Synthesis of 4-benzyl-3-phenylbutenolide natural products

Article abstract of DOI:10.1016/j.tetlet.2013.07.101

The first total synthesis of eutypoid A and a new synthesis of racemic microperfuranone and gymnoascolide A have been achieved. The key steps in our synthetic strategy involve a Suzuki coupling reaction to install the C3 aryl ring and a Mannich-type reaction for the construction of the 4-benzylbutenolide core.

Full text of DOI:10.1016/j.tetlet.2013.07.101

Tetrahedron Letters 54 (2013) 5322–5324
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Tetrahedron Letters
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Synthesis of 4-benzyl-3-phenylbutenolide natural products
⇑
Anna N. Parker, Matthew J. Lock, John M. Hutchison
Auburn University Montgomery, 7061 Senators Dr., Montgomery, AL 36117, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of eutypoid A and a new synthesis of racemic microperfuranone and gymnoas-
colide A have been achieved. The key steps in our synthetic strategy involve a Suzuki coupling reaction
to install the C3 aryl ring and a Mannich-type reaction for the construction of the 4-benzylbutenolide
core.
Received 14 June 2013
Revised 12 July 2013
Accepted 18 July 2013
Available online 26 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Mannich-type amino alkylation
Suzuki coupling
Microperfuranone
Gymnoascolide A
Eutypoid A
Since 1998, a limited number of natural products possessing the
unique 4-benzyl-3-phenylbutenolide motif have been isolated as
metabolites of terrestrial and marine fungi.1–5 Many of these natu-
ral products differ in the presence or absence of hydroxyl substit-
uents on the aromatic and butenolide rings (Fig. 1). Despite the
relatively simple structure, some members possessing this struc-
tural motif exhibit interesting biological activities.
Microperfuranone (1) was isolated from the terrestrial and mar-
ine fungi Anixiella micropertusa,1a Emericella quadrilineate,1b and
Emericella nidulans.1c Although survey of the literature has yet to
reveal microperfuranone (1) as a biologically active compound,
role as a key regulator in numerous signaling pathways, aberrant
regulation of GSK-3b has been implicated in a variety of patholo-
gies, including Type II diabetes, cancer, and Alzheimer’s disease.8
As a result, selective inhibitors of GSK-3b are emerging as popular
targets for the potential treatment of these diseases.9 With the end
goal of investigating the role of aryl and benzylic substituents on
the inhibition of GSK-3b, we sought to develop an efficient and
flexible synthetic strategy for the construction of the 4-benzyl-3-
phenylbutenolide core.
the c-hydroxybutenolide moiety is a common structural compo-
nent of many biologically active agents.6 Gymnoascolide A (2)
was isolated from the soil ascomycete Gymnoascus reessii2 and
Malbranchea filamentosa.3 Gymnoascolide A (2) has demonstrated
moderate and selective activity against the pathogenic plant fun-
gus Septoria nodorum,2 as well as vasodilatory activity.3 Finally,
eutypoid A (3) was isolated from a south China sea marine fungus
Eutypa sp. (#424).4 Although the biological activity of eutypoid A
(3) was never determined due to the low yield obtained in its iso-
lation, four related butenolides eutypoids B–E (4–7) were recently
isolated and determined to possess glycogen synthase kinase-3b
(GSK-3b) inhibitory activity.5
Of the 4-benzyl-3-phenylbutenolide natural products, we were
particularly interested in the eutypoid family and their kinase
inhibitory activity. GSK-3b is a multifunctional serine/threonine
kinase known to be involved in a variety of physiological processes
ranging from glycogen metabolism to gene transcription.7 Given its
⇑
Corresponding author.
E-mail address: jhutchi4@aum.edu (J.M. Hutchison).
Figure 1. Naturally occurring butenolides 1–7.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.101

A. N. Parker et al. / Tetrahedron Letters 54 (2013) 5322–5324
5323
Scheme 3. Synthesis of gymnoascolide A (2).
Scheme 1. Retrosynthesis of butenolides 1–3.
Scheme 4. Synthesis of eutypoid A (3).
group could be removed prior to the installation of the C3 aryl ring
(Scheme 3). Thus, hydrolysis of acetal 8, followed by methanolic
NaBH4 reduction gave 3-bromofuranone 9 in good yield.11b Suzuki
coupling of vinyl bromide 9 with phenylboronic acid afforded gym-
noascolide A (2) in 91% yield.
Scheme 2. Synthesis of racemic microperfuranone (1).
Finally, eutypoid A (3) was prepared from 3-bromofuranone 9
via a Suzuki coupling/demethylation sequence (Scheme 4). The
coupling of 4-methoxyphenylboronic acid with 3-bromofuranone
9 gave 3-(4-methoxyphenyl)furanone 12 in excellent yield. Subse-
quent demethylation of the methyl-aryl ether with BCl3 and Bu4NI
afforded eutypoid A (3) in 87% yield.16
In summary, we have developed an efficient and operationally
simple approach to the 4-benzyl-3-phenylbutenolide core utilizing
two well established methodologies: the Suzuki–Miyaura coupling
reaction and the Mannich-type reaction involving glyoxylic acid.
With this synthetic strategy we are able to report the first total
synthesis of eutypoid A (3) (8 steps, 46%), as well as an improved
synthesis of racemic microperfuranone (1) (6 steps, 56% yield)
and gymnoascolide A (2) (7 steps, 49%).
c
-Hydroxybutenolides [5-hydroxy-2(5H)-furanones] can be
readily prepared through the oxidation of furans or by Mannich-
type reactions.10,11 The Mannich-type amino alkylation involving
glyoxylic acid, an enolizable aldehyde, and a secondary amine
was first developed by Wermuth and Bourguignon in 1981.11a They
had demonstrated that 4-alkyl-5-hydroxy-2(5H)-furanones could
easily be obtained in this one-pot reaction methodology. Given
that the 4-benzylbutenolide core could be prepared in a single
step, we sought to utilize this methodology in the synthesis of
three natural products 1–3 (Scheme 1).
To date, there has been no reported synthesis of any member of
the eutypoid family. Furthermore, we felt our synthetic approach
would be applicable to the synthesis of racemic microperfuranone
(1)12 and gymnoascolide A (2),13 offering a more efficient and oper-
ationally simple strategy. The key steps in our approach involve the
Suzuki coupling14 of an aryl boronic acid with the appropriate 4-
benzyl-3-bromofuranone (8 or 9) and a Mannich-type aminoalky-
lation of commercially available 3-phenylpropionaldehyde
(Scheme 1).11
Acknowledgments
Financial support for this project was provided by AUM Faculty
Grant-In-Aid and the Physical Sciences Department of Auburn Uni-
versity Montgomery.
Initial attempts to prepare 4-benzyl-5-hydroxyfuranone 10 in a
single step via condensation of 3-phenylpropionaldehyde with gly-
oxylic acid in the presence of piperdine hydrochloride resulted in
lower than expected yields (50–53%). The low yields were due to
incomplete elimination of the initially formed amino product.
Optimization of this reaction sequence was achieved by conduct-
ing the Mannich-type aminoalkylation/elimination in two separate
steps affording furanone 10 in 78% yield (Scheme 2).
Conversion to the methoxy acetal followed by a bromination
in situ dehydrobromination sequence gave 3-bromofuranone 8 in
excellent yield. Using the reaction conditions reported by Zhang
et al., the Suzuki coupling of 3-bromofuranone 8 with phenylbo-
ronic acid proceeded smoothly, affording 3-phenylfuranone 11 in
97% yield.14c Finally, racemic microperfuranone (1) was obtained
in 85% yield following hydrolysis of the methoxy acetal.15
Gymnoascolide A (2) was prepared by two different routes.
Methanolic NaBH4 reduction of microperfuranone (1) afforded
gymnoascolide A (2) in 87% yield. Alternately, the C5 hydroxyl
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data, 1H and 13C NMR spectra for all compounds) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.07.101.
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