A new synthetic entry to furofuranoid lignans, methyl piperitol and fargesin

Article abstract of DOI:10.3987/COM-04-10296

An efficient and general process is described for the preparation ofthe unsymmetrically substituted diequatorial and axial-equatorial furofuran lignans, methyl piperitol and fargesin. The synthetic strategy is based on a stereoselective manner by nucleoph

Full text of DOI:10.3987/COM-04-10296

HETEROCYCLES, Vol. 65, No. 3, 2005
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HETEROCYCLES, Vol. 65, No. 3, 2005, pp. 519 - 522
Received, 30th November, 2004, Accepted, 21st January, 2005, Published online, 21st January, 2005
A NEW SYNTHETIC ENTRY TO FUROFURANOID LIGNANS,
METHYL PIPERITOL AND FARGESIN
Hidemi Yoda,* Yuji Suzuki, Daisuke Matsuura, and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University,
3-5-1 Johoku, Hamamatsu 432-8561, Japan; e-mail: tchyoda@ipc.shizuoka.ac.jp
Abstract – An efficient and general process is described for the preparation of
the unsymmetrically substituted diequatorial and axial-equatorial furofuran
lignans, methyl piperitol and fargesin. The synthetic strategy is based on a
stereoselective manner by nucleophilic addition of organometallic reagent to the
monoterpene lactone elaborated from dihydroxyacetone dimer followed by
condensation with the corresponding aromatic aldehyde counter part.
Natural lignans, a class of phenylpropanoid, display a wide variety of constitution based on phenolic and
O-heterocyclic substructures1 and an equally wide range of biological activities. Especially, those
attributed to the furofuran series (Figure) are diverse and include many activities such as antitumor
promotion, antiallergic, antihypertensive, antimitotic, stress reducing, cAMP phosphodiesterase inhibitory,
Ca2+ and PAF antagonist, insecticidal and toxicity enhancement activities.2 Their unique structural
complexity containing the bisfuran component as well as the equatorial or axial stereochemistry of the
substituents coupled with diverse and potentially useful characteristics make them inviting targets for
synthesis.3
Although much effort as described above has been devoted to developing efficient methods for syntheses
of the furofuran series of lignans, very few synthetic strategies for natural methyl piperitol (1) and
fargesin (2)4 themselves have been reported.5 In this connection we have also recently disclosed the total
syntheses of dibenzylbutyrolactone-type lignans, (-)-hinokinin6a and (-)-enterolactone,6b and tri- and
tetrasubstituted tetrahydrofuran lignans, (-)-sesaminone6c and (-)-virgatusin,6d the latter was the first
example of the asymmetric total synthesis. Herein we wish to communicate a new and expeditious
synthetic pathway for the preparation of the unsymmetrically substituted diequatorial and axial-equatorial
furofuran lignans (1) and (2) starting from the monoterpene lactone, a crucial key compound for the
synthesis of many kinds of lignans, developed in this laboratory.

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HETEROCYCLES, Vol. 65, No. 3, 2005
O
O
O
O
OH
O
O
O
O
OCH
3
O
O
O
O
O
O
O
O
O
O
H
H
H
OH
HO
H
H
H
H
H
CH O
O
3
CH O
O
O
CH O
3
3
CH O
O
CH O
3
HO
3
Methyl piperitol (1)
Fargesin (2)
Sesamin (3)
Wodeshiol (4)
Epipinoresinolin (5)
Figure. Furofuran Lignans.
As shown in Scheme 1, the key monoterpene lactone (6) prepared from dihydroxyacetone dimmer
according to our preceding procedure6c,d,7 was protected with the benzyl or tert-butyldiphenylsilyl
(TBDPS) group and treated with dimethylamine to give the amide alcohols (7). Then, Swern oxidation of
7a and 7b followed by nucleophilic addition of piperonyl Grignard reagent in situ at 0 °C afforded the
corresponding amide alcohols (8a) and (8b) as a predominant product, respectively (8a:9a = 96:4, 8b:9b
= >99:1, isolated ratio). These results can be explained in terms of the thermodynamically more stable
Cram’s non-chelation model based on our previous results.6c Initial experiments have been performed
with 8b in expectation of the direct preparation of the non-protected β-substituted hydroxylactone (11).
Thus, subsequent reactions of desilylation and cyclization under mild acidic conditions gave the desired
lactone (11) via the diol (10) in 33% yield (two steps), but disappointingly accompanied with the
β,γ-disubstituted lactone (12) as a major component (66%) after chromatographic separation.
OR
OH
6c,d, 7
O
O
CH OH
2
a
HO
OH
OH
(CH ) N
3 2
HOH C
2
O
O
6
O
7a: R=Bn
OR
OR
7b: R=TBDPS
b
(CH ) N
(CH ) N
OH
O
OH
O
+
3 2
3 2
O
O
8a:9a = 96:4
9a: R=Bn
8a: R=Bn
8b: R=TBDPS
8b:9b = >99:1
9b: R=TBDPS
O
O
O
OH
O
O
HO
OH
O
c
d
(CH ) N
OH
3 2
8b
+
H
O
O
O
O
O
O
10
11
12
O
Scheme 1. Reagents and conditions: (a) 1. BnBr, Ag2O, CH3CO2C2H5; 2. (CH3)2NH, 73% (7a) (2 steps); 1. TBDPSCl,
CH2Cl2, imidazole; 2. (CH3)2NH, 96% (7b) (2 steps); (b) 1. (COCl)2, DMSO, THF then (C2H5)3N, -78 to -45 °C; 2.
3,4-methylenedioxyphenylmagnesium bromide, THF, 0 °C, 75% (8a), 3% (9a) (2 steps), 76% (8b), trace (9b) (2 steps);
(c) (C4H9)4NF, THF, 99%; (d) p-TsOH, toluene, 33% (11), 66% (12).
In light of the above outcome, we turned our attention to another synthetic route for the target natural
product. An attempt to obtain the different hydroxyl-protected lactones of 11 is outlined in Scheme 2.
Protection of the hydroxyl group of 8a with TIPSOTf and debenzylation followed by cyclization yielded
the TIPS-lactone (14a). On the other hand, the silylated amide alcohol (8b) was reversely subjected to the
successive reactions of benzylation, desilylation and cyclization, leading to the desired benzyl-lactone
(14b) in satisfactory yield.

HETEROCYCLES, Vol. 65, No. 3, 2005
521
OBn
OH
OBn
a
(CH ) N
(CH ) N
OTIPS
3 2
3 2
c
O
O
O
O
O
O
RO
O
O
O
8a
13a
O
O
O
O
H
OTBDPS
OH
OTBDPS
O
d
14a: R=TIPS
14b: R=Bn
b
(CH ) N
(CH ) N
OBn
3 2
3 2
O
O
8b
13b
Scheme 2. Reagents and conditions: (a) TIPSOTf, 2,6-lutidine, CH2Cl2, 86%; (b) BnBr, Ag2O, CH3CO2C2H5, 75%; (c) 1.
5% Pd/C, H2, CH3OH; 2. PPTS, toluene, 45 °C, 88% (14a) (2 steps); (d) 1. (C4H9)4NF, THF; 2. p-TsOH, toluene, 81%
(14b) (2 steps).
With these two intermediates in hand, we then focused our research on the synthesis of methyl piperitol
(1) and fargesin (2) (Scheme 3). 14a and 14b thus obtained were effected by coupling reaction with
3,4-dimethoxybenzaldehyde in the presence of LiHMDS8 at low temperature, respectively. We were
delighted to find that these reactions smoothly brought about the desired α,β-trans adduct (15a) or (15b)
alone6c,7,9 based on their spectral data, including the almost equivalent amount of stereoisomers at the
1
benzyl position in each case (determined by H NMR spectrum). Then, these two compounds (15a) and
(15b) were independently submitted to deprotection reaction with (C4H9)4NF or 5% Pd/C in an
atmosphere of H2 in almost quantitative yield, followed by reduction with LiAlH4 to afford the
corresponding tetraol intermediate (17) in 87% yield. Finally, 17 was subjected to mesylation, providing
the dimesylate which in turn underwent the intramolecular cyclization spontaneously to complete the total
synthesis of 1 and 2. Both spectral data of synthesized 1 and 2 were completely identical with those of the
reported synthetic5 and natural4 compounds.
In summary, this work constitutes a general and new synthetic opportunity for the total syntheses of
diequatorial and axial-equatorial furofuran lignans, such as methyl piperitol and fargesin, through
stereoselective manipulation of the mono-terpene lactone and will be widely applicable to the synthesis of
other lignan natural products.
CH O
O
O
CH O
3
3
O
O
RO
OH
OH
O
O
OH OR
a
b
CH O
CH O
3
3
H
H
O
H
H
O
H
14a: R=TIPS
14b: R=Bn
15a: R=TIPS
15b: R=Bn
O
O
16
O
O
O
O
O
O
O
O
HO
O
O
O
H
HO
c
d
CH O
3
H
H
H
H
H
+
OH
CH O
CH O
CH O
3
3
3
O
OH
17
CH O
CH O
3
3
Methyl piperitol (1)
Fargesin (2)
Scheme 3. Reagents and conditions: (a) LiHMDS, 3,4-dimethoxybenzaldehyde, THF, -78 °C, 77% (15a, 59:41), 95%
(15b, 47:53); (b) (C4H9)4NF, THF (to 15a), 96% or 5% Pd/C, H2, CH3CO2C2H5 (to 15b), 97%; (c) LiAlH4, THF, 87%;
(d) MsCl, pyridine, CH2Cl2, 38% (1), 24% (2).

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HETEROCYCLES, Vol. 65, No. 3, 2005
ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research from Japan Society for the
Promotion of Science.
REFERENCES AND NOTES
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products (1) and (2), these coupling reactions were performed purposely with the use of LiHMDS
instead of KHMDS, since erythro-selective aldol reaction at the benzyl position was recently
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9. The trans-structure was ascertained after completion of the syntheses of 1 and 2, whose spectral data
were completely identical with those of the reported values, respectively.