Asymmetric synthesis of the natural erythro-(1R,2S)-8-O-4′-neolignan myrislignan

Article abstract of DOI:10.1007/s00706-010-0420-3

An efficient and practical asymmetric synthesis of erythro-(1R,2S)-8-O- 4′-neolignan myrislignan was achieved by using vanillin and pyrogallic acid as the starting materials. Two key steps are involved: preparation of an enantiopure threo alcohol of predictable stereochemistry by dihydroxylation with AD-mix-β, and inversion of the absolute configuration from the threo to the erythro isomer using a Mitsunobu reaction. The route illustrates a new methodology for the synthesis of erythro-8-O-4′-neolignan. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-010-0420-3

Monatsh Chem (2011) 142:93–96
DOI 10.1007/s00706-010-0420-3
ORIGINAL PAPER
Asymmetric synthesis of the natural
erythro-(1R,2S)-8-O-40-neolignan myrislignan
•
Y. Xia Wei Wang
Received: 13 January 2010 / Accepted: 8 November 2010 / Published online: 8 December 2010
Ó Springer-Verlag 2010
Abstract An efficient and practical asymmetric synthesis
of erythro-(1R,2S)-8-O-40-neolignan myrislignan was
achieved by using vanillin and pyrogallic acid as the starting
materials. Two key steps are involved: preparation of an
enantiopure threo alcohol of predictable stereochemistry by
dihydroxylation with AD-mix-b, and inversion of the abso-
lute configuration from the threo to the erythro isomer using a
Mitsunobu reaction. The route illustrates a new methodology
for the synthesis of erythro-8-O-40-neolignan.
extensive library of representatives of the class [7]. However,
obtaining supplies from nature is an arduous task because of
the low quantity of isolable compounds and the fact that most
of the isolated neolignans reported are racemic mixtures [8].
On the other hand, the alternative of obtaining useful quan-
tities of enantiopure materials via synthesis has not been
carefully pursued. Most of the pioneering synthetic studies
afforded racemic mixtures of threo- and erythro-configured
products, while existing enantioselective routes appear lim-
ited by low overall efficiency and poorly enantioselective
processes; most of asymmetric synthesis gave threo-8-O-40-
neolignans [9–13].
Keywords Asymmetric dihydroxylation ꢀ Myrislignan ꢀ
Neolignan ꢀ Mitsunobu reaction
Herein, an efficient asymmetric synthesis of erythro-8-
O-40-neolignans is presented. The synthetic route involved
two key steps: preparation of an enantiopure threo alcohol
of predictable stereochemistry by dihydroxylation with
AD-mix-b, and inversion of the absolute configuration
from threo to erythro using a Mitsunobu reaction. By this
method the erythro-(1R,2S)-8-O-40-neolignan myrislignan
was obtained for the first time.
Introduction
Myrislignan is found in the seeds (nutmeg) or aril (mace)
of Myristica fragrans Houtt (Myristicaceae) used as tra-
ditional Chinese medicine in China and Japan owing to its
carminative, anxiogenic, and anti-ulcerogenic activities
[1, 2]. Since erythro-(1R,2S)-myrislignan was discovered
in 1973, it has attracted increasing interest because of its
biological activities. Various studies suggest that it may
affect hepatic mixed-function oxidase enzyme activity and
have antifungal properties [3–5]. In 2006, Yang reported
the biotransformation of myrislignan by rat liver micro-
somes in vitro [6].
Results and discussion
As shown in Scheme 1, synthesis of the target compound
started from vanillin. Protection of the hydroxyl group with
benzyl chloride afforded compound 2 [14]. A Wittig
reaction between compound 2 and Ph3PCHCOOEt gave
the unsaturated ester (E)-3 [15]. Reduction of (E)-3 with
LiAlH4 afforded the corresponding unsaturated alcohol
(E)-4 in high yields. Asymmetric dihydroxylation of
compound 4 with AD-mix-b directly afforded threo-
(1R,2R)-5 in 93% ee [16], i.e., with creation of two adja-
cent stereocenters with threo configuration [17]. Treatment
of threo-(1R,2R)-5 with p-toluenesulfonyl chloride in
erythro-(1R,2S)-Myrislignan belongs to the very inter-
esting class of 8-O-40-neolignans, and nature offers an
Y. Xia (&) ꢀ W. Wang
College of Chemical Engineering,
Qingdao University of Science and Technology,
Qingdao 266042, People’s Republic of China
e-mail: xiaym@qust.edu.cn
123

94
Y. Xia, W. Wang
Scheme 1
O
H3CO
BnO
CHO
Ph3PCHCOOEt
H3CO
H3CO
HO
CHO
BnCl, K2CO3
OEt
LiAlH4/AlCl3
THF, 90%
EtOH, reflux, 90%
C6H6, reflux, 70% BnO
OH
2
3
OH
H3CO
BnO
H3CO
BnO
H3CO
BnO
OH
AD-mix-β, MeSO2NH2
TsCl, pyridine
OH
OTs
OH
OH
tBuOH/H2O, 0 oC, 94%
CH2Cl2, rt, 83%
4
5
6
OH
OTHP
1) Dihydropyran, pyridinium
H3CO
BnO
H3CO
BnO
-toluenesulfonate, CH Cl
K2CO3, MeOH
rt, 95%
p
2
2
O
OH
2) LiAlH4, THF, rt
82%
7
8
pyridine provided the primary tosylate threo-(1R,2R)-6. As
a result of steric hindrance, only the primary hydroxyl
group of threo-(1R,2R)-5 was tosylated. Ring closure of
(1R,2R)-6 was promoted by K2CO3 in methanol, generat-
ing the oxirane (1R,2R)-7. The hydroxyl group of 7 was
protected with dihydropyran to afford the corresponding
tetrahydropyran (THP) ether, followed by oxirane reduc-
tion using LiAlH4 to give threo-(1R,2R)-8 in 82% yield.
As shown in Scheme 2, trimethylation of pyrogallic acid
with CH3I afforded compound 9. Selective cleavage of the 2-O-
methyl ether in compound 9 by ZnCl2 in propionic acid gave
compound 10; the 1-O- and 3-O-methyl ethers were stable
under these reaction conditions. The reaction of 10 and allyl
bromide afforded compound 11. The Claisen rearrangement of
allyl phenyl ether 11 at 170 °C produced p-allylphenol 12 [18].
This reaction was also accelerated by pressure.
were in agreement with those reported in the literature
[5, 20].
Experimental
Melting points were taken on a Gallenkamp melting point
apparatus. Optical rotations were determined on a Perkin-
Elmer 341 polarimeter. Chiral analysis was performed on a
Varian Dynamax SD-300 using chiralcel column CDMPC
(150 9 4.6 mm ID) with hexane/isopropyl alcohol as elu-
ent. Infrared spectra were recorded on a Nicolet NEXUS
670 FT-IR. The 1H NMR and 13C NMR spectra were
recorded on Mercury Plus 300 MHz and Bruker 500 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 plates (GF254).
The benzyl group of compound 8 was removed by hy-
drogenolysis, then the resulting phenol was protected with
methoxymethyl chloride (MOMCl) to afford threo-(1R,2R)-
13. Mitsunobu reaction between threo-(1R,2R)-13 and
compound 12 gave a product with erythro configuration,
where the absolute configuration at the C-8 stereogenic
center was inverted completely by the SN2-type nucleophilic
displacement by 12 ([92% ee) [19]. Then, the MOM and
THP groups were cleaved by HCl in MeOH and (1R,2S)-
myrislignan 1 was obtained as a single erythro isomer in 62%
yield. The total yield of compound 1 is 9.7%. The data of 1
threo-(1R,2R)-1-(4-Benzyloxy-3-methoxyphenyl)-3-O-
tosyl-1,2,3-propanetriol (6, C24H26O7S)
Compound 5 (6.1 g, 20 mmol) and 20 cm3 pyridine were
added to a solution of 3.8 g p-toluenesulfonyl chloride
(20 mmol) in 70 cm3 CH2Cl2 at room temperature. The
mixture was stirred vigorously until TLC revealed the
absence of 5, then quenched with HCl solution and
OH
Scheme 2
OCH3
OH
HO
OH
CH3I, K2CO3
Acetone, 93%
H3CO
OCH3
H3CO
OCH3
Ally bromide
ZnCl2
C2H5COOH, 78%
K2CO3, Acetone, 92%
10
9
H3CO
O
H3CO
170oC, 92%
HO
H3CO
H3CO
11
12
H3CO
OH
2
5
9
7
OTHP
3
4
OTHP
H3CO
HO
1
1) 12, Ph3P, DEAD
OCH3
6'
8
H3CO
BnO
1) Pd/C (10%), H2, rt
THF, reflux
O
6
5'
OH
1'
H3CO
OH
2) HCl,MeOH, rt
62%
2) MOMCl, K2CO3
Acetone
MOMO
13
7'
9'
4'
2'
8'
3'
8
1
123

Natural erythro-(1R,2S)-8-O-40-neolignan myrislignan
95
extracted with EtOAc. The organic layer was washed with
saturated NaHCO3 and NaCl solution, dried over MgSO4,
and concentrated in vacuo. Flash chromatography of the
residue over silica gel afforded 7.6 g (83%) 6 as amor-
quenched with water, filtered, and concentrated in vacuo.
Flash column chromatography of the residue over silica gel
gave 3.1 g (82%) 8 as a colorless liquid in 93% ee.
[a]2D0 = ?31.8° cm3 g-1 dm-1 (c = 0.3, CHCl3); IR
(KBr): m = 3,418, 2,936, 2,869, 1,593, 1,513, 1,457,
1,418, 1,380, 1,263, 1,226, 1,137, 1,075, 1,028,
809 cm-1 1H NMR (300 MHz, CDCl3): d = 1.00 (d,
;
phous powder with 95% ee. Mp: 130–132 °C; [a]D20
=
ꢀ
?42.3° cm3 g-1 dm-1 (c = 0.5, CHCl3); IR (KBr): m =
3,420, 2,941, 2,845, 1,641, 1,520, 1,422, 1,318, 1,235,
1,102, 1,023 cm-1; 1H NMR (300 MHz, CDCl3): d = 2.44
(s, 3H, ArCH3), 3.90 (s, 3H, ArOCH3), 3.84–3.96 (m, 1H,
CHOHCH2OTs), 3.98–4.11 (m, 2H, CH2OTs), 4.60 (d, 1H,
J = 6.0 Hz, ArCHOH), 5.14 (s, 2H, ArCH2OAr),
6.72–7.76 (m, 12H, Ar) ppm; 13C NMR (75 MHz, CDCl3):
d = 21.6 (ArCH3), 56.0 (OCH3), 70.3 (CH2OTs), 70.9
(CHOHCH2OTs), 73.4 (ArCH2OAr), 73.7 (ArCHOHCH),
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 ppm; 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
C24H30NO7S (M ? NH4?) 476.1738, found 476.1732.
ꢀ
3H, J = 7.0 Hz, OHCHCH3), 1.44–1.72 (m, 6H, CH2),
3.20 (m, 1H, CH2CH2O), 3.45 (m, 1H, CH2CH2O), 3.89 (s,
3H, OCH3), 3.84–4.05 (m, 1H, CHOHCH3), 4.16 (d, 1H,
J = 7.5 Hz, ArCHOTHP), 4.84 (s, 1H, OCHO), 5.14 (s,
2H, ArCH2OAr), 6.82–6.90 (m, 3H, Ar), 7.30–7.44 (m, 5H,
Ar) ppm; 13C NMR (75 MHz, CDCl3): d = 18.2
(CH2CH2), 19.3 (HOCHCH3), 25.2 (CH2CH2), 30.5
(CH2CH2), 55.9 (CH3O), 62.4 (CH2OCH), 71.0
(CH3CHOH), 71.1 (ArCH2O), 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 ppm; 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 C22H32NO5 (M ? NH4
)
threo-(1R,2R)-1-(4-Benzyloxy-3-methoxyphenyl)-2,3-
epoxy-1-propanol (7, C17H18O4)
390.2273, found 390.2275.
Compound 6 (6.9 g, 15 mmol) was added to a solution of
2.1 g K2CO3 (15 mmol) in methanol. The mixture was
stirred at room temperature for 5 h and concentrated in
vacuo. The residue was dissolved in EtOAc, then washed
with water and saturated NaCl aqueous solution for three
times. The extract was dried over MgSO4 and concentrated
in vacuo. Flash column chromatography of the residue over
silica gel afforded 4.1 g (95%) 7 as a colorless liquid in
92% ee. [a]2D0 = ?36.2° cm3 g-1 dm-1 (c = 0.6, CHCl3);
threo-(1R,2R)-1-[3-Methoxy-4-(methoxymethoxy)phenyl]-
1-(tetrahydropyran-2-yloxy)-2-propanol (13, C17H26O6)
Palladized charcoal (10%, 80 mg) was added to a stirred
solution of 2.2 g 8 (6 mmol) in 20 cm3 methanol. After
stirring for 4 h at room temperature under atmospheric
pressure of hydrogen, the solvent was filtered and
concentrated under reduced pressure. A solution of 0.6 g
MOMCl (6 mmol) was added (in one go) to a rapidly
stirred mixture of the resulting residue and 1.2 g K2CO3
(8 mmol) in 40 cm3 acetone under N2 at room temper-
ature. The mixture was stirred for 3 h and quenched with
water. The aqueous layer was extracted with ethyl acetate
and the extracts were washed with brine and dried with
Na2SO4. Then the solvent was removed in vacuo and
flash column chromatography of the residue over silica
gel afforded 1.8 g (90%) 13 as a colorless liquid.
[a]2D0 = ?28.7° cm3 g-1 dm-1 (c = 0.2, CHCl3); IR
ꢀ
IR (KBr): m = 3,450, 2,983, 2,936, 2,840, 1,732, 1,604,
1
1,592, 1,512, 1,465, 1,262, 1,140, 1,027, 916 cm-1; H
NMR (300 MHz, CDCl3): d = 2.80–2.89 (m, 2H,
CHOCH2), 3.16–3.25 (m, 1H, CHCH2O), 3.97 (s, 3H,
OCH3), 4.43 (d, 1H, J = 5.8 Hz, ArCHOHCH), 5.17 (s,
2H, ArCH2OAr), 6.87–7.45 (m, 8H, ArH) ppm; 13C NMR
(75 MHz, CDCl3): d = 45.6 (CHCH2O), 56.2 (OMe-3),
56.7 (CHCH2O), 71.3 (ArCH2OAr), 74.8 (ArCHOHCH),
109.3, 113.9, 121.5, 126.7, 127.2, 127.2, 127.9, 128.5,
128.5, 137.1, 147.3, 149.6 ppm; EI-MS: m/z = 286 (M?,
5), 243 (0.7), 165 (0.4), 123 (0.2), 91 (100); HRMS: calcd
for C17H22NO4 (M ? NH4?) 304.1544, found 304.1547.
ꢀ
(KBr): m = 3,452, 2,943, 2,852, 1,602, 1,513, 1,467,
1,382, 1,263, 1,135, 1,028, 902 cm-1 1H NMR
;
(500 MHz, CDCl3): d = 1.06 (d, 3H, J = 7.0 Hz,
OHCHCH3), 1.47–1.78 (m, 6H, CH2), 3.20 (m, 1H,
CH2CH2O), 3.43 (m, 1H, CH2CH2O), 3.52 (s, 3H,
OCH3), 3.85–4.02 (m, 4H, CHOHCH3, OCH3), 4.15 (d,
1H, J = 8.0 Hz, ArCHOTHP), 4.87 (s, 1H, OCHO), 5.29
(s, 2H, CH3OCH2OAr), 6.85–7.10 (m, 3H, Ar) ppm; 13C
NMR (75 MHz, CDCl3): d = 17.8 (CH2CH2), 19.5
(HOCHCH3), 24.9 (CH2CH2), 31.2 (CH2CH2), 55.7
(CH3O), 56.9 (CH3OCH2Ar), 62.4 (CH2OCH), 71.8
(CH3CHOH), 82.7 (ArCHOTHP), 95.8 (CH3OCH2Ar),
100.2 (OCHO), 111.8, 116.5, 120.2, 123.8, 144.3,
149.7 ppm; EI-MS: m/z = 326 (M?, 3.8), 294 (12.3),
threo-(1R,2R)-1-(4-Benzyloxy-3-methoxyphenyl)-1-(tetra-
hydropyran-2-yloxy)-2-propanol (8, C22H28O5)
Dihydropyran (0.9 g, 10 mmol) and a catalytic amount of
pyridinium p-toluenesulfonate were added to a solution of
2.9 g 7 (10 mmol) in dry CH2Cl2 and the mixture was
stirred at room temperature until TLC revealed the absence
of 7. Then the solvent was evaporated under reduced
pressure and the residue was added to a solution of 0.6 g
LiAlH4 (15 mmol) in an appropriate amount of dry THF.
The mixture was stirred at room temperature for 24 h,
123

96
Y. Xia, W. Wang
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280 (4.5), 263 (23.1), 91 (100); HRMS: calcd for
C17H30NO6 (M ? NH4?) 344.2068, found 344.2073.
erythro-(1R,2S)-Myrislignan (1, C21H26O6)
A mixture of 0.7 g (1R,2R)-13 (2 mmol), 0.4 g 12
(2 mmol), 0.6 g triphenylphosphine (2 mmol), and
0.3 cm3 diethyl azodicarboxylate (2 mmol) in 20 cm3
anhydrous THF was heated to reflux for 24 h under
nitrogen. The mixture was concentrated under reduced
pressure. A solution of HCl in MeOH (1 N, 20 cm3) was
added to the residue and the mixture was stirred at room
temperature for 8 h. The solution was neutralized with
saturated NaHCO3 solution and concentrated in vacuo. The
residue was taken up in EtOAc, washed with water, dried
over Na2SO4, and the solvent was evaporated under
reduced pressure. Flash column chromatography of the
residue over silica gel gave 0.5 g (62%) (1R,2S)-myrislig-
nan (1) as amorphous powder in 91% ee. The data of 1
were in agreement with those reported in the literature
[5, 20].
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Acknowledgments This work was supported by National Natural
Sciences Foundation of Shandong (No. ZR2010HM023), Specialized
Research Fund for the Doctoral Program of Higher Education of
China (No. 20093719120004), Open Foundation of Chemical Engi-
neering Subject, Qingdao University of Science & Technology.
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123