Synthesis of spiro C-arylglycoriboside via Pd(II)-catalyzed spirocyclization

Article abstract of DOI:10.1055/s-0030-1258560

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. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258560

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
x
x
.x
x
.2
0
1
0
Advanced online publication: 03.09.2010
DOI: 10.1055/s-0030-1258560; Art ID: U05410ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Spiro C-Arylglycoriboside via Pd(II)-Catalyzed Spirocyclization
2393
cally pure acetate 3. The enantiopurity of 3 was confirmed sis of our previous work, the cyclization was conducted in
by NMR analysis of both MPA esters of 3 and was deter- THF and PdCl2(PhCN)2 was used as a Pd(II) catalyst.8
mined to be >98%. Protection of the hydroxy group of 3 When the hemiketal 2¢ was treated with 10 mol% of the
as its TBS ether, followed by methanolysis, afforded the Pd(II) catalyst in THF (0.1 M) at room temperature, the
alcohol 7. Swern oxidation of the alcohol 7 followed by spirocyclization proceeded smoothly and the spiro com-
Horner–Wadsworth–Emmons reaction of the resulting al- pound 1 was isolated as a diastereomeric mixture
dehyde afforded the a,b-unsaturated ester 8. Reduction of (1a:1b:1c = 7.7:2.2:1) in 60% yield (entry 1). The diaste-
1
the ester 8 with DIBAL-H followed by protection of the reomeric ratio was determined from 600-MHz H NMR
resulting alcohol as its THP ether and deprotection of the spectra, and the stereochemistry at C1 and C4 was con-
TBS group with TBAF afforded the alcohol 9. Oxidation firmed by single-crystal X-ray diffraction analysis after
of the alcohol 9 in the presence of 2,2,6,6-tetramethyl- transformation of 1 into the corresponding crystalline
piperidine 1-oxyl (TEMPO), NaClO2 and bleach,7 fol- compound. Then, we investigated the effect of concentra-
lowed by condensation of the resulting carboxylic acid tion on the reaction. When the spirocyclization was con-
and N,O-dimethylhydroxylamine with carbonyldiimida- ducted in more dilute THF solution (0.05 M or 0.01 M),
zole (CDI), provided Weinreb’s amide, which was treated the yield was improved and 1 was obtained in 77% and
with o-bromobenzyl alcohol and n-BuLi to afford not keto 83% yield, respectively (entries 2 and 3). We next inves-
alcohol 2, but hemiketal 2¢ in 47% overall (Scheme 2) tigated the effect of the amount of the Pd(II) catalyst.
yield from cis-2-butene-1,4-diol (5). The presence of the When the hemiketal 2¢ was treated with 2 mol% of the
hydroxy group in the hemiketal 2¢ was confirmed by the Pd(II) catalyst, the spirocyclization did not proceed com-
presence of a strong absorption band in the region of 3384 pletely and the yield was much lower than that in the case
cm–1 in the IR spectrum.
of entry 3 (entry 4). This was because the Pd(II) catalyst
was deactivated and precipitated as palladium black be-
fore the substrate 2¢ was completely consumed. In con-
trast, when the spirocyclization was conducted in the
presence of 20 mol% of Pd(II) catalyst, the reaction pro-
ceeded smoothly and 1 was obtained in 91% yield (entry
5).
1) BzCl, pyridine
BzO
OBz
CH2Cl2, r.t., 99%
HO
OH
2) OsO4, NMO
H2O–acetone
r.t., 95%
HO
OH
5
6
1) Me2C(OMe)2, p-TsOH,
CH2Cl2, 40 °C, 98%
2) K2CO3, MeOH, r.t., 98%
Table 1 Pd(II)-Catalyzed Spirocyclizationa
AcO
OH
HO
OH
O
1
O
4
Lipase AK
O
O
PdCl2(PhCN)2
O
O
vinyl acetate
r.t., 90% (>98%ee)
2
THF, r.t.
O
O
3
4
1
1) TBSCl, imidazole, DMF, r.t., 99%
2) K2CO3, MeOH, r.t., 99%
Entry Pd(II) Concn
Time
Yield
(%)
Ratiob
(mol%) (mol/L) (min)
1a/1b/1c
1R,4R/1R,4S/1S,4Rc
TBSO
1) (COCl)2, DMSO
EtO2C
TBSO
1
2
3
4
5
10
10
10
2
0.1
60
60
60
60
15
60
77
83
51
91
7.7:2.2:1
13.2:4.4:1
11.5:3.4:1
16.8:1.8:1
12.6:4.6:1
CH2Cl2, –78 °C, then Et3N
HO
0.05
0.01
0.01
0.01
2) (EtO)2P(O)CH2CO2Et
NaH, THF, –78 °C to r.t.
94% in 2 steps
O
O
O
O
7
8
1) DIBAL-H, THF, 0 °C, 99%
2) DHP, p-TsOH, CH2Cl2, 0 °C, 97%
3) TBAF, THF, 5 °C to r.t., 95%
20
a All reactions were conducted under an argon atmosphere.
b The ratio was determined from 600-MHz 1H NMR spectra.
c The stereochemistry at C1 and C4 was confirmed by single-crystal
X-ray diffraction analysis after transformation of 1 into a crystalline
compound.
OTHP
O
OTHP
1) TEMPO, NaClO2
O
HO
bleach, MeCN-PBS
HO
(0.8 M, pH 7.0), 40 °C
2) CDI, HN(OMe)Me
CH2Cl2, 5 °C to r.t.
71% in 2 steps
3) o-bromobenzyl alcohol
n-BuLi, THF
–40 to 0 °C, 96%
O
O
O
We then focused on the further transformation of 1a into
diol 12 (Scheme 3). Oxidative cleavage of the olefin in
2'
9
9
spirocyclo adduct 1a with OsO4–NaIO4 followed by re-
duction of the resulting aldehyde gave the alcohol 10a10 in
76% yield over two steps. Protection of the hydroxy group
of 10a with benzoyl chloride and pyridine provided the
benzoate 11a in 99% yield. Removal of the acetonide
group with 70% aqueous trifluoroacetic acid gave 12a and
Scheme 2
With the requisite hemiketal 2¢ in hand, we next focused
on Pd(II)-catalyzed spirocyclization (Table 1). On the ba-
Synlett 2010, No. 16, 2392–2396 © Thieme Stuttgart · New York

2394
K.-i. Awasaguchi et al.
LETTER
12c as an epimeric mixture (R:S = 1:10) in 98% yield. The cloadducts were transformed into the alcohol 10 in the
two epimers were separated and purified by silica gel col- same manner as described for 1a in 87% yield over two
umn chromatography. The stereochemistry of 12a was steps. The inseparable alcohol 10 was treated with 4-bro-
confirmed unequivocally by single-crystal X-ray diffrac- mobenzoyl chloride and pyridine to afford the benzoate
tion analysis (Figure 2).
13. The diastereomers could be separated and purified by
silica gel column chromatography at this stage.
HO
O
O
1) OsO4
NaIO4, 2,6-lutidine
dioxane–H2O, 5 °C
O
O
4
1
2) NaBH4
MeOH, 5 °C
87% in 2 steps
O
O
O
O
10b,10c
1b,1c
O
O
O
O
O
O
Br
4-bromobenzoyl chloride
pyridine
13b (1R,4S)
+
CH2Cl2, r.t.
68%
O
O
O
O
O
O
Br
13c (1S,4R)
Scheme 4
The stereochemistry of 13b and 13c was confirmed un-
equivocally by single-crystal X-ray diffraction (Figure 3).
Figure 2 ORTEP diagram of 10a and 12a
HO
O
1) OsO4
NaIO4, 2,6-lutidine
dioxane–H2O, 5 °C
O
O
O
2) NaBH4
O
O
MeOH, 5 °C
O
O
76% in 2 steps
1a
10a
BzO
O
O
70% TFA (aq)
BzCl, pyridine
0 °C, 98%
12a/12c = 1:10
CH2Cl2, r.t.
99%
O
O
11a
BzO
BzO
+
O
1
O
O
O
4
HO
OH
HO
OH
12a (1R,4R)
12c (1S,4R)
Scheme 3
The stereochemistry at C1 and C4 in the cycloadducts 1b
and 1c was also confirmed by single-crystal X-ray diffrac-
tion analysis after transformation of the olefin 1 into the
4-bromobenzoate 13 (Scheme 4). The inseparable cy-
Figure 3 ORTEP diagram of 13b and 13c
Synlett 2010, No. 16, 2392–2396 © Thieme Stuttgart · New York

LETTER
Synthesis of Spiro C-Arylglycoriboside via Pd(II)-Catalyzed Spirocyclization
2395
OTHP
O
HO
step 1: hemiketal formation
step 2: coordination of hemiketal to Pd(II)
step 3: cyclization
O
O
2'
OTHP
OTHP
O
OTHP
HO
O
O
O
HO
HO
step 1
O
O
O
O
O
hemiketal A
hemiketal B
step 2
keto-alcohol
– HCl
THPO
Pd
O
O
O
O
O
O
no
THPO
Pd
O
O
O
O
O
O
O
H
Cl
O
THPO
H
O
Pd
σ*c–o
THPO
Pd
Cl
H
Cl
A1,2
H
O
Cl
A1,2
TS1
stabilization by an anomeric effect
TS2
TS3
TS4
destabilization by A1,2
step 3
– PdCl(OTHP)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
1a (1R,4R)
1b (1R,4S)
1c (1S,4R)
1d (1S,4S)
major cycloadduct
Scheme 5 Plausible mechanism of Pd(II)-catalyzed spirocyclization
A plausible mechanism of Pd(II)-catalyzed spirocycliza- PdCl(OTHP) may catalyze the reaction by itself or regen-
tion is illustrated in Scheme 5.11 The hemiketal 2¢ exists in erate PdCl2 with chloride ion. For this reason, this Pd(II)-
equilibrium with hemiketal A, B and keto alcohol. Pd-p catalyzed spirocyclization proceeds smoothly in the ab-
complex is formed by coordination of PdCl2 with allylic sence of any reoxidant.
ether at one p-face of the olefin with the assistance of the
Finally, methanolysis of 12c provided spiro C-arylglyco-
adjacent hydroxy group. This complex may be present as
riboside in 87% yield (Scheme 6).
an equilibrium mixture of four structures (TS1, TS2, TS3
and TS4) through the formation of hemiketal having alter-
BzO
O
O
O
native stereochemistry and coordination of PdCl2 with the
other p-face of the olefin. Although the conformations
TS1 and TS2 are stabilized by anomeric effect (no-s*c–o),
the conformations TS3 and TS4 are not. In addition, al-
though the conformations TS2 and TS4 are destabilized
by A1,2 strain, the conformations TS1 and TS3 are not.
Therefore, spirocyclization of hemiketal 2¢ should pro-
ceed preferentially through the most likely conformation
TS1. A syn-attack of the hydroxy group in the hemiketal
on the electrophilic sp2 carbon in TS1 occurs intramolec-
ularly from the same side of the Pd-complex in a 5-exo-
trigonal fashion to give a s-Pd complex followed by syn-
elimination of PdCl(OTHP), affording spiro compound
1a with (1R,4R) configuration. In the catalytic cycle,
O
K2CO3
HO
MeOH, r.t.
87%
HO
OH
HO
OH
12c
spiro C-arylglycoriboside
Scheme 6 Synthesis of spiro C-arylglycoriboside
In conclusion, spiro C-arylglycoriboside has been synthe-
sized from cis-2-butene-1,4-diol in 21 steps by using
Pd(II)-catalyzed spirocyclization as a key reaction. Fur-
ther application of this synthetic strategy to the synthesis
of spiro C-arylglycofuranoside analogues for evaluation
of their pharmacological activity is in progress.
Synlett 2010, No. 16, 2392–2396 © Thieme Stuttgart · New York

2396
K.-i. Awasaguchi et al.
LETTER
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Acknowledgment
This work was partly supported by a Grant-Aid for Scientific Rese-
arch from the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
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Synlett 2010, No. 16, 2392–2396 © Thieme Stuttgart · New York