Asymmetric synthesis of 8-O-4′-neolignan perseal B

Article abstract of DOI:10.3906/kim-0908-201

Full details of an enantioselective total synthesis of 8-O-4'-neolignan perseal B are presented for the first time. The synthesis was achieved in 8 steps from vanillin and involved the asymmetric dihydroxylation reaction using AD-mix-α to give the key intermedium (1S,2S)-1-(4-(benzyloxy)-3- methoxyphenyl)propane-1,2,3-triol, and the Mitsunobu reaction between phenylpropanoid and vanillin formed perseal B. The synthetic method of perseal B exhibits a new route for 8-O-4'-neolignan. TUBITAK.

Full text of DOI:10.3906/kim-0908-201

Turk J Chem
34 (2010) , 375 – 380.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-0908-201
Asymmetric synthesis of 8-O-4ꢀ-neolignan perseal B
Ya-Mu XIA∗, Wei WANG, Ying-Lan GUO and Jun-Feng LI
College of Chemical Engineering, Qingdao University of Science and Technology,
Qingdao 266042, P.R. China
e-mail: xiaym@qust.edu.cn
Received 15.08.2009
Full details of an enantioselective total synthesis of 8-O-4ꢀ -neolignan perseal B are presented for the
first time. The synthesis was achieved in 8 steps from vanillin and involved the asymmetric dihydroxylation
reaction using AD-mix-α to give the key intermedium (1S ,2S)-1-(4-(benzyloxy)-3-methoxyphenyl)propane-
1,2,3-triol, and the Mitsunobu reaction between phenylpropanoid and vanillin formed perseal B. The syn-
thetic method of perseal B exhibits a new route for 8-O-4ꢀ -neolignan.
Key Words: Neolignans; perseal B; enantioselective synthesis.
Introduction
Neolignans are a class of secondary plant metabolites produced by oxidative dimerization of 2 phenylpropane
(C6-C3) units, which are formed biogenetically through the shikimate pathway.1 They are widespread in
nature and are found in many kinds of plants.2−4 Neolignans, especially 8-O-4ꢀ neolignans, exhibit a wide
range of biological activities, including against Trypanosoma cruzi, and antileukemic, antitumor, antifungal,
antimicrobial, insect antifeedant, and other diverse types of activity.5,6
8-O-4ꢀ neolignans have stimulated substantial synthetic efforts due to their biological activity.2,7 As
reported previously, the synthesis of 8-O-4ꢀ neolignans was mainly achieved using oxidative coupling of mono-
lignols and reduction of ketones, which were prepared from bromoketone and phenols in basic conditions.8−10
However, these methods led to the mixture of erythro- and threo-isomers in all cases tested. Recently, Lourith
developed a biosynthetic pathway for the synthesis of 8-O-4ꢀ neolignans in Eucommia ulmoides.7 Curti reported
the synthesis of 8-O-4ꢀ neolignans by modular synthesis.11
In this paper, the main objective of our study was to develop a new stereoselective synthesis approach to
8-O-4ꢀ neolignans perseal B, which was isolated from the leaves of Persea obovatifolia, and exhibited biological
∗Corresponding author
375

Asymmetric synthesis of 8-O-4ꢀ -neolignan perseal B, Y. M. XIA, et al.,
activities of against leishmaniasis and a tropical disease transmitted by mosquitoes.3,4 As shown in the Scheme,
we obtained 2 chiral centers by dihydroxylation of AD-mix-α, and condensated phenylpropanoid with vanillin
using the Mitsunobu reaction. By this method, perseal B was synthesized stereoselectively for the first time.
O
H3CO
BnO
CHO
H3CO
HO
CHO
H3CO
BnO
a
b
OEt
c
2
3
OH
OH
H3CO
BnO
OH
H3CO
BnO
H3CO
BnO
OH
OTs
d
e
f
OH
OH
4
7
5
6
OH
OTHP
2S
OH
2
3
9
7
1
H3CO
HO
H3CO
BnO
H3CO
BnO
8
1S
g
h
5'
2'
O
O
OH
6
6'
4
5
4'
7'
H3CO
CHO
1'
3'
8
1
Scheme. Reagents and conditions: (a) BnCl, K2 CO3 , EtOH, reflux, 4 h; (b) C6 H6 , (Ph)3 PCHCOOEt, reflux, 10 h;
(c) LAH, AlCl3 , THF, 10 h; (d) AD-mix-α, MeSO2 NH2 , t BuOH, H2 O, 0 ˚C, 30 h; (e) TsCl, pyridine, CH2 Cl2 , rt;
(f) K2 CO3 , MeOH, rt; 5 h (g) DHP, PPTS, CH2 Cl2 , LAH, THF, rt, 24 h; (h) vanillin, Ph3 P, DIAD, THF, reflux, 24
h; HCl, MeOH, rt, 8 h; Pd/C (10%), H2 , AcOEt, rt, 6 h.
Experimental
General
Melting points were taken on a Gallenkamp melting point apparatus and are uncorrected. Optical rotations were
determined on a Perkin-Elmer 341 polarimeter. Chrial analysis was performed on a Varian Dynamax SD-300
using a chiralcel column CDMPC (150 × 4.6 mm D) with hexane/isopropyl alcohol as eluant. Infrared spectra
were recorded on a Nicolet NEXUS 670 FT-IR. The 1 H-NMR and 13 C-NMR spectra were recorded on a Mercury
Plus-300 MHz and Avance–200 MHz spectrometers. Mass spectra were recorded on a ZAB-HS spectrometer.
HRMS were obtained on a Bruker Daltonics APEXII47e spectrometer. Flash column chromatography was
performed on silica gel (200-300 mesh) and TLC inspections on silica gel GF254 plates.
4-(benzyloxy)-3-methoxybenzaldehyde (2) To a well-stirred solution of K2 CO3 in ethanol was
added dropwise a mixture of vanillin (5.2 g, 0.035 mol) and benzyl chloride (3.64 g, 0.035 mol). The mixture
was stirred and warmed to reflux for 4 h, and then concentrated in vacuo. The residue was dissolved in AcOEt
376

Asymmetric synthesis of 8-O-4ꢀ -neolignan perseal B, Y. M. XIA, et al.,
(300 mL), filtered, and washed with 10% aqueous NaOH and NaCl saturated solution 3 times consecutively.
The extract was dried over MgSO4 , filtered, and then concentrated in vacuo to remove AcOEt. The solids were
recrystallized in C2 H5 OH to yield compound 2 as a colorless crystal (7.64 g, 92%). Mp 62-63 ˚C. 1 H-NMR
(200 MHz, DMSO-d6), δ: 3.83 (s, 3H, OCH3), 5.17 (s, 2H, ArCH2 O), 7.01-7.67 (m, 8H, Ar-H), 9.87 (s, 1H,
CHO). EI-MS, m/z: 242 (M+ , 14.3), 214 (3.2), 91 (100), 65 (13.5), 51 (5.2).
(E)-ethyl 3-(4-(benzyloxy)-3-methoxyphenyl)acrylate (3) Compound 2 (7.28 g, 0.30 mol) and
(Ph)3 PCHCOOEt (10.44 g, 0.030 mol) in dry benzene were refluxed for 10 h and concentrated in vacuo. Flash
column chromatography of the residue gave compound 3 as a white crystal (6.78 g, 72%). Mp 68-72 ˚C.
1 H-NMR (200 MHz, CDCl3), δ: 1.44 (t, 3H, J = 7.2 Hz, COCH2 CH3), 3.98 (s, 3H, OCH3), 4.26 (q, 2H, J =
7.2 Hz, COCH2 CH3), 5.10 (s, 2H, ArCH2 O), 6.25 (d, 1H, J = 14.2 Hz, ArCH=CH), 6.70-7.52 (m, 8H, ArH),
7.63 (d, 1H,J = 14.2 Hz, ArCH =CH). EI-MS, m/z: 312 (M+ , 15), 267 (12), 221 (1.2), 153 (8), 91 (100).
(E)-3-(4-(benzyloxy)-3-methoxyphenyl)prop-2-en-1-ol (4). At 0 ˚C, to a suspension of LiAlH4
(2.40 g, 63.4 mmol) in dry THF (100 mL), dry AlCl3 (2.82 g, 21.2 mmol) was added and stirred for 20 min.
Then compound 3 (6.6 g, 21.2 mmol) was added. The mixture was stirred for 10 h at room temperature, and
then quenched with H2 O, filtered, and concentrated in vacuo. Flash column chromatography of the residue
gave 4 as a white crystal (5.0 g, 88%). Mp 79-80 ˚C. 1 H-NMR (300 MHz, CDCl3): 3.88 (s, 3H, OCH3),
4.28 (d, 2H,J = 6.0 Hz, CH2 OH), 4.61 (s, 1H, OH), 5.13 (s, 2H, ArCH2 O), 6.24 (dt, 1H, J = 6.0, 15.9 Hz,
ArCH=CH), 6.53 (d, 1H,J = 15.9 Hz, ArCH =CH), 6.68-7.44 (m, 8H, ArH). EI-MS, m/z: 270 (M+ , 25),
179 (12), 151 (8), 119 (18), 91 (100).
(1S,2S)-1-(4-(benzyloxy)-3-methoxyphenyl)propane-1,2,3-triol (5) To a stirred solution of t-
BuOH (50 mL) and H2 O (50 mL) was added AD-mix-a (14 g) and MeSO2 NH2 (960 mg), and the mixture
was stirred at room temperature until both phases were clear, and then cooled to 0 ˚C. Compound 4 (2.7 g, 10
mmol) was added at once, and the mixture was stirred vigorously at 0 ˚C until TLC revealed the absence of
4. The reaction was quenched at 0 ˚C by addition of Na2 SO3 (15 g), then warmed to room temperature, and
stirred for 0.5 h. The reaction mixture was extracted with AcOEt (3 × 100 mL) and dried over MgSO4 ; then
the AcOEt was distilled off. Flash chromatography of the residue over silica gel gave compound 5 (2.9 g, 95%)
as a white crystal in 93% e.e. Mp 153-155 ˚C. [α]2D0 = –71.0 (c 1.0, acetone). IR (KBr/cm−1): 3410, 2935,
2840, 1655, 1516, 1460, 1155, 990. 1 H-NMR (300 MHz, CDCl3): 3.40 (dd, 1H, J = 3.0, 9.4 Hz, CH2 OH),
3.47 (dd, 1H, J = 3.0, 9.4 Hz, CH2 OH), 3.60-3.73 (m, 1H, CH OHCH2 OH), 3.82 (s, 3H, OCH3), 4.61 (d, J
= 6.5 Hz, 1H, ArCH OH), 5.10 (s, 2H, ArCH2 OAr), 6.86-7.04 (m, 3H, ArH), 7.31-7.51 (m, 5H, ArH). EI-MS,
m/z: 304 (M+ , 0.9), 286 (5), 243 (17), 153 (24), 91 (100). HRMS calcd for C17 H24 NO5 (M+NH+4 ): 322.1649.
Found: 322.1652. The data are consistent with the literature.12
(2S,3S)-3-(4-(benzyloxy)-3-methoxyphenyl)-2,3-dihydroxypropyl 4-methylbenzenesulfonate
(6) At room temperature to a solution of TsCl (1.52 g, 8 mmol) in CH2 Cl2 (60 mL) was added compound
5 (2.4 g, 8 mmol) and pyridine (30 mL). The mixture was stirred vigorously until TLC revealed the absence
of 5. The mixture was quenched with HCl solution and then extracted with AcOEt. The organic layer was
washed with NaHCO3 and NaCl saturated solution consecutively, then dried over MgSO4 , and concentrated
in vacuo. Flash chromatography of the residue over silica gel gave compound 6 (3.0 g, 83%) as amorphous
powder in 95% e.e. [α]2D0 = –42.3 (c 0.5, CHCl3). IR (KBr/cm−1): 3420, 2941, 2845, 1641, 1520, 1422,
1318, 1235, 1102, 1023. 1 H-NMR (300 MHz, CDCl3): 2.44 (s, 3H, ArCH3), 3.90 (s, 3H, ArOCH3), 3.84-3.96
377

Asymmetric synthesis of 8-O-4ꢀ -neolignan perseal B, Y. M. XIA, et al.,
(m, 1H, CH OHCH2 OTs), 3.98-4.11 (m, 2H, CH2 OTs), 4.60 (d, 1H, J = 6.0 Hz, ArCH OH), 5.14 (s, 2H,
ArCH2 OAr), 6.72-7.76 (m, 12H, ArH). 13 C-NMR (75 MHz, CDCl3), δ: 21.6 (ArCH3), 56.0 (OCH3), 70.3
(CH2 OTs), 70.9 (C HOHCH2 OTs), 73.4 (ArCH2 OAr), 73.7 (ArC HOHCH), 109.9, 113.7, 118.8, 127.2, 127.2,
127.9, 127.9, 128.6, 128.6, 129.9, 129.9, 132.5, 132.5, 136.9, 136.9, 146.1, 148.1, 149.8. EI-MS, m/z: 458 (M+ ,
2.4), 286 (1.2), 268 (0.7), 243 (4.8), 123 (7.8), 91 (100). HRMS calcd for C24 H30 NO7 S (M+NH+4 ): 476.1738.
Found: 476.1732.
(S)-(4-(benzyloxy)-3-methoxyphenyl)((S)-oxiran-2-yl)methanol (7) To a solution of K 2 CO3 (0.32
g, 2.2 mmol) in methanol was added compound 6 (2.0 g, 4.4 mmol). The mixture was stirred at room tem-
perature for 5 h; then the reaction mixture was concentrated in vacuo. The residue was dissolved in AcOEt
and washed with water and NaCl saturated solution 3 times consecutively. The extract was dried over MgSO4
and concentrated in vacuo. Flash column chromatography of the residue over silica gel gave compound 7 (1.2
g, 96%) as colorless liquid in 92% e.e. [α]D20 = –36.2 (c 0.6, CHCl3). IR (KBr/cm−1): 3450, 2983, 2936,
2840, 1732, 1604, 1592, 1512, 1465, 1262, 1140, 1027, 916. 1 H-NMR (300 MHz, CDCl3), δ: 2.80-2.89 (m, 2H,
CHOCH2), 3.16-3.25 (m, 1H, CH CH2 O), 3.97 (s, 3H, OCH3), 4.43 (d, 1H, J = 5.8 Hz, ArCH OHCH), 5.17
(s, 2H, ArCH2 OAr), 6.87-7.45 (m, 8H, ArH). 13 C-NMR (75 MHz, CDCl3), δ: 45.6 (CHC H2 O), 56.2(OMe-3),
56.7 (C HCH2 O), 71.3 (ArCH2 OAr), 74.8 (ArC HOHCH), 109.3, 113.9, 121.5, 126.7, 127.2, 127.2, 127.9, 128.5,
128.5, 137.1, 147.3, 149.6. EI-MS, m/z: 286 (M+ , 5), 243 (0.7), 165 (0.4), 123 (0.2), 91 (100). HRMS calcd
for C17 H22 NO4 (M+NH+4 ): 304.1544. Found: 304.1547. The data are consistent with the literature.12
(1S,2S)-1-(4-(benzyloxy)-3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yloxy)propan-2-ol (8)
To a solution of compound 7 (0.86 g, 3.0 mmol) in dry CH2 Cl2 were added DHP (0.26 g, 3.0 mmol) and a
catalytic amount of PPTS. The mixture was stirred at room temperature until TLC revealed the absence of 7.
Then the mixture was concentrated in vacuo. The residue was added to a solution of LiAlH4 (120 mg, 3.0 mmol)
in dry THF. The mixture was stirred at room temperature for 24 h. The mixture was quenched with H2 O,
filtered, and concentrated in vacuo. Flash column chromatography of the residue over silica gel gave compound
20
D
8 (0.92 g, 82%) as a colorless liquid in 93% e.e. [α]
=–31.8 (c 0.3, CHCl3). IR (KBr/cm−1): 3418, 2936,
2869, 1593, 1513, 1457, 1418, 1380, 1263, 1226, 1137, 1075, 1028, 809. 1 H-NMR (300 MHz, CDCl3), δ: 1.00
(d, 3H, CHOHCH3), 1.44-1.72 (m, 6H, CH2), 3.20 (m, 1H, CH2 CH2 O), 3.45 (m, 1H, CH2 CH2 O), 3.89 (s,
3H, OCH3), 3.84-4.05 (m, 1H, CH OHCH3), 4.16 (d, 1H, J = 7.5 Hz, ArCHOTHP), 4.84 (s, 1H, OCHO), 5.14
(s, 2H, ArCH2 OAr), 6.82-6.90 (m, 3H, ArH), 7.30-7.44 (m, 5H, ArH). 13 C-NMR (75 MHz, CDCl3), δ: 18.2
(HOCHC H3), 19.3 (CH2C H2), 25.2 (CH2C H2), 30.5 (CH2C H2), 55.9 (CH3 O), 62.4 (CH2C HOCH), 71.0
(CHOH), 71.1 (ArCH2 O), 85.7 (ArCHOTHP), 100.0 (OCHO), 110.8, 113.4, 119.7, 127.3, 127.3, 127.8, 128.5,
128.5, 133.3, 137.1, 147.6, 149.3. EI-MS, m/z: 372 (M+ , 0.4), 328 (1.6), 288 (0.3), 271 (0.6), 243 (37), 91 (98),
85 (100). HRMS calcd for C22 H32 NO5 (M+NH+4 ): 390.2273. Found: 390.2275.
4-((1S,2S)-1-hydroxy-1-(4-hydroxy-3-methoxyphenyl)propan-2-yloxy)-3-methoxybenzal-
dehyde (1) A mixture of (1S ,2S)-8 (0.74 g, 2.0 mmol), vanillin (0.46 g, 3.0 mmol), triphenylphosphine (0.80
g, 3.0 mmol), and diethylazodicarboxylate (0.48 mL, 3.0 mmol) was heated to reflux in anhydrous THF (30 mL)
for 24 h under nitrogen. The mixture was concentrated under reduced pressure. The residue was added to a
solution of HCl in MeOH (0.3 N, 50 mL), and the mixture was stirred at room temperature for 8 h. The solution
was neutralized with NaHCO3 saturated solution. Subsequently the solvent was concentrated in vacuo and the
residue was taken up in AcOEt. The organic phase was separated, washed with H2 O, dried with Na2 SO4 ,
378

Asymmetric synthesis of 8-O-4ꢀ -neolignan perseal B, Y. M. XIA, et al.,
and concentrated in vacuo. To a stirred solution of residue (0.43 g, 1.1 mmol) in methanol (70 mL) was added
10% palladized charcoal (50 mg). After stirring for 8 h at room temperature under atmospheric pressure of
hydrogen, the solvent was concentrated under reduced pressure. Flash column chromatography of the residue
20
D
over silica gel gave compound (1S ,2S)-1 (0.29 g, 44%) as amorphous powder in 91% e.e. [α]
=+58.3 (c
0.6, CHCI3). IR (KBr/cm−1): 3420, 2930, 2850, 1675, 1590, 1510. 1 H-NMR (300 MHz, CDCl3): δ: 1.22 (d,
3H, J = 6.4 Hz, Me-8), 3.90 (s, 3H, OMe-3), 3.96 (s, 3H, OMe-3’), 4.40 (m, 1H, H-8), 4.71 (d, 1H, J = 8.0
Hz, H-7), 6.88-6.94 (m, 3H, Ar-H), 7.05-7.46 (m, 3H, Ar-H’), 9.86 (s, 1H, CHO). 13 C-NMR (75 MHz, CDCl3),
δ: 16.4 (Me-9), 56.0 (OMe-3), 56.0 (OMe-3’), 78.0 (C-7), 82.1 (C-8), 109.3 (C-2), 109.9 (C-6’), 114.2 (C-5),
115.2 (C-5’), 120.6 (C-6), 126.3 (C-2ꢀ ), 131.0 (C-1), 131.4 (C-1ꢀ ), 145.8 (C-4), 146.7 (C-3), 150.8 (C-3), 153.2
(C-4ꢀ ), 190.8 (CHO).El-MS, m/z: 332 (M+ , 3.46), 180 (84.7), 153 (83.8), 151 (100), 135 (46). HRMS calcd for
C
18 H24 NO6 (M+NH+4 ): 350.1605. Found: 350.1599. The data are consistent with the literature.3
Results and discussion
As shown in the Scheme, synthesis of the target compound 1 began from vanillin. Protection of the hydroxyl
group with benzyl bromide afforded compound 2. The Wittig reaction was carried out between compound 2
and (Ph)3 PCHCOOEt, and unsaturated ester (E)-3 was synthesized. Reduction of (E)-3 with LAH gave
the corresponding unsaturated alcohol (E)-4 in high yields. It is interesting to note that compound 4 was
treated with AD-mix-α to afford directly compound (1S ,2S)-5 in 93% e.e.13 In fact, this reaction was a
dihydroxylation of AD-mix-α to the double bond of 4 to obtain 2 chiral centers. Treatment of (1S ,2S)-5
with sterically hindered acid chlorides TsCl in pyridine provided the primary tosylate (1S ,2S)-6. Because of
the steric hindrance, this reaction only occurred in primary hydroxyl. This was followed by ring closure using
K2 CO3 in methanol to afford (1S ,2S)-7. The hydroxy group of 7 was protected by DHP, and then ring
opening using LiAlH4 in THF gave (1S ,2S)-8. Mitsunobu reaction between compound 8 and vanillin could
give (1S ,2S)-1, The Mitsunobu reaction provided an uncharacterized mixture and the absolute configuration
at the C-8 stereogenic center was not inverted completely. 14 Then the THP group was removed with 0.3N HCl
in MeOH and the benzyl group was cleaved by hydrogenation with a 10% palladium on charcoal catalyst, and
(1S ,2S)-perseal B 1 was obtained. The data of (1S ,2S)-perseal B 1 were agreement with those reported in
the literature.3
In summary, we have developed an efficient chiral synthetic method to give perseal B. With cheap
materials, short experimental procedures, mild conditions, and simple operations, the route will exhibit more
potential value in the future.
Acknowledgements
This work was financially supported by Specialized Research Fund for the Doctoral Program of Higher Education
of China (NO.20093719120004), Taishan Scholar Project of Shandong Province (NO.2005011036), and Open
Foundation of Chemical Engineering Subject, Qingdao University of Science & Technology, China.
379

Asymmetric synthesis of 8-O-4ꢀ -neolignan perseal B, Y. M. XIA, et al.,
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380

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