Studies toward a synthesis of trilobatin B, a lignan from the liverwort Bazzania trilobata: Asymmetric construction of the tetrahydrofuran segment

Article abstract of DOI:10.1016/j.tetlet.2004.04.025

A novel and stereocontrolled process is described for the asymmetric synthesis of the tetrahydrofuran segment of a 2,3-dicarboxy-6,7-dihydroxy-1- (3′,4′-dihydroxyphenyl)-1,2- dihydronaphthalene mono-ester, trilobatin B, a lignan from the liverwort Bazzani

Full text of DOI:10.1016/j.tetlet.2004.04.025

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4217–4220
Studies toward a synthesis of trilobatin B, a lignan from the
liverwort Bazzania trilobata: asymmetric construction of the
tetrahydrofuran segment
Hidemi Yoda,* Yuka Nakaseko and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 432-8561, Japan
Received 10 March 2004; revised 1 April2004; accepted 8 April2004
Abstract—A novel and stereocontrolled process is described for the asymmetric synthesis of the tetrahydrofuran segment of a 2,3-
dicarboxy-6,7-dihydroxy-1-(30,40-dihydroxyphenyl)-1,2- dihydronaphthalene mono-ester, trilobatin B, a lignan from the liverwort
Bazzania trilobata. The key cis-substituted lactone ring was constructed in a stereoselective manner by Horner–Emmons reaction
followed by the subsequent tandem Michael addition and cyclization of two types of lactol intermediates elaborated from natural
sources.
Ó 2004 Elsevier Ltd. All rights reserved.
Substituted tetrahydrofurans feature in many biologi-
cally potent natural products such as annonaceous ace-
togenins,1 macrolides,2 cytotoxic polyethers,3 marine
toxins,4 pheromones,5 and epoxylipids.6 To fully exploit
the opportunities offered by these compounds requires
access to synthetic methodology capable of targeting
chiralsubstituted tetrahydrofurans. In this connection
many strategies have been explored in developing syn-
thetic routes to these compounds and the naturalprod-
ucts themselves. However, most methods were concerned
with the construction of 2,5-disubstituted furans, while
few focused on tri- and tetrasubstituted ones,7 although
the synthesis of this type of compounds poses interesting
and often unsolved problems of stereocontrol. We have
recently succeeded in the development of novel and
stereoselective asymmetric syntheses of biologically ac-
tive tri-8a;b and tetrasubstituted8c;d furan-type of natural
products through elaboration of commercially available
materials based on new routes exploited in this labora-
tory. On the other hand, new interesting lignans such as
trilobatin A (1), methylester derivative of 1 (2), and
trilobatin B (3) containing a polysubstituted tetrahydro-
pyran or furan skeleton were recently isolated from the
liverwort Bazzania trilobata in a research for the genus
Bazzania with its severalhundred species distributed in
the tropics and subtropics, which represents one of the
four European species, that grow in dense, widespread
pads on forest ground, boggy soil, and trunks (Fig. 1).9
The structuraland stereochemicalcompelxity of these
secondary metabolites with respect to the heterocyclic
moiety coupled with their diverse and potentially useful
characteristics would make them hereafter inviting targets
for synthesis. In this communication we wish to report the
OH
HO
O
HO
HO
O
O
OH
CO H
2
*
CO R
2
R=H: Trilobatin A (1)
R=CH3: Trilobatin A-1"-
methyl ester (2)
HO
HO
OH
OH
O
O
HO
HO
O
OH
*
OH
HO
OH
CO H
2
Trilobatin B (3)
Keywords: Trilobatin; Substituted tetrahydrofuran; Horner–Emmons
reaction; Xylose; Glucuronolactone.
* Corresponding author. Tel./fax: +81-53-478-1150; e-mail: tchyoda@
ipc.shizuoka.ac.jp
Figure 1. Trilobatins.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.025

4218
H. Yoda et al. / Tetrahedron Letters 45 (2004) 4217–4220
O
OH
4
HO
1
path A
2
3
H
HO
H
OH
H
(III)
O
O
4
RO
1
OH
RO
2
3
OH
O
O
HO
OH
RO
H
RO
HO
O
H
O
O
OH
OH
4
1
Tetrahydrofuran fragment (4)
(IV)
3
2
path B
RO
(II)
O
O
O
(I)
O
H
HH
Figure 2. Retrosynthetic pathways.
details of a novel route for the stereoselective construction
of the requisite tetrasubstituted tetrahydrofuran segment
of trilobatin B (3) from two naturalsources.
O-isopropylidene-D-xylofuranose (5) was effected with
ethyldiethylphosphonoacetate in the presence of base at
24
D
low temperature to afford the desired cis-fused 7a, ½aꢀ
+12.8° (c 1.06, MeOH), fortunately in moderate yield
through a three-step sequence such as Horner–Emmons
reaction, Michael addition, and intramolecular cycliza-
tion, but disappointingly accompanied with the trans-
furanoester 8 (2.8:1, isolated ratio).10
In formulating the synthetic plan for the core segment 4,
we recognized that nucleophilic addition of an organo-
metallic reagent to the lactone (IV) followed by its
transformation could undergo the desired reaction,
allowing the synthesis of the target 4 (Fig. 2). In this
case,
D
-xylofuranose (III) would be selected as one of
In light of the above outcome, we next focused our
research on the reaction employing the same type of the
bicyclic lactol derivative 10 under these Horner–Em-
mons reaction conditions (Scheme 1). This compound
was easily prepared from readily available and inex-
the starting material, since the absolute configurations at
C(2), C(3), and C(4) in 4 are the same as the configu-
rations at the corresponding centers C(2), C(3), and C(4)
of (III) (path A). Meanwhile, the tricyclic lactone (II),
which would have to be set in an asymmetric transfor-
pensive
D-glucuronolactone (9) through a seven-step
mation of the corresponding commercially available
glucuronolactone (I), could be independently regarded
as an another precursor of 4 (path B).
D
-
sequence in 55% overall yield as follows; thus, three
hydroxylgroups of 9 were successively protected by the
reactions of acetonide formation and benzylation with
Ag2O followed by exchange of the acetonide protecting
group to the TBS ethers, giving the corresponding bis-
TBS product.8d This was then submitted to the following
reactions of DIBAL-H reduction, protection of the
resulting hydroxyl function with CH3I and finally desil-
ylation to provide the desired lactol precursor 10
To begin with, an attempt to synthesize the crucial
intermediate furanolactone 7a based on path A is out-
lined in Scheme 1. Regioselectively benzyl-protected
D
-xylofuranose 6 obtained from reactions of benzyl-
ation and deacetalization of commercially available 1,2-
O
O
OH
OH
HO
HO
BnO
BnO
a
O
HO
H
O
b
5
6
H
H
BnO
O
O
O
O
OH
OH
OH
c
RO
CO Et
2
RO
+
O
MeO
O
O
O
O
OH
R'O
RO
OH
8
H
H
H
e
9
10
H
H
BnO
7a: R=R'=Bn
O
d
7b: R=DPS, R'=MOM
O
11
MeO
O
O
HH
O
SPDO
MOMO
f
7b
OH
12
OH
O
O
O
O
g
h
OMOM
OMOM
OMOM
SPDO
MOMO
OH
OH
HO
OH
13
14
Scheme 1. Reagents and conditions: (a) 1, NaH, BnBr, cat. Bu4N, THF; 98%; 2, 1.8% HCl, 1,4-dioxane, 80 °C; 85%; (b) 1, NaH,
(EtO)2POCH2CO2Et, THF, )78 to )17 °C; 2, cat. p-TsOH, benzene, 50 °C; 39% (two steps) (7a); 14% (two steps) (8); (c) 1, acetone, H2SO4; 2, BnBr,
Ag2O, CH3CO2Et; 3, TFA, THF; 4, TBSCl, imidazole, DMF; 5, DIBAL-H, THF, )78 to 0 °C; 6, t-BuOK, CH3I, cat. Bu4NI, THF, )78 to )40 °C; 7,
Bu4NF, THF, 0 °C; 55% (seven steps); (d) NaH, (EtO)2POCH2CO2Et, THF, )78 to )17 °C; 87%; (e) 1, 5% HCl, 1,4-dioxane, 80 °C; 94%; 2, NaBH4,
i-PrOH, 0 °C; 92%; 3, TBSCl, Et3N, CH2Cl2; 98%; 4, (i-Pr)2NEt, MOMCl, CH2Cl2; 5, 1.8% HCl, MeOH; 97% (two steps); 6, Pd/C, H2, CH3CO2Et;
quant.; 7, NaIO4, Et2O–H2O (1:1), 0 °C; 8, NaBH4, THF, 0 °C; 9, DPSCl, imidazole, CH2Cl2; 86% (three steps) (7b); (f) 1, vinylmagnesium bromide,
CeCl3, THF, )78 °C; 2, NaBH4, CeCl3, MeOH, )40 °C; 53% (two steps); (g) 1, (i-Pr)2 NEt, MOMCl, CH2Cl2; 90%; 2, cat. OsO4, NMO, acetone;
quant.; 3, NaIO4, Et2O–H2O (1:1), 0 °C; 4, NaBH4, MeOH, 0 °C; 5, (i-Pr)2NEt, MOMCl, CH2Cl2; 88% (three steps); (h) 1, Bu4NF, THF, 0 °C; 91%;
2, 2-naphthoic acid, EDCI, DMAP, CH2Cl2, 0 °C; quant.; 3, 10% HCl, MeOH; 98%.

H. Yoda et al. / Tetrahedron Letters 45 (2004) 4217–4220
4219
smoothly. Whereas treatment of 6 with ethyldi-
References and notes
ethylphosphonoacetate gave the separable mixture of
the two compounds 7a and 8 as mentioned above, we
were delighted to find that the use of 10 brought about,
in turn, the desired tricyclic lactone 11 as the single as
well as the sole product in 87% isolated yield (as the
anomer mixture) under the same reaction conditions.
This high stereoselective performance compared with
that of the analogous compound 6 would be attributed
simply to the steric demand of the tricyclic core.
1. (a) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.;
He, K.; McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275;
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(b) Cave, A.; Figadere, B.; Laurens, A.; Cortes, D. In
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Huang, S. Tetrahedron Lett. 1995, 36, 709; (b) Sakai, R.;
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With these results in hand, 11 was further transformed
into the desired bicyclic lactone 7b by the routine reac-
tion sequence of hydroxylation under acidic conditions,
reduction of the corresponding lactol with NaBH4 and
regioselective protection of the secondary hydroxyl
group with MOMClvia the TBS-ether. This was then
subjected to the reactions of oxidative cleavage after
hydrogenation, reduction again, and protection of the
3. (a) Matsuo, Y.; Suzuki, M.; Masuda, M. Chem. Lett.
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ꢀ
26
D
½aꢀ +13.8° (c 1.03, MeOH). Then, 7b thus obtained was
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effected with vinylmagnesium bromide at low tempera-
ture to afford the labile hemiketal intermediate, which
was readily treated with NaBH4 in the presence of CeCl3
at )40 °C, leading to the corresponding vinyl alcohol 12,
27
½aꢀ )9.91° (c 0.54, MeOH), surprisingly with complete
D
stereoselectivity (determined by 13C NMR analysis). No
other stereoisomer was observed in this reaction.11 After
protection with MOMClof 12, the olefinic part was then
cleavaged via dihydroxylation to give the aldehyde,
which was successively subjected to reduction and
7. (a) Stevens, D. R.; Whiting, D. A. J. Chem. Soc., Perkin
Trans. 1 1992, 633; (b) Mitra, J.; Mitra, A. K. J. Chem.
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S.; Roy, S. C. J. Chem. Soc., Perkin Trans. 1 1995, 927;
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Org. Chem. 1997, 62, 1310; (e) Chen, I.-S.; Chen, J.-J.;
Duh, C.-Y.; Tsai, I.-L. Phytochemistry 1997, 45, 991; (f)
MOM-protection again, leading to the tetramethoxy-
27
D
methylether 13, ½aꢀ )15.9° (c 0.55, MeOH). Finally, 13
was effected by deprotection of DPS group with Bu4NF
and esterification with 2-naphthoic acid (the similar
framework of the naturalproduct, triolbatin B ( 3)) in
the presence of EDCI (1-ethyl-3-(3-dimethylaminoprop-
yl)carbodiimide hydrochloride) and DMAP,12 followed
by deprotection of the resulting tetramethoxymethyl
ꢀ
ꢀ
ꢀ
Garcia, C.; Martın, T.; Martın, V. S. J. Org. Chem. 2001,
66, 1420; (g) Chakraborty, T. K.; Das, S.; Raju, T. V.
J. Org. Chem. 2001, 66, 4091; (h) Gadikota, R. R.;
Callam, C. S.; Lowary, T. L. J. Org. Chem. 2001, 66,
9046.
ether to accomplish the synthesis of trilobatin B deriv-
8. (a) Yoda, H.; Kimura, K.; Takabe, K. Synlett 2001, 400;
(b) Yoda, H.; Maruyama, K.; Takabe, K. Tetrahedron:
Asymmetry 2001, 12, 1403; (c) Yoda, H.; Mizutani, M.;
Takabe, K. Tetrahedron Lett. 1999, 40, 4701; (d) Yoda,
H.; Nakaseko, Y.; Takabe, K. Synlett 2002, 1532.
9. (a) Martini, U.; Zapp, J.; Becker, H. Phytochemistry 1998,
49, 1139; (b) Martini, U.; Zapp, J.; Becker, H. Phyto-
chemistry 1998, 47, 89.
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Asymmetry 2000, 11, 743; (b) Sun, K. M.; Dawe, R. D.;
Fraser-Reid, B. Carbohydrate Res. 1987, 171, 35,
The obtained stereoselectivity would be attributed
to the presence of the 2,3-disubstituted dibenzyloxyl
groups.
26
D
ative 14, ½aꢀ +32.3° (c 0.085, MeOH).
In summary, this work constitutes the first asymmetric
synthesis of the tetrahydrofuran segment of the natural
lignan product, trilobatin B, based on a stereoselectively
tandem reaction sequence via Horner–Emmons reac-
tion, stereoselective Michael addition, and intramolec-
ular cyclization and will be widely applicable to the
synthesis of other chiraltetrahydrofuran-containing
naturalproducts.
Acknowledgements
11. The absolute configuration of the newly created stereo-
genic center of 12 was easily characterized to be R after
derivatization to the corresponding d-lactone derivative
through a five-step sequence as shown below:
This work was supported in part by a Grant-in-Aid (no
15550031) for Scientific Research from the Japan Soci-
ety for the Promotion of Science.
The observed vicinalcoupling constants of Ja;b and Ja;c were
Hb
1) Ac O
2
OH
H
Hc
Ha
Hb
CHO
OAc
O
O
H
O
SPDO
O
1) K CO
2
2) OsO
3
4
SPDO
MOMO
SPDO
MOMO
SPDO
MOMO
OH
Ha
O
O
MOMO
OH
2) MnO
2
3)NaIO
OAc
OH
O
4
Hc
, J =2.4, 4.8 Hz
O
12
15
16
J
a,b a,c

4220
H. Yoda et al. / Tetrahedron Letters 45 (2004) 4217–4220
2.4 and 4.8 Hz, respectively, which indicate the hydroxyl
12. Kikuchi, H.; Saito, Y.; Komiya, J.; Takaya, Y.; Honma, S.;
Nakahata, N.; Ito, A.; Oshima, Y. J. Org. Chem. 2001, 66,
6982.
group in 16 could occupy the axial position. It is not clear at
present, which effect (stereoelectronic or steric effect) would
be more predominant on this stereoselectivity.