Tetrahedron Letters
Total synthesis of (3R,16E,20E,23R)-(ꢀ)-eushearilide and structural
determination of naturally occurring eushearilide
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Takayuki Tonoi , Ryo Kawahara, Yutaka Yoshinaga, Takehiko Inohana, Keiko Fujimori, Isamu Shiina
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric total synthesis of the proposed structure of (16Z,20E)-eushearilide, a novel 24-membered
macrolide, was achieved via an enantioselective aldol reaction and 2-methyl-6-nitrobenzoic anhydride-
mediated macrolactonization. The obtained synthetic compounds were not identical to the natural
product. The newly proposed most likely structure of eushearilide, (±)-(16E,20E)-eushearilide, was
determined on the basis of detailed NMR analysis, and (3R,16E,20E,23R)-(ꢀ)-eushearilide was success-
fully synthesized. A comparison of the optical rotation of (3R,16E,20E,23R)-(ꢀ)-eushearilide with that
of the natural product confirmed that the true structure of naturally occurring eushearilide is the
Received 3 December 2014
Revised 25 January 2015
Accepted 28 January 2015
Available online 4 February 2015
Keywords:
Eushearilide
Antifungal activity
Total synthesis
(3S,16E,20E,23S)-(+)-form.
Ó 2015 Elsevier Ltd. All rights reserved.
Structural determination
Asymmetric synthesis
Lactonization
Introduction
substituted benzoic anhydrides, such as 2-methyl-6-nitrobenzoic
anhydride (MNBA), as condensing agents in the presence of a
4
Eushearilide (1) was first isolated from a culture of the fungus
Eupenicillium shearii in 2006 by Hosoe et al., who then structurally
nucleophilic catalyst such as 4-(dimethylamino)pyridine (DMAP)
or 4-(dimethylamino)pyridine N-oxide (DMAPO). As it has already
been demonstrated that MNBA is one of the most effective dehy-
drating reagents to produce macrocyclic lactones by promoting
1
characterized and demonstrated its antifungal activity against
diverse fungi and yeasts (Fig. 1). The chemical structure of 1 was
proposed to have a 24-membered lactone framework as the main
structure, bearing two stereogenic centers (C3 and C23). Moreover,
unlike general polyene macrolides, which mostly contain a conju-
gated polyene structure and a 1,3-polyol section, such as ampho-
tericin B, nystatin, and pimaricin, which are extensively used as
effective antifungal drugs, the present compound comprises a
non-conjugated diene system (16Z and 20E) and a phosphorylcho-
line group in the molecule. Thus, compound 1 possesses unique
structural characteristics and a promising structure–activity rela-
tionship; however, the absolute configuration at the C3 and C23
stereogenic centers of compound 1 has not been determined yet.
5
basic catalysts, we explored the asymmetric total synthesis of
compound 1 using the proposed 24-membered lactone structure
with the purpose of applying the present method to the total syn-
thesis of a natural macrolide antibiotic.
Results and discussion
Our retrosynthetic analysis for compound 1 is depicted in
2
Scheme 1. We planned to exploit an MNBA-mediated lactoniza-
6
tion to construct a 24-membered macrolide ring, followed by
7
the introduction of a highly polar phosphorylcholine to a hydroxyl
2
During our research on the synthesis of eushearilide, Higashiyama
group at the C3 position in the final stage. The seco-acid containing
a b-hydroxy ester moiety could be synthesized through the concur-
rent two-carbon elongation and construction of a stereogenic cen-
3
et al. reported the first total synthesis of 1 but found that the syn-
thetic product was not identical to the natural compound.
We have developed methods to synthesize carboxylic esters
and lactones with diverse ring sizes using symmetrically
8
ter using the asymmetric Mukaiyama aldol reaction of aldehyde 3
with enol silyl ether. The aldehyde 3 containing (Z)-alkene could be
stereoselectively constructed by the Wittig reaction of siloxyalde-
9
hyde 5 with phosphonium ylide generated from 4, which could
be prepared through the conventional transformations from the
simple and commercially available alkynyl primary alcohol and
chiral propylene oxide.
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(
I. Shiina).
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
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