First practical asymmetric synthesis of a new tetrasubstituted tetrahydrofuran, (-)-goniothalesdiol

Article abstract of DOI:10.1055/s-2002-33531

An efficient and practical strategy has been developed for the construction of the antipode of 3,4-dihydroxy-2,5-disubstituted tetrahydrofuran, goniothalesdiol, isolated from the bark of the Malaysian tree. The synthetic process is based on the convenient manipulation via Lewis acid-induced deoxygenation of the highly functionalized lactone derived from D-glucuronolactone.

Full text of DOI:10.1055/s-2002-33531

1532
LETTER
First Practical Asymmetric Synthesis of a New Tetrasubstituted
Tetrahydrofuran, (–)-Goniothalesdiol
Synthesis of
a
N
ew
i
Tetra
d
e
etrahydrofu
m
ran i Yoda,* Yuka Nakaseko, Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 432-8561, Japan
Fax +81(53)4781150; E-mail: tchyoda@ipc.shizuoka.ac.jp
Received 11 July 2002
OCH3
O
Abstract: An efficient and practical strategy has been developed
HO
R
OCH3
for the construction of the antipode of 3,4-dihydroxy-2,5-disubsti-
tuted tetrahydrofuran, goniothalesdiol, isolated from the bark of the
Malaysian tree. The synthetic process is based on the convenient
manipulation via Lewis acid-induced deoxygenation of the highly
functionalized lactone derived from D-glucuronolactone.
H3CO
H3CO
O
Magnone A: R = H
Magnone B: R = OCH3
HO
Key words: goniothalesdiol, tetrasubstituted tetrahydrofuran, ste-
reoselective deoxygenation, trisubstituted -lactone, D-glucurono-
lactone
O
H
OH
3-Furanol derivative (no name)
H3CO
OCH3
HO
OH
Substituted tetrahydrofurans feature in many biologically
potent natural products such as annonaceous acetoge-
nins,1 macrolides,2 cytotoxic polyethers,3 marine toxins,4
pheromones,5 and epoxylipids.6 To fully exploit the op-
portunities offered by these compounds requires access to
synthetic methodology capable of targeting chiral substi-
tuted tetrahydrofurans. In this conncetion many strategies
have been explored in developing synthetic routes to these
compounds and the natural products themselves. Howev-
er, most methods were concerned with the construction of
2,5-disubstituted furans, while few focused on tri- and tet-
rasubstituted ones,7 since the synthesis of this type of
compounds poses interesting and often unsolved prob-
lems of stereocontrol (Figure 1). We have recently suc-
ceeded in the development of novel and stereoselective
asymmetric syntheses of biologically active tri-8a,b and
tetrasubstituted8c furan-type of natural products through
elaboration of commercially available materials based on
new routes exploited in this laboratory.
5
2
H3CO
H3CO
O
COOCH3
O
O
O
Virgatusin
Goniothalesdiol (1)
Figure 1
pode of natural 1 by means of requisite elaboration of the
functionalized lactone derived from D-glucuronolactone
whose outlined synthetic pathway is described in
Scheme 1 together with the preceding method of 2-epi-
form.
OH
RO
OR
ref. 11
HOOC
COOH
O
O
OH
H
HO
OH
D-tartaric acid
X
Y
HO
O
COOCH3
O
O
(1): X = H, Y = Ph
(2): X = Ph, Y = H
OH
D-glucuronolactone
RO OR
O
On the other hand, another type of dihydroxylated tetrahy-
drofuran, (+)-goniothalesdiol (1), was first isolated in
1998 from the bark of the Malaysian tree Goniothalamus
borneensis (Annonaceae).9 This was revealed to have sig-
nificant cytotoxicity against P388 mouse leukemia cells
and strong insecticidal activities,9 and a new addition to
the styryl-type lactone series.10 However, no report con-
cerning the total synthesis of the (–)-enantiomer of 1 as
well as the natural product itself, to our knowledge, has
been appeared to date despite these pharmacological ac-
tivities and interesting structural features except our
asymmetric synthesis of 2-epigoniothalesdiol (2) starting
from D-tartaric acid.11 We wish to communicate herein the
first novel and practical asymmetric synthesis of the anti-
H
OH
Antipode of (1)
OH
O
OH
Scheme 1
As shown in Scheme 2, three hydroxyl groups of conve-
niently functionalized D-glucuronolactone were protected
successively through acetonide formation followed by si-
lylation to give the lactone 4. To begin with, treatment of
4 with Grignard reagents in the presence of CeCl312 at low
temperature provided the labile hemiketal intermediates,
which were readily effected by BF3 OEt2-promoted hy-
drogenation with Et3SiH13 at the same temperature, lead-
ing directly to the tetrahydrofuran derivatives 5a and 5b,
respectively. The reactions in both cases proceeded within
5 minutes in high yields with complete stereoselectivity
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1532,1534,ftx,en;U03802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Synthesis of a New Tetrasubstituted Tetrahydrofuran
1533
(determined by 13C NMR analysis) and no other product tonide deprotection with TFA yielded the diol deriva-
was observed. Stereochemistry of the new asymmetric tive,15 which was subsequently reduced with LiAlH4 to
center in 5a was unambiguously determined to be S,14 and give the triol 7 in reasonable yield. This was next effected
5b was also estimated to have the same configuration by the reactions of chemoselective acetalization and ben-
based on the similarity of its spectral data and confirmed zylation, followed by deprotection of the acetonide again,
after completion of the synthesis of (–)-1.
leading to the corresponding diol product 8 in three steps.
Then, 8 was cleaved with NaIO4 to the crucial aldehyde
and submitted to an olefination reaction with methyl di-
ethylphosphonoacetate to provide the unsaturated methyl
ester 9 in 77% yield (two steps). Finally, removal of the
benzyl groups together with hydrogenation of 9 was per-
formed employing Pd (black) in 4.4% HCOOH–MeOH16
to complete the total synthesis of the (–)-enantiomer of
natural goniothalesdiol 1, [ ]D27.4 –7.1 (c 0.15, EtOH) [lit.
SBTO
O
HO
H
H
H
H
O
O
a
b
OH
O
O
O
O
O
OH
3
4
SBTO
R
HO
H
H
H
O
O
c
25
[ ]D +7.5 (c 0.23, EtOH)],9 in 66% isolated yield. The
5b
O
O
O
O
H
spectral data of synthesized (–)-1 were completely identi-
O
O
5a: R = C5H11
5b: R = Ph
6
cal to those of the reported natural compound.9
In summary this work constitutes the first efficient asym-
metric synthesis of the enantiomer of natural goniothales-
diol from D-glucuronolactone and verifies the structure
proposed in the literature for this compound. This will be
widely applicable to the synthesis of other important tet-
rasubstituted tetrahydrofuran natural products.
BnO
OBn
BnO
OH
d
e
OH
OH
O
O
H
H
OH
OH
7
8
BnO
OBn
HO
OH
g
f
COOCH3
COOCH3
O
O
Acknowledgement
9
antipode of (1)
We thank Prof. Kenji Mori (Science University of Tokyo) for his
valuable suggestions and discussions. This work was supported in
part by a Grant-in-Aid for Scientific Research from Japan Society
for the Promotion of Science.
Scheme 2 Reagents and conditions: (a) 1. Acetone, H2SO4; 82%; 2.
TBSCl, DMF, imidazole; quant.; (b) 1. Grignard reagents, CeCl3,
THF, –78 to –60 ºC; 2. Et3SiH, BF3 OEt2, CH2Cl2, –78 ºC; 78% (two
steps) (5a); 79% (two steps) (5b); (c) 1. Bu4NF, THF; 99%; 2. DEAD,
Ph3P, C6H5COOH, THF; 3. K2CO3, MeOH; 86% (two steps); (d) 1.
NaH, PhCH2Br, Bu4NI, THF; 95%; 2. TFA, THF; 93%; 3. LiAlH4,
THF; 63%; (e) 1. (CH3)2C(OCH3)2, acetone, cat. PPTS; 74%; 2. NaH,
PhCH2Br, Bu4NI, THF; 95%; 3. TFA, THF; 93%; (f) 1. NaIO4, Et2O–
H2O (1:1); 2. (EtO)2POCH2COOCH3, NaH, THF; 77% (two steps);
(g) Pd (black), 4.4% HCOOH–MeOH, 45 ºC; 66%.
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Synlett 2002, No. 9, 1532–1534 ISSN 0936-5214 © Thieme Stuttgart · New York

1534
H. Yoda et al.
LETTER
BnO
OH
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2) BnBr-Ag2O
1) NaIO4
5a
OH
3) TFA
4) LiAlH4
O
2) Ph3P=CH(CH2)2CH3
yield 84%
H
OH
10
yield 72% (four steps)
HO
OH
BnO
OH
Pd (black)
yield 92%
O
O
12
11
Figure 2
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compound 12 through sequential seven steps as shown
below (Figure 2).
Figure 3
(16) Hydrogenation and simultaneous removal of the benzyl
groups in 9 with Pd on carbon (10%) under H2 atmosphere
were proved to give a complex mixture. In addition, the
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Emmons reagent interestingly brought about the tricyclic
Synlett 2002, No. 9, 1532–1534 ISSN 0936-5214 © Thieme Stuttgart · New York