DOI: 10.1002/asia.201501080
Communication
Total Synthesis
Concise Asymmetric Construction of C2-symmetric 1,9-
Diarylnonanoids Using a Hypervalent Silicon Complex: Total
Synthesis of (À)-Ericanone
Shunsuke Kotani,*[a, b] Kosuke Kai,[a] Yasushi Shimoda,[a] Hao Hu,[c] Shen Gao,[c]
Masaharu Sugiura,[a] Masamichi Ogasawara,[c] and Makoto Nakajima*[a]
Abstract: By using a phosphine oxide-catalyzed enantio-
selective double aldol reaction, we achieved the concise
construction of C2-symmetric 1,9-diarylnonanoids, ena-
bling the synthesis of (À)-ericanone from p-hydroxyben-
zaldehyde in 6 steps with 65% overall yield. The enantio-
Figure 1. Structure of (À)-ericanone (1).
selective double aldol reaction is useful for establishing
C2-symmetric 1,9-diaryl-3,7-dihydroxy-5-nonanones with
such as antioxidant and antitumor properties.[3] The first syn-
a single operation. Furthermore, the use of o-nosyl-pro-
thesis of (À)-1 was achieved by Dias and co-workers in 2013.[4]
tected p-hydroxybenzaldehyde and a 4,4’-disubstituted
BINAP dioxide catalyst dramatically improved the reactivi-
They conducted the total synthesis of (À)-1 from p-hydroxy-
ty and selectivity in the double aldol reaction, enabling
the total synthesis of (À)-ericanone with high yield and
with excellent enantiopurity.
benzaldehyde in 10 steps with 16% overall yield and assigned
its absolute configuration as 3S,7S. Key elements of their syn-
thetic approach constituted achieving the C2-symmetric struc-
ture using the stereoselective allylation/aldol reaction se-
quence (i.e., stepwise manipulation).
Our research group has previously demonstrated the utility
of chiral phosphine oxides as Lewis base organocatalysts.[5]
Phosphine oxide coordinates with a chlorosilane to form a hy-
pervalent silicon complex in dynamic equilibrium and catalyzes
various asymmetric transformations.[6–8] In addition, we have
recently developed the asymmetric double aldol reaction of
ketone 2 with aromatic aldehyde 3 using the hypervalent sili-
con complex to obtain 3-pentanone derivative 4 with high ste-
reoselectivity (Figure 2).[9,10] The hypervalent silicon complex 6,
generated from phosphine oxide (S)-5 and silicon tetrachloride,
first promotes the asymmetric aldol reaction. Phosphine oxide
5 is dislocated from the complex to yield silyl aldolate 7 and
then regenerates 6 with another silicon tetrachloride, which
further promotes the second aldol reaction of silyl aldolate 7
with aldehyde 3 to afford 4 in a highly stereoselective fashion.
The stereochemical relationship between the two hydroxy moi-
eties of 4 as well as those of 1 is 1,5-anti. Therefore, it is ex-
pected that the double aldol reaction of acetone (2) and a cin-
namaldehyde derivative directly furnished the core skeleton of
(À)-1 with C2-symmetric 1,9-diarylnonanoid structure. Herein,
we report the enantioselective synthesis of (À)-ericanone (1)
by means of the phosphine oxide-catalyzed asymmetric
double aldol reaction.
(À)-Ericanone (1) is a C2-symmetric 1,9-diarylnonanoid, isolated
in 2011 from the acetone extract of the aerial parts of fresh
Erica Cinerea L. (Figure 1).[1] While the structure of (À)-1 appears
simple and characteristic with a linear C2-symmetry, it is in fact
quite rare in nature. Several 1,9-diarylnonanoids have recently
been discovered.[2] However, the bioactivities of these 1,9-dia-
rylnonanoid families remain unexplored. Nevertheless, they are
expected to possess useful bioactivities because 1,7-diarylhep-
tanoids represented by curcumin have efficient bioactivities
[a] Prof. Dr. S. Kotani, K. Kai, Dr. Y. Shimoda, Prof. Dr. M. Sugiura,
Prof. Dr. M. Nakajima
Graduate School of Pharmaceutical Sciences
Kumamoto University
5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973 (Japan)
[b] Prof. Dr. S. Kotani
Priority Organization for Innovation and Excellence
Kumamoto University
5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973 (Japan)
[c] H. Hu, S. Gao, Prof. Dr. M. Ogasawara
Catalysis Research Center and Graduate School of Life Science
Hokkaido University
Kita 21, Nishi 10, Kita-ku, Sapporo 001-0021 (Japan)
We first explored the reactivity of aldehydes in the double
aldol reaction. The reaction, conducted by treating three
equivalents of 3-phenylpropanal with ketone 2 in the presence
of 10 mol% (S)-5, four equivalents of silicon tetrachloride, and
five equivalents of N,N-diisopropylethylamine in dichlorome-
Supporting information for this article is available on the WWW under
This manuscript is part of a special issue on catalysis and transformation
Chem. Asian J. 2016, 11, 376 – 379
376
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