2392
LETTER
Synthesis of Spiro C-Arylglycoriboside via Pd(II)-Catalyzed Spirocyclization
S
ynthesisof Spiro
e
C
-Arylglyc
n
oriboside via
-
Pd(II)-
i
C
atalyz
c
edSpirocy
h
clization iro Awasaguchi,a Masahiro Miyazawa,*b Ikuyo Uoya,b Koichi Inoue,b Koji Nakamura,b Hajime Yokoyama,b
Hiroko Kakuda,c Yoshiro Hirai*a
a
Graduate School of Innovative Life Science, University of Toyama, 3190 Gohuku, Toyama 930-8555, Japan
Fax +81(764)456115; E-mail: hirai@adm.u-toyama.ac.jp
Faculty of Science, Department of Chemistry, University of Toyama, 3190 Gohuku, Toyama 930-8555, Japan
b
E-mail: miyazawa@sci.toyama-u.ac.jp
Faculty of Medicine, Laboratory of Chemistry, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
c
Received 10 June 2010
O
O
O
O
O
O
Abstract: Spiro C-arylglycoriboside was synthesized in 21 steps
via Pd(II)-catalyzed spirocyclization as a key reaction. Hemiketal
was obtained in 47% overall yield from cis-2-butene-1,4-diol and
spirocyclized with PdCl2(PhCN)2 in dilute THF solution (0.01 M)
to afford the 1,6-dioxaspiro[4.4]nonane skeleton in high yield. The
spirocyclo adduct was transformed into spiro C-arylglycoriboside
in five steps.
1,6-dioxaspiro
[4.5]decane
1,7-dioxaspiro
[5.5]undecane
1,6-dioxaspiro
[4.4]nonane
HO
OH
O
Key words: spiro compound, palladium, heterocycles, stereoselec-
tivity, cyclization
HO
RO
O
OH
HO
HO
O
O
HO
OH
spiro C-arylglycopyranoside
framework of papulacandin D
Spiroketals such as 1,6-dioxaspiro[4.5]decane, 1,7-dioxa-
spiro[5.5]undecane and 1,6-dioxaspiro[4.4]nonane occur
widely as substructures of natural products from many
sources, including insects, microbes, plants, fungi and
marine organisms.1 Papulacandin D is also a naturally oc-
curring spiroketal compound which contains a 1,6-dioxa-
spiro[4.5]decane skeleton with an aryl-b-D-C-
glycopyranoside.2 Its pharmacological activities, along
with the structural complexity of spiro C-arylglycopyra-
nosides, have triggered intense interest in the synthesis
and chemical reactivity of these compounds.3 On the other
hand, spiro C-arylglycofuranoside does not occur natural-
ly and has received less attention (Figure 1), although C-
arylnucleosides are biologically important nucleoside mi-
metics.4 Recently, Yamamoto and co-workers have re-
ported a synthesis of acetonide-protected spiro C-
arylglycoriboside using Cp*RuCl-catalyzed [2+2+2]-
cycloaddition.5 We report here a synthesis of spiro C-
arylglycoriboside via palladium(II)-catalyzed spirocy-
clization, in order to examine its pharmacological activi-
ties.
spiro C-arylglycoriboside
..
Figure 1 Spirocyclic compounds
O
O
O
O
HO
O
O
HO
OH
1
spiro C-arylglycoriboside
OTHP
O
HO
AcO
OH
O
O
O
O
3
2
HO
OH
HO
OH
O
O
Our retrosynthetic analysis is illustrated in Scheme 1. We
envisioned that spiro C-arylglycoriboside would be ob-
tained by transformation of the spiro compound 1, and its
spiroketal moiety would be constructed by palladium(II)-
catalyzed cyclization of the keto alcohol 2. The keto alco-
hol 2 would be readily prepared by side chain elongation
of the acetate 3.6 Optically active acetate 3 would be syn-
thesized by asymmetric acetylation of the meso-diol 4 us-
4
5
Scheme 1 Retrosynthesis of spiro C-arylglycoriboside
ing lipase. Finally, the meso-diol 4 would be readily
available from cis-2-butene-1,4-diol (5).
Our synthesis commenced with benzoylation of the diol 5
followed by dihydroxylation with a catalytic amount of
OsO4, using NMO as a reoxidant, to afford the diol 6. Pro-
tection of 6 as its acetonide, followed by methanolysis,
gave the meso-diol 4 as a key intermediate. Then, the
meso-diol 4 was subjected to asymmetric acetylation with
lipase AK Amano 20 in vinyl acetate to give almost opti-
SYNLETT 2010, No. 16, pp 2392–2396
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Advanced online publication: 03.09.2010
DOI: 10.1055/s-0030-1258560; Art ID: U05410ST
© Georg Thieme Verlag Stuttgart · New York