Asymmetric syntheses of trisubstituted tetrahydrofuran lignans, sesaminone and 4-epidihydrosesamin

Article abstract of DOI:10.1055/s-2001-11419

An efficient and stereodefined process is described for the preparation of 2,3,4-trisubstituted tetrahydrofuran lignans, sesaminone and 4-epidihydrosesamin. The synthetic strategy is based on the similar chemoselective hydrogenation of functionalized lactol derivatives, elaborated through asymmetric condensation of a 4,5-trans-disubstituted lactone.

Full text of DOI:10.1055/s-2001-11419

400
LETTER
Asymmetric Syntheses of Trisubstituted Tetrahydrofuran Lignans,
Sesaminone and 4-Epidihydrosesamin
Hidemi Yoda,* Kohei Kimura, Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan
Tel/Fax +81(53)4781150; E-mail: yoda@mat.eng.shizuoka.ac.jp
Received 11 December 2000
O
X, Y
Abstract: An efficient and stereodefined process is described for
the preparation of 2,3,4-trisubstituted tetrahydrofuran lignans, ses-
aminone and 4-epidihydrosesamin. The synthetic strategy is based
on the similar chemoselective hydrogenation of functionalized lac-
tol derivatives, elaborated through asymmetric condensation of a
4,5-trans-disubstituted lactone.
O
HO
3
4
O
Sesaminone (1a): X, Y = O
4-Epidihydrosesamin (1b): X, Y = H
O
O
Key words: sesaminone, dihydrosesamin, lignan, chemoselective
deoxygenation, trisubstituted γ-lactone
OCH3
OCH3
O
O
H3CO
OCH3
H
H
H3CO
H3CO
O
O
O
The lignan class of natural products displays a wide vari-
ety of constitution based on phenolic and O-heterocyclic
substructures, and an equally wide range of biological ac-
tivities such as antitumor activity, platelet-activating fac-
tor (PAF) antagonists, and inhibitory effects on
microsomal monooxygenases in insects.1 Due to their in-
teresting activity as well as unique structural characteris-
tics, they have been the subject of an extensive synthetic
effort which has culminated in numerous syntheses.2
Noteworthy members among this class of compounds are
optically active tetrahydrofuran derivatives with tri- and
tetrasubstituents serving as good templates for the con-
struction of pharmacologically important furanoid groups
and exhibiting various degrees of potency and specificity
(Figure).3 Since the synthesis of this type of compounds
poses interesting and often unsolved problems of stereo-
control, very few synthetic strategies for the furanolignans
have been reported.4 In this connection we have also re-
cently reported a novel and stereoselective conversion of
lactones to polysubstituted cyclic ethers5a,b employing nu-
cleophilic addition of Grignard reagents in the presence of
CeCl3 followed by the Lewis acid-induced deoxygenation
and the first total synthesis of a tetrasubstituted tetrahy-
drofuran lignan, (-)-virgatusin (3).5c Herein we wish to
communicate the asymmetric syntheses of 2,3,4-trisubsti-
tuted tetrahydrofuran lignans, sesaminone (1a) and
4-epidihydrosesamin (1b) based on chemoselectively
requisite hydrogenation starting from dihydroxyacetone
dimer. The former, first isolated in 1994 by Nakayama et
al., revealed micromolar activity against Enterococcus
faecium6 and, to our knowledge, only one approach to the
total synthesis has been reported to date.7
O
O
Methyl piperitol (2)
Virgatusin (3)
Figure
introduction of a new stereogenic center at the C-5 posi-
tion in 4, aminolysis with Me2NH opened the lactone ring
to give the amide intermediate. Then, Swern oxidation
followed by the nucleophilic addition of Grignard reagent
in situ was investigated under various conditions. Finally,
the desired amide alcohol 5a8 was produced exclusively
under the conditions as described in Scheme 1. These re-
sults can be explained in terms of the thermodynamically
more stable Cram's non-chelation transition model. 5a
thus obtained was cyclized to afford the trans-substituted
lactone 6 ([α]D25+40.6° (c 1.03, MeOH)). For the purpose
BnO
O
O
CH2OH
OH
ref. 5a,c
a
HO
HOH2C
O
O
4
BnO
BnO
O
O
O
O
O
O
+
N(CH3)2
5b
N(CH3)2
5a
OH
OH
b
O
OR
1'
BnO
O
BnO
4
3
c
O
O
O
O
O
d
O
6
O
7a: R = H
7b: R = MOM
7c: R = TBS
O
As shown in Scheme 1, the homochiral benzylated lactone
cheme 1 Reagents and conditions: (a) 1. (CH3)2NH, -20 ~ 0 ºC;
7%; 2, (COCl)2, DMSO, THF, then Et3N, -78 ~ -45 ºC; 3, 3,4-me-
hylenedioxyphenylmagnesium bromide, THF, 0 ºC; 68% (5a)
2 steps); trace (5b) (2 steps); (b) p-TsOH, benzene, 50 ºC; 69%;
c) LiHMDS, piperonal, THF, -78 ºC; 91%; (d) MOMCl, (i-Pr)2NEt,
H2Cl2; 83% (7b); TBSOTf, 2,6-lutidine, CH2Cl2; 93% (7c).
26
4 ([α]D -32.1° (c 1.05, CHCl3), 99% e.e.), a key com-
pound for the synthesis of these furanoid lignans, was eas-
ily prepared in an enantiomerically pure form according to
our procedure through diastereomer separation.5a,c For the
Synlett 2001, No. 3, 400–402 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Syntheses of Trisubstituted Tetrahydrofuran Lignans
401
of creating the third asymmetric center, treatment of 6 MeOH)) as a predominant product. These results show
with piperonal in the presence of LiHMDS at -78 °C for- that the C-1' position in 9 and 10 is quite reactive under
tunately provided the 3,4-trans adduct 7a9 as a sole prod- acidic conditions. With the compound 11 in hand, the syn-
uct in 91% yield (the ratio of stereoisomers at C-1', on the thesis of 1b, (4S)-isomer of natural dihydrosesamin isolat-
contrary, was almost 1:1) and accompanying formation of ed from Daphne tangutica Maxim., the Chinese drug 'Ai
the cis-isomer was not observed in this reaction (deter- Tuotuo' used in the treatment of rheumatism, etc,11 was
mined by 13C NMR and HPLC analysis).
accomplished with Pd (black) in 60% yield as a resinous
mass ([α]D24 -12.1° (c 0.92, MeOH)).12
In light of the above outcome, we turned our attention to
the synthesis of target compounds. To begin with, we in- On the other hand, when diacetylated 12 obtained from
vestigated the conversion of a lactone to the tetrahydrofu- 10a as shown in Scheme 3 was treated carefully with
ran skeleton through ring-opening reaction (Scheme 2). Et3SiH in the presence of BF3 OEt2 in a similar manner, it
reversely provided the desired furan 13 in high yield. The
beneficial result on this chemoselectively reductive deox-
O
OR
O
BnO
ygenation was applied to the synthesis of a natural type of
sesaminone (1a). Thus, hydrolysis of 13 with K2CO3 in
MeOH smoothly afforded the alcohol, which was succes-
sively oxidized with tetrapropylammonium perruthenate
(TPAP)-NMO reagent,13 leading to the desired ketone 14
([α]D25+10.8° (c 0.59, CHCl3)) in 72% yield without race-
mization. Finally, 14 was subjected to deprotection with
7a: R = H
7b: R = MOM
7c: R = TBS
O
O
O
d
O
O
OR
BnO
O
O
O
BnO
OMOM
1'
OH
26
Pd (black) to complete the total synthesis of 1a ([α]D
O
O
-26.3° (c 0.40, CHCl314), lit.6 [α]D -25.0° (c 0.140,
25
O
OH
MeOH)) in 82% yield as a crystalline solid (mp 132-
133 °C, lit.7 133-134 °C). The spectral data of synthesized
1a were completely identical with those of the reported
natural6 and synthetic7 compound.
OH
10a: R = H
O
10b: R = TBS
O
8
b
e
O
O
O
OMOM
BnO
O
BnO
c
1'
O
O
OH
OAc
O
O
O
BnO
BnO
O
9
11
a
b
O
O
O
f
OH
OAc
O
O
O
O
O
10a
12
O
O
HO
O
O
4
O
O
OAc
O
O
O
O
BnO
BnO
O
4-Epidihydrosesamin (1b)
c
O
O
O
Scheme 2 Reagents and conditions: (a) LiAlH4, THF; 76%; (b) p-
TsCl, pyridine; 80%; (c) acidic conditions (see text); (d) DIBAL-H,
THF, -78 ºC; (e) Et3SiH, BF3 OEt2, CH2Cl2, -78 ~ -20 ºC; 64% (2
steps from 7c); (f) Pd (black), 4.4% HCOOH-MeOH; 60%.
13
14
O
O
O
O
O
O
O
HO
Thus, reduction of MOM-protected 7b gave the diol 8
which was in turn effected by tosylation followed by si-
multaneous cyclization to lead to the trisubstituted furan 9
in 61% 2 steps yield. Deprotection of 9 thus obtained,
however, did not proceed cleanly under any acidic condi-
tions (aqueous HCl, p-TsOH/MeOH, or BF3 OEt2/
CH2Cl2) to give many unknown products together with a
small amount of deoxygenated 11 (10~36% yields). Next,
we focused the transformation of 7 into the furanoid struc-
ture via lactol intermediates. Whereas the direct hydro-
genation of 10a obtained from the reduction of 7a with
Et3SiH in the presence of BF3 OEt25,10 yielded the insep-
arable mixture even at low temperature, use of TBS-pro-
tected 10b prepared from 7c in analogy with 10a changed
the result and brought about the concomitantly deoxgenat-
ed and desilyloxgenated product 11 ([α]D24+38.3° (c 0.22,
d
O
O
Sesaminone (1a)
O
Scheme 3 Reagents and conditions: (a) Ac2O, Et3N, cat. DMAP,
CH2Cl2; quant.; (b) Et3SiH, BF3 OEt2, CH2Cl2, -78 ~ 0 ºC; 54%; (c)
1, K2CO3, MeOH; 76%; 2, cat. Pr4NRuO4(TPAP), NMO, CH2Cl2;
72%; (d) Pd (black), 4.4% HCOOH-MeOH; 82%.
In summary, an efficient and novel synthetic pathway
starting from dihydroxyacetone dimer to two furanoid lig-
nans has been established by means of the choice of hy-
droxy-protecting groups on hydrogenation. This
procedure will serve for the synthesis of other lignan nat-
ural products.
Synlett 2001, No. 3, 400–402 ISSN 0936-5214 © Thieme Stuttgart · New York

402
H. Yoda et al.
LETTER
Acknowledgement
O
O
BnO
1) Pd/C, H2
H3CO OCH3
O
O
This work was supported in part by a Grant-in-Aid for Scientific
Research from Japan Society for the Promotion of Science.
Hb
O
O
N(CH3)2
15
N(CH3)2
Ha
2)
O
OH
5a
O
References and Notes
(CH3)2NOCCH2
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Hb
O
O
O
O
Ha
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(9) The absolute configuration at the C-3 position in 7a was
unambiguously determined to be R based on its spectral data
of the synthsized 1a6,7 and 1b.4a
(10) (a) Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett.
1996, 37, 5531. (b) Yoda, H.; Yamazaki, H.; Kawauchi, M.;
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3220, 2779, 1504, 1245, 1099. 1H NMR δ 1.65 (1H, bs), 1.78-
2.15 (1H, m), 2.30-2.54 (1H, m), 2.65-2.85 (2H, m), 3.60 (2H,
d, J = 5.4 Hz), 3.80-4.20 (2H, m), 4.57 (1H, d, J = 8.3 Hz),
5.91 (2H, s), 5.93 (2H, s), 6.55-6.89 (6H, m). 13C NMR δ 39.4,
44.1, 55.6, 62.7, 72.9, 84.0, 100.8, 101.0, 106.6, 108.1, 108.2,
109.0, 119.6, 121.5, 133.9, 136.1, 146.0, 147.0, 147.5, 147.9.
(13) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
(14) Since the synthetic 1a was a crystalline solid in analogy with
the product described in the preceding synthetic report7 and
insoluble in MeOH, its specific rotation was measured in
CHCl3.
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Article Identifier:
1437-2096,E;2001,0,03,0400,0402,ftx,en;Y21300ST.pdf
(8) The absolute stereochemistry of the newly created carbon
center in 5a was proved to be S by the transformation into the
acetonide 15, since the observed vicinal coupling constant
(Ja,b) in 15 was 2.7 Hz, indicating the axial-equatorial
relationship.
Synlett 2001, No. 3, 400–402 ISSN 0936-5214 © Thieme Stuttgart · New York