Asymmetric synthesis of (+)-machilin f by unusual stereoselective mitsunobu reaction

Article abstract of DOI:10.3987/COM-10-S(E)88

First synthesis of (+)-machilin F (1c) has been achieved in 16 steps as part of systematic synthetic studies on (-)-talaumidin (1) and its stereoisomers. The 2,3,4,5-tetrasubstituted tetrahydrofuran with the (2S,3S,4S,5S)-configuration has been constructe

Full text of DOI:10.3987/COM-10-S(E)88

HETEROCYCLES, Vol. 82, No. 2, 2011
1127
HETEROCYCLES, Vol. 82, No. 2, 2011, pp. 1127 - 1132. © The Japan Institute of Heterocyclic Chemistry
Received, 30th June, 2010, Accepted, 12th August, 2010, Published online, 13th August, 2010
DOI: 10.3987/COM-10-S(E)88
ASYMMETRIC SYNTHESIS OF (+)-MACHILIN F BY UNUSUAL
STEREOSELECTIVE MITSUNOBU REACTION
Kenichi Harada, Naoko Kubo, Kazuma Tanabe, Miwa Kubo, Tomoyuki
Esumi, Hideaki Hioki, and Yoshiyasu Fukuyama*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho,
Tokushima, 770-8514, Japan
E-mail: fukuyama@ph.bunri-u.ac.jp
Abstract – First synthesis of (+)-machilin F (1c) has been achieved in 16 steps as
part of systematic synthetic studies on (!)-talaumidin (1) and its stereoisomers.
The 2,3,4,5-tetrasubstituted tetrahydrofuran with the (2S,3S,4R,5R)-configuration
has been constructed stereoselectively from diol 14 by Mitsunobu reaction.
Talaumidin (1),1 a 2,5-biaryl-3,4-dimethyltetrahydrofuran neolignan with successive four stereogenic
centers, was isolated from Brazilian plant Aristolochia arcuata Masters along with a series of
2,5-biaryl-3,4-dimethyltetrahydrofuran type lignans. In addition to this structural feature, 1 not only
significantly promotes neurite-outgrowth but also exhibits neuroprotective activity in the primary cultured
rat cortical neurons and NGF-differentiated PC12 cells.2,3 Thus, 1 is expected to be a lead compound for
the treatment of neurodegenerative diseases such as Alzheimer’s disease. While 1 possesses the four
stereogenic centers on a tetrahydrofuran ring, there are the eight diastereomers without their enantiomers.
4
3
2
5
O
O
O
O
1
O
O
O
O
HO
HO
HO
HO
O
O
O
O
OMe
OMe
(2S,3S,4S,5R)-1a
OMe
(2S,3S,4R,5S)-1b
OMe
(2S,3S,4S,5S)-1
talaumidin
(2S,3S,4R,5R)-1c
machilin F
Figure 1. Talaumidin and its (2S,3S)-stereoisomers 1a-1c
Dedicated to Prof. Dr. Albert Eschenmoser on the occasion of his 85th birthday.

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HETEROCYCLES, Vol. 82, No. 2, 2011
From synthetic and biological points of view, it is desirable to develop a stereoselective approach toward
each synthesis of the seven diastereomers, which are specifically intended to compare the neurotrophic
activity of 1 and its stereoisomers. In the preceding papers,4,5 we reported the stereo-controlled syntheses
of (–)-talaumidin (1) and its stereoisomers (2S,3S,4S,5R)-1a and (2S,3S,4R,5S)-1b, but the synthesis of
(2S,3S,4R,5R)-1c, which is the sole remaining (2S,3S)-series, has not been achieved (Figure 1). As part of
our studies on the systematic synthesis of all the stereoisomers of talaumidin, we herein report the
efficient synthesis of (2S,3S,4R,5R)-1c by applying unusual setereoselective Mitsunobu reaction to
construct a tetrahydrofuran ring bearing (2S,5R)-configuration. It should be noted that the stereoisomer 1c
is a natural product, named machilin F6 and also 7-epi-austrobailignan,7 isolated from Machilus
thunbergii and Aristlochia Chilensis, respectively and no asymmetric synthesis of (2S,3S,4R,5R)-series
such as 1c has been reported though a number of syntheses of 2,5-biaryl-3,4-dimethyl tetrahydrofuran
lignans were reported. 8-14
Our synthetic strategy for machilin F (1c) is outlined in Scheme 1. An optically active compound 2 is
prepared by anti-selective Evans aldol reaction and diastereoselective hydroboration according to the
synthetic route of 1.4,5 (1S,2S,3R,4R)-Diol 3 would be derived from 2 by oxidation and Grignard reaction.
We envisioned the construction of the tetrahydrofuran ring of the target molecule 1c from diol 3 through
an intramolecular Mitsunobu reaction. This strategy introduces an intriguing question concerning the
stereochemical course of its reaction toward benzylic alcohols in 3.
O
O
OR
Mitsunobu-type
reaction
OH
OH
O
O
HO
RO
OH
O
OMe
RO
?
OMe
OMe
(1S,2S,3R,4R)-3
(2S,3S,4R,5R)-1c
machilin F
2
Scheme 1. Synthetic strategy for machilin F
The synthesis of machilin F began with the anti-selective Evans aldol reaction15-18 (Scheme 2). Reaction
of 4-benzyloxy-3-methoxybenzaldehyde (4) with (+)-4-benzyl-3-propionyloxazolidinone (5) catalyzed by
10 mol% MgCl2 in the presence of TMSCl and Et3N gave the (2S,3S)-aldol 6 in 86% yield with 98% de.
The alcohol 7 was obtained from 6 in 91% yield by TBS protection of secondary alcohol followed by
reductive removal of the oxazolidinone auxiliary. Swern oxidation of 7 followed by treatment with
CH3MgBr provided secondary alcohol 8 in 89% yield. Swern oxidation of 8 gave the ketone, which was
converted to the exo-methylene 9 by Tebbe olefination in 77% yield. The subsequent hydroboration of 9
with 9-BBN generated a new chiral center C-3, giving rise to the alcohol 10 in 71% yield with 99%
de.5,19,20

HETEROCYCLES, Vol. 82, No. 2, 2011
1129
O
TBSO
OH
O
O
O
CHO
a, b
c, d
OH
N
O
+
N
O
BnO
BnO
BnO
Bn
OMe
Bn
OMe
OMe
4
5
7
6
TBSO
TBSO
TBSO
OH
g, h
e, f
i
OH
BnO
BnO
BnO
OMe
OMe
OMe
8
9
10
Scheme 2. Reagents and Conditions: (a) 10 mol% MgCl2, TMSCl, Et3N, EtOAc, rt; (b) HF, pyridine,
MeCN, rt, 86% in 2 steps, 98% de; (c) TBSCl, imidazole, DMF, rt; (d) LiBH4, MeOH, ether, rt, 91% in 2
steps; (e) (COCl)2, DMSO, CH2Cl2, !78 oC, then Et3N, !10 oC; (f) MeMgBr, THF, 0 oC, 89% in 2 steps;
o
o
o
(g) (COCl)2, DMSO, CH2Cl2, !78 C, then Et3N, !10 C; (h) Tebbe reagent, THF, !40 C, 77% in 2
steps; (i) 9-BBN, THF, 0 oC, then H2O2, NaOH, 0 oC, 71%, 99% de.
Our next attention was directed toward preparation of (1S,4R)-diol and the subsequent intramolecular
Mitsunobu-type cyclization. Dess-Martin oxidation of 10 gave an aldehyde, which was reacted with
3,4-methylenedioxyphenyl magnesium bromide, giving rise to the undesired diastereomer as the main
product (desired 4R : undesired 4S = 1:2) (Scheme 3). The 4S isomer, however, could be readily converted
to the necessary 4R-configuration with a high selectivity by Dess-Martin oxidation and the subsequent
Luche reduction.9 This stereochemical inversion is rationalized as proceeding through Felkin-Anh
fashion.
O
O
O
O
TBSO
TBSO
l
j, k
m
4
10
4R : 4S
= 1:2
OH
O
BnO
BnO
OMe
OMe
11
12
O
O
O
O
HO
TBSO
Ar
H!
n
H
4
R
OH
OH
BnO
4R : 4S
= 11:1
BnO
Me
O
OMe
OMe
14
13
Scheme 3. Reagents and Conditions: (j) Dess-Martin periodinane, CH2Cl2, rt; (k) 3,4-methylenedioxy-
o
phenyl magnesium bromide, THF, 0 C, ratio of 4R : 4S = 1:2; (l) Dess-Martin periodinane, CH2Cl2, rt,
71% in 3 steps; (m) NaBH4, CeCl3"7H2O, MeOH, 0 oC, 72%, ratio of 4R : 4S = 11:1; (n) TBAF, THF, 0
oC, 85%.

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HETEROCYCLES, Vol. 82, No. 2, 2011
DIAD, PPh3
CH2Cl2, rt
O
14
O
O
O
HO
O
HO
O
HO
56%
15:16:17 = 13:1:1
O
O
OMe
OMe
O
OMe
15
17
16
H2, Pd(OH)2/C
O
15
benzene
87%
O
HO
O
OMe
(2S,3S,4R,5R)-1c
machilin F
Scheme 4. Mitsunobu reaction of diol 14 and total synthesis of machilin F
The diol 14 was obtained by deprotecting the TBS group in 13 with TBAF in 85% yield. This diol 1421
had all configurations necessary for the crucial Mitsunobu-type reaction to construct the tetrahydrofuran
ring of 1c (Scheme 4). Mitsunobu-type cyclization of 14 was carried out under normal conditions, with
DIAD and PPh3 in CH2Cl2 at room temperature. It should be emphasized that our desired product 15
was predominantly produced along with small amounts of diastereomers 16 and 17 (15:16:17=13:1:1) in
56% yield. It is important to note that major product 15 is the result of a net retention stereochemical
process. Finally, removal of the benzyl group with Pd(OH)2/C in benzene furnished (+)-machilin F,
13
(2S,3S,4R,5R)-1c, in 87% yield. All the spectroscopic data22 (1H NMR, C NMR, and mass spectra) of
the synthetic 1c were identical with those of natural machilin F.
The surprising stereoselectivity of this Mitsunobu reaction is rationalized as follows: normal Mitsunobu
reaction occurs via SN2 inversion mechanism after activation of hydroxy group.23 In this case, the
activated hydroxy group preferentially eliminates over the normal substitution pathway giving rise to
9,24
quinone methides B and E, presumably due to the benzylic nature of the hydroxy group
(Scheme 5).
The steric repulsion between an aryl subsutituent and a methyl group results in forcing the active
intermediates B and E to adopt trans configurations C and F to adjacent methyl group.
As results, the cyclization would proceed with net retention of the original configuration at C-1 and C-4.
This mechanistic insight can account for the stereoselective formation of the same product 15 with
(2S,3S,4R,5R)-confiuguration from A and D even if either a hydroxy group at C-1 or C-4 is activated by
the Mitunobu reaction conditions.
In conclusion, we have achieved the first asymmetric synthesis of (+)-machilin F, (2S,3S,4R,5R)-1c, by
applying Mitsunobu reaction to the diol 14, and thus all (2S,3S)-series of talaumidin are now prepared for
assessment of comparable neurotrophic activity. Further synthetic studies on the remaining four
stereoisomers with (2S,3R)-configuration are now in progress and will be reported in due time.

HETEROCYCLES, Vol. 82, No. 2, 2011
1131
O
O
O
O
O
Ph3PO
OMe
OH
OH
4
O
1
OH
HO
OPPh3
BnO
BnO
BnO
OMe
OMe
A
D
1S,2S,3R,4R-configuration
O=PPh3
O=PPh3
OH
O
O
O
O
PPh3
iPrO2C
N
N
H
CO2iPr
OH
Me
BnO
BnO
OMe
OMe
B
E
Me
Me
Me
H
H
O
2
4
O
O
1
RO
MeO
BnO
O
O
MeO
BnO
O
O
OMe
O
O
2S,3S,4R,5R-configuration
C
F
Scheme 5. The unusual stereoselectivity of Mitsunobu reaction
ACKNOWLEDGEMENTS
We thank Dr. Masami Tanaka and Ms. Yasuko Okamoto for measuring NMR and MS spectra. This work
was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan and MEXT-Senryaku.
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2.04-2.11 (2H, m), 3.90 (3H, s), 4.52 (2H, d, J = 7.4 Hz), 5.14 (2H, s), 5.94 (2H, s), 6.73-6.91 (6H,
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D
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4.45 (1H, d, J = 6.4 Hz), 4.46 (1H, d, J = 6.7 Hz), 5.57 (1H, s), 5.96 (2H, s), 6.79 (1H, d, J = 7.8 Hz),
13
6.88 (1H, dd, J = 7.8, 1.6 Hz), 6.90 (1H, s), 6.94 (1H, d, J = 1.6 Hz), 6.97 (2H, s); C NMR (100
MHz, CDCl3) # 12.9, 12.9, 44.5, 44.5, 55.9, 87.4, 87.5, 101.0, 106.8, 108.0, 109.0, 114.1, 119.4,
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m/z (rel. int.) 342 [M]+ (54), 190 (100), 145 (67); HREIMS calcd 342.1470 for C20H22O5, found
342.1467; [$]20D +8.4 (c 0.65, CHCl3). Machilin F was reported as optically inactive form.6
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