Total synthesis of (±)-agastinol

Article abstract of DOI:10.3184/174751911X13082938433857

A synthesis of the tetrahydrofuran lignan (±)-agastinol, starting from the cheap Vanillin, has been developed based on Stobbe reaction with diethyl succinate to give the skeleton of lignan, which was then reduced to afford meso- and threo-(±)-secoisolanciresinol. threo-(±)- Secoisolanciresinol was treated with DDQ in acetic acid to give the 2-aryl tetrahydrofuran lignan, and which was then condensed with ferulic acid to give (±)-agastinol for the first time.

Full text of DOI:10.3184/174751911X13082938433857

352 RESEARCH PAPER
JUNE, 352–354
JOURNAL OF CHEMICAL RESEARCH 2011
Total synthesis of ( )-agastinol
Haitang Zhou, Bin Jiao and Yamu Xia
Junwei Ding,
*
College of Chemical Engineering, Qingdao University of Science andTechnology, Qingdao 266042, P. R. China
A synthesis of the tetrahydrofuran lignan ( )-agastinol, starting from the cheap Vanillin, has been developed based
on Stobbe reaction with diethyl succinate to give the skeleton of lignan, which was then reduced to afford meso- and
threo-( )-secoisolanciresinol. threo-( )-Secoisolanciresinol was treated with DDQ in acetic acid to give the 2-aryl
tetrahydrofuran lignan, and which was then condensed with ferulic acid to give ( )-agastinol for the first time.
Keywords: synthesis, lignan, agastinol, Stobbe reaction
Lignans are a class of secondary plant metabolites produced
by the oxidative dimerisation of two phenylpropanoid units.
Although their backbone consists of only two phenylpropane
(C6−C3) units, lignans show an enormous structural diversity.1–3
Natural products of the lignan family display interesting
and diverse biological activities, including anti-spasmodic,
anticancer, anti-inflammatory activity.4–7 In 2002, the lignan
compound agastinol (1) isolated from Agastache rugosa, was
shown to inhibit etoposide-induced apoptosis in U937 cells
with IC50 values of 15.2 and 11.4 μg mL−1, respectively. From
these results, agastinol seems to be a worthy candidate for
further research as a potential anti-apoptotic agent.8
acid gave 2,3,4-trisubstituted tetrahydrofurans related to the
tetrahydrofuran lignan family of natural producs.11 Maiti
developed a route involving a radical cyclisation step which
proceeds with high stereoselectivity. 12,13
We now provide full details of the total synthesis of agasti-
nol. The synthesis involved a Stobbe reaction to construct the
skeleton of lignan (C6–C4–C6) and resolution of threo- and
meso-isomers. Treatment with DDQ in acetic acid then gave
the 2-aryl tetrahydrofuran lignan. The 2-aryl tetrahydrofuran
lignan was condensed with 4-hydroxybenzoic acid to give the
natural product, agastinol.
Agastinol is a tetrahydrofuran lignan, whose core is a
2,3,4-trisubstituted tetrahydrofuran. The majority of the tetra-
hydrofuran lignan which have the substituents arranged with
2,3-trans, 3,4-cis stereochemistry, exhibit greater biological
activity. There is a growing interest in the synthesis of tetrahy-
drofuran lignans due to applications in various pharmacologi-
cal effects. 9 Several efficient methods for their synthesis have
been reported. Meyer introduced the stereoselective synthesis
of all-cis-2,3,5-trisubstituted tetrahydrofurans by the Lewis
acid-mediated condensation of aldehydes with 7-substituted
1-oxa-2-silacyclohept-4-enes.10 Miles preferred reagent-
controlled stereoselective synthesis of lignan-related tetrahy-
drofurans. The reaction of ring-closing metathesis-derived
cyclic allylsiloxanes with aldehydes in the presence of a Lewis
Results and discussion
Our approach to the synthesis of agastinol is outlined in
Scheme 2. It was anticipated that condensation of 2 with ethyl
succinate would furnish 3, which after the second condensa-
tion of with 2 into threo-( )-4 and subsequent treatment
with DDQ would provide the desired key intermediate 5. The
acylation of 5 give the agastinol 1.
Our investigations began with cheap vanillin as the starting
material. The 4-hydroxyl group of vanillin was protected with
benzyl chloride to afford the product 2. Compound 2 under-
went Stobbe condensation with diethyl succinate in the pres-
ence of sodium ethoxide in ethanol to produce compound 3.
The trans-(E)-configuration of the olefinic double bond was
evident from the appearance of the deshielded vinylic proton at
δ 7.87 in its 1H NMR spectrum. Compound 3 was methylated
with diazomethane in methanol to yield the diester 6. QA
second Stobbe condensation of 6 with 2 in methanol in the
presence of sodium methoxide yielded compound 7. The
deshielded vinylic proton at δ 7.96 in the 1H NMR spectrum of
7 indicated the trans-(E)-configuration for both the olefinic
double bonds.14 Compound 7 was again methylated to produce
a diester 8. Treatment of 8 with LiAlH4/AlCl3 afforded the
unsaturated diol 9. This was followed by hydrogenation over
a 10% palladium on charcoal catalyst to produce a readily
separable mixture (approximate 1:1) of the diols meso-secoiso-
lariciresinol (10a) and threo-( )-secoisolariciresinol (10b).
Scheme 1
Scheme 2
* Correspondent. E-mail: xiaym@qust.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2011 353
Scheme 3
127.8, 128.5, 133.9 (C-1′, C-1″), 137.4, 146.7 (C-4′, C-4″), 149.8
(C-3′, C-3″). HRMS Calcd for C34H42NO6(M+NH4+): 560.3007.
Found: 560.3012.
Threo-( )-10b had consistently larger Rf values than those of
the corresponding meso-10a, and each pair were easily sepa-
rated by flash column chromatography over silica gel. The
data for the configuration of threo-( )-10b was in agreement
with that reported in the literature.15
The 4-hydroxyl group of threo-( )-10b was protected with
benzyl chloride to afford the compound 4. Threo-( )-4 was
treated with DDQ in acetic acid to give the 2-aryl-tetrahydro-
furan lignan 5.16 After acylation of 5 with 4-benzyloxybenzoic
acid, and then hydrogenation, natural product agastinol 1 was
obtained (Scheme 3). The spectroscopic data of agastinol was
in agreement with the literature.8
In summary, we have developed an efficient and practical
synthesis of a tetrahydrofuran lignan based on Stobbe reaction
to construct the skeleton of lignan, oxidation with DDQ to give
the tetrahydrofuran ring. Agastinol, a potential anti-apoptotic
agent, was obtained for the first time by this route.
4,4′-Dibenzyloxy-3,3′-dimethoxybenzyl-9-hydroxy-7,9′-epoxylig-
nan (5): DDQ (0.9 g, 4 mmol) was added to a solution of compound 4
(1.1 g, 2 mmol) in glacial acetic acid. The mixture was stirred for 5 h.
The reaction mixture was poured onto crushed ice and extracted with
EtOAc (20 mL). The organic layer was washed with a saturated solu-
tion of NaHSO3 (3 × 20 mL) and a saturated solution of NaHCO3
(3 × 20 mL). The extract was dried over MgSO4 and concentrated
in vacuo. Flash column chromatography of the residue gave ( )-
dihydrosesamin 5 as a colourless oil (0.5 g, 46%). IR (KBr/cm−1):
3448, 2936, 1595, 1512, 1456, 1226, 1023. 1H NMR (CDCl3,
500 MHz) δ: 2.76 (dd, 1H, J = 13.0, 11.0 Hz, H-7α), 2.76−2.87 (m,
1H, H-8′), 3.01−3.09 (m, 1H, H-8), 3.22 (dd, 1H, J = 13.5, 5.5 Hz,
H-7β), 3.80 (s, 6H, 2 × OCH3), 4.06 (dd, 1H, J = 8.5, 6.5 Hz, H-9α),
4.17 (dd, 1H, J = 11.0, 6.5 Hz, H-9′α), 4.25 (dd, 1H, J = 11.0, 7.0 Hz,
H-9′β), 4.30 (dd, 1H, J = 8.5, 6.5 Hz, H-9β), 5.15 (s, 4H, 2 ×ArCH2O),
5.28 (d, 1H, J = 6.0 Hz, H-7′), 6.90−7.45 (m, 16H, ArH). 13C NMR
(CDCl3, 125 MHz) δ: 33.1 (C-9), 42.3 (C-8), 52.5 (C-8’), 56.0 (2 ×
OCH3), 60.8 (C-9’), 71.2 (ArCH2), 72.7 (C-7), 82.5 (C-7’), 108.7,
111.2, 112.1, 112.4, 117.9, 120.5, 127.1, 127.7, 128.4, 132.3, 134.9,
137.3, 147.4, 148.2, 148.8, 148.9. HRMS Calcd for C34H40NO6
(M+NH4+):558.2851. Found: 558.2847.
Agastinol (1): A solution of 5 (0.54 g, 1 mmol) in dry CH2Cl2
(20 mL) was added dropwise to a solution of 4-benzyloxybenzoic acid
(0.23 g, 1 mmol), DCC (2.1 g, 10 mmol) and DMAP (0.13 g, 1 mmol)
in dry CH2Cl2 (20 mL) at 0 °C for 2 h under nitrogen. After stirring
the mixture overnight at room temperature, the reaction mixture was
filtered and the solvent was distilled. The residue was dissolved in
20 mL MeOH and was stirred under a hydrogen atmosphere for 7 h in
the presence of 10% Pd/C (0.6 g). The reaction mixture was filtered
through a pad of Celite, and then the solvent was removed in vacuo.
Flash column chromatography of the residue gave an amorphous
powder of Agastinol 1 (0.42 g, 87%) (no melting point). IR (KBr,
cm−1) v: 3452, 2918, 1720, 1590, 1507, 1455, 1152. 1H NMR (CD3OD,
500 MHz) δ: 2.62 (dd, 1H, J = 13.5, 10.5 Hz, H-7α), 2.65−2.73 (m,
1H, H-8′), 2.81−2.89 (m, 1H, H-8), 2.93 (dd, 1H, J = 13.5, 5.5 Hz,
H-7β), 3.74 (dd, 1H, J = 8.5, 6.5 Hz, H-9α), 3.77 (s, 3H, OCH3), 3.82
(s, 3H, OCH3), 4.02 (dd, 1H, J = 8.5, 6.5 Hz, H-9β), 4.38 (dd, 1H, J =
11.0, 6.5 Hz, H-9′α), 4.60 (dd, 1H, J = 11.0, 7.5 Hz, H-9′β), 4.85 (d,
1H, J = 6.5 Hz, H-7′), 6.70−7.83 (m, 10H, ArH). 13C NMR (CD3OD,
Experimental
Melting points were taken on Gallenkamp melting point apparatus
and are uncorrected. Infrared spectra were recorded on a Nicolet
NEXUS 670 FT−IR. The 1H NMR and 13C NMR spectra were recorded
on a Brucker AM−500 MHz spectrometers. Mass spectra were
recorded on a ZAB−HS spectrometer. HRMS were obtained on
a Bruker Daltonics APEXII47e spectrometer. Flash column chroma-
tography was performed on silica gel (200–300 mesh) and TLC
inspections on silica gel GF254 plates.
Threo-( )-Secoisolariciresinol(10b) was synthesised according to
the procedure which has been described previously.17
Threo-( )-2,3-bis(4′-benzyloxy-3′-methoxybenzyl)-1,4-butanediol
(4): Following the procedure described for the preparation of 2,
and starting with the diester 10b (3.6 g, 10 mmol), compound 4 was
obtained as a yellow oil (4.8 g, 89%). IR (KBr/cm−1): 3383, 2921,
1
1521, 1245, 1037, 928. H NMR (CDCl3, 500 MHz) δ: 1.85−1.95
(m, 2H, 2 × ArCH2CH), 2.62−2.67 (m, 4H, 2 × ArCH2CH), 3.54−3.56
(m, 2H, CH2OH), 3.60−3.62 (m, 2H, CH2OH), 3.80 (s, 6H, 2 × OCH3),
5.13 (s, 4H, 2 × ArCH2O), 6.61−6.71 (m, 6H, ArH), 7.27−7.37 (m,
10H, ArH). 13C NMR (CDCl3, 125 MHz) δ: 35.9 (C-3, C-4), 45.0
(C-7′, C-7″), 56.1 (2 × OCH3), 63.4 (C-1, C-4), 71.3 (2 × ArCH2O),
113.0 (C-2′, C-2″), 114.4 (C-5′, C-5″), 121.0 (C-6′, C-6″), 127.3,

354 JOURNAL OF CHEMICAL RESEARCH 2011
3
4
H. Otsuka, H. Kuwabara and H. Hoshiyama, J. Nat. Prod., 2008, 71,
1178.
125 MHz) δ: 33.9 (C-9), 43.9 (C-8), 50.5 (C-8′), 56.4 (2 × OCH3),
63.7 (C-9′), 73.3 (C-7), 84.1 (C-7′), 110.6, 111.5 (C-3″, C-5″), 113.2,
115.2, 115.8, 119.6, 122.0, 122.5(C-1″), 132.6 (C-2″, C-6″), 132.8,
135.7, 145.8, 146.8, 148.4, 148.5, 162.9 (C-4’’), 166.5 (C=O). HRMS
Calcd for C27H32NO8 (M+NH4+): 498.2123. Found: 498.2125. The
data are consistent with the literature.8
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5
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This work was financially supported by the National Natural
Science Foundation of Shandong (No.ZR2010HM023) and
Specialized Research Fund for the Doctoral Program of Higher
Education of China (No.20093719120004).
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Received 1 April 2011; accepted 27 May 2011
Paper 1100639 doi: 10.3184/174751911X13082938433857
Published online: 11 July 2011
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