1020
Published on the web June 1, 2013
Synthesis and Biological Evaluation of Aspergillide A/Neopeltolide Chimeras
Haruhiko Fuwa,* Kenkichi Noto, Masato Kawakami, and Makoto Sasaki
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577
(Received April 9, 2013; CL-130322; E-mail: hfuwa@m.tohoku.ac.jp)
OH
O
In this study, stereoisomeric aspergillide A/neopeltolide
MeO
Me
OMe
O
chimeras were synthesized in a parallel manner, and their
antiproliferative activity was evaluated to demonstrate the
potential utility of the 14-membered macrolactone structure
embedded with a tetrahydropyran substructure as a template for
developing natural product-like antiproliferative agents.
OH
OH
MeO
OMe
O
O
O
Me
O
O
O
O
O
Because of their unique molecular architecture and potent
biological activities, there is an emerging interest in marine
natural products as a source of novel therapeutics.1 A number of
14-membered macrolide natural products containing a tetrahy-
dropyran ring have been isolated from various marine organ-
isms. Examples of such secondary metabolites include asper-
gillides A and B (1 and 2, respectively),2 auriside A (3),3
lyngbyaloside B (4),4 and neopeltolide (5),5 as shown in
Figure 1. These naturally occurring macrolides have attracted
considerable attention from the organic and medicinal chemistry
communities owing to their synthetically intriguing structure
and antiproliferative and/or cytotoxic activity;6-9 e.g., 1 and 2
showed cytotoxicity against mouse lymphocytic leukemia cells
(L1210) with LD50 values of 2.1 and 71 ¯g mL¹1, respectively.2a
The mechanisms of action of these natural products have not
been fully elucidated so far.10 However, we envision that the
tetrahydropyran-containing 14-membered macrolactone struc-
ture, commonly found in this class of natural products, might be
a potentially useful template for developing natural product-like
antiproliferative agents. In this context, structural hybridization
of natural products would be an attractive means of generating
natural product-like compounds.11 Herein, we report the synthe-
sis and biological evaluation of aspergillide A/neopeltolide
stereoisomeric chimeras.
HO
Me
Me
Me
Me
aspergillide A (1)
Me
O
aspergillide B (2)
O
O
O
Br
Me
auriside A (3)
OMe
MeO
Me
OH
O
N
O
O
O
O
O
Me
HN
HO
OMe
O
Me
O
O
O
Me
MeO
O
O
OH
Me
Br
Me
neopeltolide (5)
lyngbyaloside B (4)
Figure 1. Structures of aspergillides
respectively), auriside A (3), lyngbyaloside B (4), and neopeltolide
(5).
A and B (1 and 2,
We designed the aspergillide A/neopeltolide chimera 6a
and its stereoisomers 6b-6h as the target of this study because of
the structural simplicity of the macrolactone backbone of 1 and 5
(Scheme 1 and Table 1). Thus, structural hybridization of the
upper-half domain of 1 and the lower-half domain of 5 would
generate stereoisomeric chimeras 6a-6h. We have previously
reported the total syntheses of 1,12 2,12 and 5,13 and learned that
the 14-membered macrolactone backbone structure of 5 could be
efficiently constructed via an esterification-ring-closing meta-
thesis (RCM)14 sequence. Accordingly, we planned to synthe-
size 6a-6h from the carboxylic acids 7a,12 7b15 and the alcohols
8a-8d13a in a parallel manner.
The synthesis of 6a-6h commenced with esterification of 7a
and 7b with 8a-8d under Yamaguchi conditions17 to give the
esters 9a-9h in excellent yields (Scheme 1). RCM of 9a-9h
proceeded efficiently under the influence of the second-gener-
ation Grubbs catalyst ((H2IMes)(PCy3)Ru(=CHPh)Cl2, H2IMes:
1,3-dimesityl-4,5-dihydroimidazol-2-ylidene)18 and 1,4-benzo-
quinone19 in toluene at 100 °C to afford the macrolactone 10a-
10h in moderate to excellent yields. The stereochemistry of the
newly generated double bond was determined to be Z by an
NOE experiment. Finally, the MOM group of 10a-10h was
removed under acidic conditions (HCl, MeOH or LiBF4,
aqueous CH3CN20) to furnish 6a-6h.21 The stereochemistry of
6a-6h is summarized in Table 1.
The antiproliferative activity of 6a-6h was evaluated
against mouse leukemia P388 cells by the WST-8 assay,22 and
the results are summarized in Table 2. A pair of enantiomers 6b
and 6g showed significant activity among 6a-6h. The IC50
¹1
values for 6b and 6g were determined to be 23 and 28 ¯g mL
,
respectively. These results indicate the importance of the
stereoisomerism of the macrocyclic backbone structure. Mean-
while, compounds 6a-6h were found to be inactive against HL-
60 human promyelocytic leukemia cells and HT1080 human
¹1 23,24
fibrosarcoma cells at 75 ¯g mL
.
Notably, reflecting the backbone chirality, each of the
1
stereoisomers 6a-6d showed distinct H and 13C NMR spectra,
indicating that each stereoisomer has its unique conformational
profile.25 The solution structures of 6a-6d, deduced on the basis
of NMR-based conformational analysis and molecular model-
Chem. Lett. 2013, 42, 1020-1022
© 2013 The Chemical Society of Japan
Fuwa, Haruhiko
