, although the related sesquiterpene coumarin, karatavicinol (2, Figure 1), was synthesized using an
enzymatic resolution by Faber et al.4 In the course of studying anti-virus agents, we became interested in
this class of compounds. Herein we report a practical asymmetric synthesis of 1 using regioselective
Sharpless asymmetric dihydroxylation.
Figure 1. The structure of 10’R-acetoxy-11’-hydroxyumbelliprenin (1).
Our synthetic plan is outlined in Scheme 1. Compound 1 is constructed by the coupling of a coumarin unit
(umbelliferone) and sesquiterpene unit, which is prepared by single step stereoselective dihydroxylation of
a commercially available trans,trans-farnesol (3).
Scheme 1. Synthetic route for 1.
Synthesis of 1 according to the above plan is shown in Scheme 2. The regioselective asymmetric
dihydroxylation of trans,trans-farnesol (3), a key step in the synthesis, was examined first.5 No selectivity
was observed resulting in an equal mixture of C-6 and C-10 isomers when the conventional ligand
(DHQD)2PHAL was used in the Sharpless asymmetric dihydroxylation. The ratio of the isomers was
1
estimated from the integration of C-6 and C-10 protons in H NMR. Among the commercially available
ligands, (DHQD)2AQN6 gave the best results; 2:1 ratio of the desired C-10 isomer 4 and undesired C-6
isomer. 1,4-Anthraquinone domain in (DHQD)2AQN might serve as an effective distance-critical spacer
for this specific substrate as does the 1,4-dioxanaphthopyridazine domain in Corey’s ligand for farnesyl
acetate.7 Since the separation of the isomer 4 was difficult, the enantiomeric excess of 4 could not be
estimated at this stage.

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425
K2OsO2(OH)4, (DHQD)2AQN
K3Fe(CN)6, K2CO3
p-TsOH
acetone
OH
HO
OH
O
10
6
t-BuOH/H2O (1:1), 0 oC
OH
3
5
4
59%
99%
60% AcOH, 60 oC
59%
DEAD, PPh3
umbelliferone
O
OH
O
O
O
O
O
6
78%
Ac2O, pyridine
53%
O
O
O
O
O
O
HO
HO
OH
OAc
2
1
Scheme 2. Synthesis of 1.
After protection of the 1, 2-diol of 4, the resulting primary alcohol of 5 was converted to bromide for the
coupling to the coumarin unit. However, the product was a complex mixture and separation of the desired
product was difficult. The conversion of the hydroxy group of 5 to the corresponding tosyl group gave
similar results. Avoiding the separate step of activation, Mitsunobu reaction using the alcohol 5 and
umbelliferone gave the desired product 6 with 78% yield. Treatment of 6 with 60% AcOH gave the desired
diol 2, although the deprotection of the acetonide with TFA gave a complex mixture. The crude product was
purified by silica gel column chromatography to remove the concomitant C-6 isomer derived from the
regioselective asymmetric dihydroxylation.8 Mono-acetylation at the secondary hydroxy group of 2 with
acetic anhydride-pyridine gave the desired product 1 with moderate yield. The spectroscopic data (1H NMR,
13C NMR, and MS) of the synthetic 1 all agreed with those of the natural product.3 The optical purity of the
synthetic 1 was confirmed by the comparison of specific rotation of the synthetic and the natural product;
[]25D +10.8 (c 0.2, CHCl3) for 1 and []25D +11.2 (c 0.5, CHCl3) for the natural product.3 Thus, we have
achieved a practical synthesis of 10’R-acetoxy-11’-hydroxyumbelliprenin (1) in 11% yield through 5 steps
using an regioselective asymmetric dihydroxylation employing (DHQD)2AQN ligand as a key step. Using
this straightforward synthetic route, the structure-activity relationship studies are now underway.
EXPERIMENTAL
General
13
1H and C NMR spectra were measured with a Bruker AM-300 FT-NMR spectrometer in CDCl3 at 300
and 75 MHz, respectively. Chemical shifts were relative to tetramethylsilane as an internal standard. The
coupling constants were given in Hz. Mass spectra were obtained on JMS-SX 102A mass spectrometer.
Optical rotations were determined with a HORIBA SEPA-300 polarimeter.

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(2E,6E,10R)-3,7,11-Trimethyldodec-2,6-diene-1,10,11-triol (4). To a suspension of 3 (63.9 mg, 0.288
mmol) in t-BuOH/H2O (1:1, 0.5 mL) were added (DHQD)2AQN (2.49 mg, 0.00291 mmol), K2OsO2(OH)4
(0.44 mg, 0.0012 mmol) K3Fe(CN)6 (284 mg, 0.864 mmol), K2CO3 (119 mg, 0.864 mmol) in t-BuOH/H2O
(1:1, 0.5 mL) at 0 oC. The mixture was stirred for 12 h at the same temperature, and then the reaction was
quenched with aqueous Na2SO3. The organic materials were extracted with EtOAc and washed with brine,
dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column
chromatography (hexane/AcOEt = 3:1) to afford 4 and C-6 isomer (42.9 mg, 0.169 mmol) as a colorless oil.
1H NMR : 5.45 (0.34H, dt, J = 6.8, 1.2 Hz), 5.37 (0.66H, dt, J = 6.7, 1.5 Hz), 5.17-5.09 (1H, m), 4.15-4.12
(2H, m), 3.40-3.33 (1H, m), 3.04 (2H, brs), 2.67 (1H, brs), 2.27, (0.34H, m), 2.20-2.05 (5.66H, m), 1.68 (1H,
s), 1.64 (2H, s), 1.62 (1H, s), 1.60 (2H, s), 1.59-1.34 (3H, m), 1.17 (2H, s), 1.14 (2H, s), 1.11 (1H, s);
HRFABMS calcd for C15H29O3 [M+H]+ 257.2117, found 257.2113.
(2E,6E,4’R)-(2’,2’,5’-Trimethyl-1’,3’-oxolan-4’-yl)-3,7-dimethylnona-2,6-dien-1-ol (5). Compound 4
(42.9 mg, 0.169 mmol) was treated with acetone (2.0 mL) and catalytic amount of p-TsOH. The mixture
was stirred for 2 h at room temperature, and then the reaction was quenched with saturated aqueous
NaHCO3. The organic materials were extracted with EtOAc and washed with brine, dried over Na2SO4,
filtered and concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt =
3:1) to afford 5 and C-6 isomer (49.7 mg, 0.168 mmol) as a colorless oil. 1H NMR : 5.48-5.34 (1H, m),
5.17 (0.66H, m), 5.12-5.07 (0.34H, m), 4.17-4.14 (2H, m), 3.73 (0.34H, dd, J = 9.6, 2.8 Hz), 3.66 (0.66H,
dd, J = 9.2, 3.6 Hz), 2.31-1.99 (5H, m), 1.70 (1H, s), 1.68 (2H, s), 1.62 (2H, s), 1.61 (1H, s), 1.67-1.44 (6H,
m), 1.43 (1H, s), 1.42 (2H, s), 1.33 (2H, s), 1.24 (1H, s), 1.10 (2H, s), 1.09 (1H, s); HRFABMS calcd for
C18H33O3 [M+H]+ 297.2430, found 297.2427.
(2’E,6’E,4’’R)-7-(2’’,2’’,5’’-Trimethyl-1’’,3’’-oxolan-4’’-yl)-3’,7’-dimethylnona-2’,6’-dienyloxy)-
chromen-2-one (6). DEAD (40% in toluene, 0.31 mL, 0.67 mmol) was added dropwise to a solution of 5
(49.7 mg, 0.168 mmol) umbeliferone (109 mg, 0.672 mmol), and triphenylphosphine (176 mg, 0.672
o
mmol) in toluene (3.0 mL) at 0 C. The mixture was stirred for 16 h at room temperature, and then the
reaction mixture was concentrated. The residue was purified by silica gel column chromatography
(hexane/AcOEt = 3:1) to afford 7 and C-6 isomer (58.2 mg, 0.132 mmol) as a colorless oil. 1H NMR : 7.63
(1H, d, J = 9.6 Hz), 7.36 (1H, d, J = 8.4 Hz), 6.86-6.80 (2H, m), 6.24 (1H, d, J = 9.6 Hz), 5.53-5.46 (1H, m),
5.17 (0.66H, t, J = 6.6 Hz), 5.11-5.08 (0.34H, m), 4.62-4.60 (2H, m), 3.73 (0.34H, dd, J = 9.8, 2.6 Hz), 3.66
(0.66H, dd, J = 9.4, 3.4 Hz), 2.34 (0.34H, m), 2.24-1.99 (4.66H, m), 1.79 (1H, s), 1.77 (2H, s), 1.68 (1H, s),
1.63 (2H, s), 1.61 (1H, s), 1.73-1.44 (3H, m), 1.42 (3H, s), 1.33 (1H, s), 1.30-1.26 (2H, m), 1.24 (2H, s),

HETEROCYCLES, Vol. 87, No. 2, 2013
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1.10 (3H, s); HRFABMS calcd for C27H37O5 [M+H]+ 441.2641, found 441.2637.
Karatavicinol (2). Compound 6 (58.2 mg, 0.132 mmol) was treated with 60% AcOH (5.0 mL). The
o
mixture was stirred for 2 h at 60 C, and then the reaction mixture was concentrated. The residue was
purified by silica gel column chromatography (hexane/chloroform/MeOH = 10:50:1) to afford 2 (31.3 mg,
0.0781 mmol) as a colorless oil. []25D +14.8 (c 0.3, CHCl3). 1H NMR : 7.64 (1H, d, J = 9.6 Hz), 7.37 (1H,
d, J = 8.4 Hz), 6.85 (1H, dd, J = 8.4, 2.4 Hz), 6.82 (1H, d, J = 2.4 Hz), 6.25 (1H, d, J = 9.2 Hz), 5.46 (1H, t,
J = 6.6 Hz), 5.18 (1H, m), 4.61 (2H, d, J = 6.4 Hz), 3.35 (1H, d, J = 10.4 Hz), 2.38 (1H, brs), 2.28-2.03 (7H,
m), 1.76 (3H, s), 1.62 (3H, s), 1.63-1.55 (1H, m), 1.46-1.36 (1H, m), 1.20 (3H, s), 1.16 (3H, s); 13C NMR :
162.1, 161.3, 155.8, 143.5, 142.0, 135.4, 128.7, 124.2, 118.6, 113.3, 112.9, 112.4, 101.5, 78.1, 72.9, 65.5,
39.3, 36.7, 29.6, 26.4, 25.9, 23.3, 16.7, 15.9; HRFABMS calcd for C24H33O5 [M+H]+ 401.2328, found
401.2324.
10’R-Acetoxy-11’-hydroxyumbelliprenin (1). To a solution of 2 (31.3 mg, 0.0781 mmol) and pyridine
(0.025 mL, 0.31 mmol) in CH2Cl2 (1.0 mL) was added acetic anhydrous (0.016 mL, 0.16 mmol) at 0 oC.
The mixture was stirred for 12 h at room temperature, and then the reaction was quenched with saturated
aqueous NH4Cl. The organic materials were extracted with AcOEt and washed with brine, dried over
Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography
(hexane/chloroform/MeOH = 10:50:1) to afford 2 (18.3 mg, 0.0414 mmol) as a colorless oil. []25D +10.8
(c 0.2, CHCl3) {lit.3 []25D +11.2 (c 0.5, CHCl3)}. 1H NMR : 7.65 (1H, d, J = 9.2 Hz), 7.37 (1H, d, J = 8.8
Hz), 6.85 (1H, dd, J = 8.4, 2.4 Hz), 6.82 (1H, d, J = 2.4 Hz), 6.25 (1H, d, J = 9.2 Hz), 5.47 (1H, dd, J = 6.6,
1.3 Hz), 5.11 (1H, m), 4.79 (1H, dd, J = 10.0, 2.8 Hz), 4.61 (2H, d, J = 6.4 Hz), 2.16-2.02 (4H, m), 2.11 (3H,
s), 1.99-1.82 (2H, m), 1.74 (3H, s), 1.73-1.62 (3H, m), 1.60 (3H, s), 1.20 (3H, s), 1.19 (3H, s); 13C NMR :
172.2, 162.1, 161.3, 155.8, 143.4, 142.2, 134.6, 128.7, 124.2, 118.5, 113.2, 112.9, 112.4, 101.5, 79.6, 72.5,
65.5, 39.4, 36.1, 27.8, 26.1, 24.9, 21.1, 16.8, 16.0; HRFABMS calcd for C26H35O6 [M+H]+ 443.2434, found
443.2440.
ACKNOWLEDGEMENTS
We thank Ms. K. Oda of Kyoto Pharmaceutical University for obtaining the Mass spectra.
REFERENCES AND NOTES
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4. K. Eddeger, S. F. Mayer, A. Steinreiber, and K. Faber, Tetrahedron, 2004, 60, 589.
5. For regioselective Sharpless asymmetric aminohydroxylation using (DHQD)2AQN as a ligand: (a) J.
A. Bodkin, G. B. Bacskay, and M. D. McLeod, Org. Biomol. Chem., 2008, 6, 2544; (b) A. J. Morgan,
C. E. Masse, and J. S. Panek, Org. Lett., 1999, 1, 1949.
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7. E. J. Corey and J. Zhang, Org. Lett., 2001, 3, 3211.
8. Data for C-6 isomer of 5: []25D +35.3 (c 0.1, CHCl3). 1H NMR : 7.64 (1H, d, J = 9.6 Hz), 7.36 (1H,
d, J = 8.8 Hz), 6.85 (1H, dd, J = 8.6, 2.6 Hz), 6.82 (1H, d, J = 2.4 Hz), 6.25 (1H, d, J = 9.6 Hz), 5.52
(1H, dt, J = 6.5, 1.3 Hz), 5.14-5.10 (1H, m), 4.60 (2H, d, J = 6.8 Hz), 3.41 (1H, dd, J = 10.4, 2.0 Hz),
2.38 (1H, ddd, J = 14.4, 9.4, 5.0 Hz), 2.28 (1H, brs), 2.20-2.06 (4H, m), 1.98 (1H, brs), 1.78 (3H, s),
1.69 (3H, s), 1.63 (3H, s), 1.76-1.42 (3H, m), 1.34-1.19 (1H, m), 1.13 (3H, s);13C NMR : 162.1, 161.3,
155.8, 143.4, 142.2, 132.2, 128.7, 124.2, 118.9, 113.2, 113.0, 112.5, 101.6, 77.2, 75.0, 65.4, 38.7, 36.5,
29.2, 25.6, 22.0, 20.9, 17.7, 16.8; HRFABMS calcd for C24H33O5 [M+H]+ 401.2328, found 401.2322.