Asymmetric synthesis of erythro-8-O-4'-neolignan Machilin C

Article abstract of DOI:10.1016/j.mencom.2010.05.009

A new methodology for the synthesis of the erythro-8-O-4'-neolignan Machilin C based on the Sharpless asymmetric dihydroxylation reaction and the Mitsunobu reaction as two key steps is described.

Full text of DOI:10.1016/j.mencom.2010.05.009

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 151–152
Asymmetric synthesis of erythro-8-O-4'-neolignan Machilin C
Yamu Xia,* Liang Chang, Yining Ding and Bin Jiao
College of Chemical Engineering, Qingdao University of Science and Technology, 266042 Qingdao, P. R. China.
Fax: +86 0532 8402 3271; e-mail: xiaym@qust.edu.cn
DOI: 10.1016/j.mencom.2010.05.009
A new methodology for the synthesis of the erythro-8-O-4'-neolignan Machilin C based on the Sharpless asymmetric dihydroxyla-
tion reaction and the Mitsunobu reaction as two key steps is described.
Machilin C was first obtained from the bard of Machilus
thunbergii, which have been used in traditional chinese medi-
cine.1 As a plant-derived natural product, Machilin C belongs to the
class of 8-O-4'-neolignans, and this class comprises a large group
of secondary plant metabolites, which are biochemically related
to the shikimic acid pathway.2 In nature, 8-O-4'-neolignans are
formed by oxidative coupling of two phenyloro-panokd units, and
display biological activities including an inhibitory effect on
seed germination and antioxidant and antimalarial activities.3–6
The representatives of 8-O-4'-neolignans occur in nature as
racemic mixtures.7 Since the natural compounds with biological
activity are usually enantiopure, the study of asymmetric
synthesis will help us to find other versions of neolignan and
similar types of compounds with higher activity. On the other
hand, the alternative of obtaining enantiopure materials via
synthesis has not been carefully pursued. Synthetic studies have
given rise to racemic mixtures of syn- and anti-configured pro-
ducts, while existing enantioselective routes appear efficiency,
poor enantioselective processes and some chiral syntheses give
threo-8-O-4'-neolignans.8–10 The modification of optical purity
under totally achiral conditions without any external action or
special environmental context was reported.11,12
As shown in Scheme 1, the synthesis of the target compound
began from vanillin. Treatment of vanillin with benzyl chloride
afforded compound 2. By the Wittig reaction between com-
pound 2 and (Ph)3PCHCOOEt, unsaturated ester (E)-3 was
synthesized. Reduction of (E)-3 with LAH gave corresponding
unsaturated alcohol (E)-4 in a high yield. Note that compound 4
was treated with AD-mix-α to afford compound (1S,2S)-5.13 In
fact, this reaction was the Sharpless dihydroxylation, and it was
used in the enantioselective preparation of 1,2-diols from pro-
chiral olefins. At 0 °C, a good result has been achieved, and
asymmetric dihydroxylation of trans-1,2-disubstituted olefin 4
with AD-mix-α [(DHQ)2PHAL] led to (1S,2S)-5. Chrial analysis
of (1S,2S)-5 was performed on Varian Dynamax SD-300 using
chiralcel column CDMPC with hexane–isopropanol (20:1 v/v,
0.5 ml min–1, 25 °C) as an eluent and reached the 93% ee.
Treatment of (1S,2S)-5 with TsCl in pyridine provided (1S,2S)-6.
Due to the steric hindrance of TsCl, this reaction only occurred
in primary hydroxyl group of compound 5. Ring closure of
(1S,2S)-6 was promoted by K2CO3 in methanol, generating
oxirane (1S,2S)-7. The hydroxy group of 7 was protected by
DHP, and then three-ring was opened by LiAlH4 in THF to give
(1S,2S)-8 in 82% yield. The 1H NMR spectrum of compound 8
showed two doublets, ascribable to H9 at d 1.00 (J 7.0 Hz) and
H7 at d 4.16 (J 7.5 Hz). The configuration was deduced to be
threo on the basis of the coupling constant (J 7.5 Hz) between
H7 and H8.† The benzyl group of compound 8 was removed;
then, it was protected with methoxymethyl chloride (MOMCl)
to produce key intermediate 9 in 90% yield.
Here, we report the design and development of a new asym-
metric route to erythro-8-O-4'-neolignans. The synthetic route
involved two key procedures: the chiral configuration of
(1S,2S)-alcohol was formed via the asymmetric dihydroxyla-
tion reaction and the absolute configuration was inverted from
threo- to erythro-isomer via the Mitsunobu reaction.†
MeO
HO
CHO
MeO
BnO
CHO
MeO
BnO
COOEt
BnCl, K2CO3
LAH/AlCl3
THF, 88%
(Ph)3PCHCOOEt
C6H6, reflux,72%
EtOH, reflux,
92%
2
3
OH
OH
AD-mix-α,
MeO
MeO
BnO
MeO
BnO
MeSO2NH2
OH
OH
OTs
TsCl, pyridine
ButOH/H2O,
0 °C, 94%
CH2Cl2, room
temperature, 83%
OH
OH
BnO
4
5
6
4'
3'
5'
i, DHP, PPTS,
CH2Cl2
ii, LAH, THF,
room temperature
i, Pd/C (10%), H2,
room temperature
ii, MOMCl, K2CO3,
acetone
2'
6'
OH
O
O1'
O
O
10
2
MeO
BnO
1
MeO
MeO
3
8
9
7
K2CO3
4
MeOH, room
temperature, 95%
O
OH
OH
6
BnO
MOM–O
5
8
9
7
Scheme 1
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© 2010 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2010, 20, 151–152
Vanillin was protected with MOMCl to obtain compound
O–THP
OH
10. The Wittig reaction carried out between compound 10
and (Ph)3P=CHMe resulted in (E)-11. Then, the MOM group
was cleaved by HCl to give intermediate (E)-isoeugenol 12
(Scheme 2).†
MeO
MeO
HO
+
MOM–O
9
12
MeO
HO
CHO
MeO
CHO
i, Ph3P, DEAD, THF, reflux
ii, HCl, MeOH, room temperature
MOMCl, NaH
THF, 93%
MOM–O
OH
10
2
9
7
MeO
HO
3
1
MeO
8
Ph3P=CHMe
THF, 82%
5'
2'
4
O
6
6'
4'
5
MOM–O
9'
3'
8'
1'
MeO
11
7'
10
1
2
5
MeO
3
1
7
9
HCl
Scheme 3
8
4
MeOH, room
temperature, 87%
6
spectrum of Machilin C, H7 resonated as a doublet signal at
d 4.84 with the coupling constant J 2.9 Hz indicates erythro-
configuration. Chiral analysis of Machilin C was in agreement
with that of compound 5 and reached 92% ee.
HO
12
Scheme 2
As shown in Scheme 3, the Mitsunobu protocol involves the
reaction of alcohol 9 and phenol 12 (NuH) in the presence
of triphenylphosphine and diethylazodicarboxylate to afford a
homologous compound containing a newly formed C–O bond.
In this reaction, the C8 stereogenic centre of compound 9 was
completely inverted from S- to R-configuration.14 Then, the
MOM and THP groups were cleaved by HCl in MeOH and
(1S,2R)-Machilin C 1 was obtained in 74% yield.† In the 1H NMR
In summary, we have developed a chiral synthetic method
of erythro-8-O-4'-neolignans to give Machilin C. With cheap
materials, short experimental procedures, mild conditions and
simple operations, the route can exhibit a more potential value
in the future.
This work was supported by the Specialized Research Fund
for the Doctoral Program of Higher Education of China (grant
no. 20093719120004), the Taishan Scholar Project of Shandong
Province (project no. 2005011036) and the Open Foundation of
Chemical Engineering Subject, Qingdao University of Science
& Technology, China.
(1S,2R)-Machilin C 1: amorphous powder in 92% ee, [a]D20 –18.4
†
(c 0.1, CHCl3). IR (KBr, n/cm–1): 3540, 2963, 2862, 1612, 1520, 1505,
1382, 1028. 1H NMR (500 MHz, CDCl3) d: 1.18 (d, 3H, C9H3, J 6.5 Hz),
1.87 (d, 3H, C9'H3, J 7.0 Hz), 3.87 (s, 3H, OMe), 3.91 (s, 3H, OMe),
4.35 (m, 1H, C8H), 4.84 (d, 1H, C7H, J 2.9 Hz), 6.18 (m, 1H, C8'H), 6.35
(m, 1H, C7'H), 6.75–7.10 (m, 6H, HAr). 13C NMR (125 MHz, CDCl3) d:
13.4 (C9), 18.3 (C9'), 56.0 (2OMe), 73.6 (C8), 82.4 (C7), 108.9 (C2),
109.4 (C2'), 113.9 (C5), 119.0 (C6'), 119.1 (C5'), 119.9 (C6), 125.0 (C8'),
130.5 (C7'), 131.9 (C1'), 133.7 (C1), 144.8 (C4), 145.6 (C3'), 146.5 (C3),
151.5 (C4'). EI-MS, m/z (%): 344 (M+, 2.6), 192 (25.7), 164 (3.8), 137
(4.6), 91 (100). HRMS, m/z: 362.1967 ([M + NH4]+, calc. for C20H28NO5:
362.1962). The spectral data are in agreement with those reported in the
literature.1
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Received: 27th October 2009; Com. 09/3409
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