Asymmetric synthesis of bis-tetrahydrofuran cores in annonaceous acetogenins

Article abstract of DOI:10.1039/c004672h

The bis-THF cores of annonaceous acetogenins were synthesized using (3R,4R)-1,5-hexadiene-3,4-diol (1) as the sole source of carbon atoms. The methylene acetal function was applied as a new linker/tether to facilitate the ring-closing metathesis.

Full text of DOI:10.1039/c004672h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric synthesis of bis-tetrahydrofuran cores in annonaceous
acetogenins† ‡
Chia-Hsiu Chen, Ting-Chun Kuan, Ke-Jhen Lu and Duen-Ren Hou*
Received 25th March 2010, Accepted 17th June 2010
First published as an Advance Article on the web 30th June 2010
DOI: 10.1039/c004672h
The bis-THF cores of annonaceous acetogenins were syn-
thesized using (3R,4R)-1,5-hexadiene-3,4-diol (1) as the sole
source of carbon atoms. The methylene acetal function was
applied as a new linker/tether to facilitate the ring-closing
metathesis.
Annonaceous acetogenins are a large family—more than 430—
of natural products isolated from tropical plants of Annonaceae.1
These compounds are potent inhibitors of mitochondrial complex
I and inducers of cell-apoptosis.1 However, their detection in edible
products and traditional medicines has also recently raised public
health concerns.2,3 Most of the known and potent acetogenins
contain adjacent bis-tetrahydrofurans (THF) with various stereo-
chemistries (Fig. 1).1,4 The bis-THF core is considered the region
Scheme 1 Retrosynthetic analysis.
for mitochondrial membrane recognition,5 and recent structure–
activity relationship studies support the supposition that the
stereochemistry of the bis-THF core affects the cytotoxicity.6
chloromethyl ether 3, which was in turn prepared from the bis-
methoxymethyl ether 2, itself obtained from 1.11 Sharpless epox-
idation allowed protection of the terminal olefins as dioxiranes
5,12 and subsequent ring-closing metathesis afforded 6.13 To our
knowledge, this is the first example of using the methylene acetal
moiety as a tether in RCM.14–16 The SN2 like, rather than acid
catalysed, formation of the methylene acetal provided a controlled,
clean way to connect three units of diene-diol 1. To continue the
synthesis, the alkenes were hydrogenated, and the epoxides were
reduced to the bis-allylic alcohol 8.17 The hydroxyl functions were
converted to the bis-benzyl ether 9, this protecting group being
selected because of its stability to the strongly acidic condition
required for hydrolyzing the methylene acetals. The formation of
the five-membered acetonide provided the desired diol 11, in which
the C2 symmetrical hydroxyl groups are differentiated (Scheme 2).
Mesylation of 11 generated 12, which was deprotected and then
cyclised to form bis-THF derivative 13 having the stereochemistry
erythro/cis/threo/cis/erythro. We found that the benzyl group
could be readily removed using titanium chloride and then
replaced with other protective groups such as the methoxymethyl
group as in 14 (Scheme 3).18
Fig. 1 Representative annonaceous acetogenins.
These interesting structural and biological properties of an-
nonaceous acetogenins have attracted considerable attention in the
synthetic community, and the construction of the bis-THF moiety
remains as the main challenge in preparing these compounds.4,7
Although many synthetic methodologies have been developed,8
an appealing and potentially very efficient strategy to prepare the
bis-THF core units of uvaricin and asimicin involves the use of C2
symmetrical intermediates.4a,9 Herein, we describe our synthesis of
the bis-THF core from C2 diene-diol 1,10 which provided the key
carbon skeleton of the bis-THF core via ring-closing metathesis
(Scheme 1).
The diol 11 could be used to prepare other diastereomers
with bis-THF cores. For example, Mitsunobu reaction pro-
vided the diester 16 with the inverted stereocenters at C4 and
C11.19 Subsequent deprotection and cyclisation afforded the
threo/trans/threo/trans/threo bis-THF 20, the key intermediate
in Marshall’s synthesis of asimicin (Scheme 4).8f
Three units of the diene-diol 1 were linked as the methylene
acetal 4. The acetal was prepared by reaction of 1 with the bis-
In summary, we have developed a new strategy for preparing
the bis-THF core of annonaceous acetogenins. This approach
features use of the methylene acetal moiety as the tether for an
RCM reaction, and of the C2 diene-diol 1 as the only source
of carbon atoms and of stereocenters. Moreover, 11 should be
a key intermediate for the synthesis of various stereoisomers
Department of Chemistry, National Central University, 300 Jhong-Da
Rd., Jhong-Li, Taoyuan, Taiwan. E-mail: drhou@ncu.edu.tw; Fax: 886-
3-4227664; Tel: 886-3-4227151 ext. 65981
† Dedicated to Prof. John C. Gilbert on the occasion of his 70th birthday.
‡ Electronic supplementary information (ESI) available: Experimen-
tal procedures and NMR spectra for all key compounds. See DOI:
10.1039/c004672h
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Scheme 4 Synthesis of threo/trans/threo/trans/threo bis-THF.
Taiwan. We are grateful to Ms Ping-Yu Lin at the Institute of
Chemistry, Academia Sinica, and Valuable Instrument Center in
National Central University for obtaining mass analysis. Thanks
are also due to the National Center for High Performance
Computing for computer time and facilities.
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This research was supported by the National Science Coun-
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