Synthesis of the C-glycosidic analog of adenophostin A, a potent IP3 receptor agonist, using a temporary silicon-tethered radical coupling reaction as the key step

Article abstract of DOI:10.1016/S0040-4039(00)00171-4

Synthesis of the C-glycosidic analog (3) of adenophostin A, a very potent IP₃ receptor agonist, was achieved using a temporary silicon-tethered reductive radical coupling reaction as the key step. Radical reaction of the silaketal substrate 6 with Bu₃SnH/AIBN in benzene occurred stereoselectively, and subsequent desilylation gave the desired C-glycosidic disaccharide 7 with the (3α,1'α-configuration as the major product. Compound 7 was converted into the target 3 via the introduction of an adenine base by a Vorbruggen glycosylation reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00171-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2391–2394
Synthesis of the C-glycosidic analog of adenophostin A, a potent
IP3 receptor agonist, using a temporary silicon-tethered radical
coupling reaction as the key step1
Hiroshi Abe, Satoshi Shuto ∗ and Akira Matsuda
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
Received 15 December 1999; revised 17 January 2000; accepted 21 January 2000
Abstract
Synthesis of the C-glycosidic analog (3) of adenophostin A, a very potent IP3 receptor agonist, was achieved
using a temporary silicon-tethered reductive radical coupling reaction as the key step. Radical reaction of the
silaketal substrate 6 with Bu3SnH/AIBN in benzene occurred stereoselectively, and subsequent desilylation gave
the desired C-glycosidic disaccharide 7 with the (3α,10α)-configuration as the major product. Compound 7 was
converted into the target 3 via the introduction of an adenine base by a Vorbrüggen glycosylation reaction. © 2000
Elsevier Science Ltd. All rights reserved.
Considerable attention has been focused on D-myo-inositol 1,4,5-trisphosphate (IP3, 1), an intracellular
Ca2+-mobilizing second messenger, because of its biological importance.2,3 Therefore, much effort has
been devoted to the development of specific ligands for the IP3 receptors, which are very useful for
proving the mechanism of IP3-mediated Ca2+ signaling pathways.4 Recently, adenophostin A (2) was
isolated from Penicillium brevicompactum by Takahashi and co-workers and identified as the strongest
IP3 receptor ligand yet known; 2 is 10–100 times more potent than IP3 with regard to both the affinity
for the IP3 receptor and the Ca2+-mobilizing ability in cells.5 This finding prompted us to synthesize the
C-glycosidic analog 3 of adenophostin A and to examine its biological features,6 since C-glycosides are
known as useful mimics of carbohydrates by enhancing their stability.7
In the synthesis of the target compound 3, the key step is the formation of the C-glycosidic linkage with
the desired (30α,100α)-configuration, as shown in our synthetic plan in Scheme 1. The key C-glycosidic
∗
Corresponding author. Fax: +81-11-706-4980; e-mail: shu@pharm.hokudai.ac.jp (S. Shuto)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00171-4
tetl 16451

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linkage is constructed by a reductive radical coupling reaction of the silaketal tethered8 substrate 6,
which can be prepared from the pyranose unit 4 and the furanose unit 5. We assumed that treatment of
6 with Bu3SnH/AIBN would produce the 10-radical I in a boat conformation, and that its 10α-selective
cyclization9 would occur at the sterically unhindered endo-position of the 3-methylene to give 3-radical
II. Subsequent reduction by Bu3SnH would occur stereoselectively from the β-face, due to the significant
steric repulsion for the isopropylidene group when the reagent approaches the 3-position from the α-
face. Accordingly, this radical reaction should proceed stereoselectively to give III, and subsequent
desilylation would give 7 with the desired (3α,10α)-configuration. From 7, the target compound 3 can be
synthesized via the introduction of an adenine base by Vorbrüggen’s procedure.10
Scheme 1.
The synthesis of 3 is summarized in Scheme 2. Removal of the acetyl groups of the known orthoester
8,11 which was readily prepared from D-glucose, and subsequent protection of the resulting hydroxyls
with p-methoxybenzyl (MPM) groups gave 9. A PhSe group was introduced at the anomeric β-position
by treating 9 with PhSeH/MS3Å,12 and the resulting 2-O-acetyl group was removed to complete the
synthesis of pyranose unit 4. On the other hand, a Wittig reaction of a 3-keto sugar 10,13 prepared
from D-xylose, with Ph3P_CH2 in THF gave the corresponding 3-methylene product, the 5-O-TBS
group of which was removed with TBAF to give the furanose unit 5. Next, the units 4 and 5 were
temporarily connected with a silaketal linkage. Thus, treatment of 4 with BuLi/Me2SiCl2 in THF yielded
the corresponding 2-O-Si(Cl)Me2 product, which was then treated with 5 in the presence of Et3N to give
the silaketal 6, the substrate for the radical coupling reaction, in 67% yield.
Next, the reductive coupling reaction of 6 was investigated with Bu3SnH/AIBN. When a solution of
Bu3SnH (2.0 equiv.) and AIBN (0.5 equiv.) in benzene was added slowly over 1.2 h to a solution of 6 in
benzene at 80°C, the best results were observed. After the reaction mixture was treated with Bu4NF in
THF and purified by silica gel flash chromatography, the desired (3α,10α)-C-glycoside 714 was obtained
as the major product (50%) along with the C-glycoside 11 having the (3α,10β)-configuration (22%)
and the directly reduced product 12 (25%). After protection of the two free hydroxyls of 7 with the
benzyl groups, the MPM groups were removed with 90% TFA, and the resulting free hydroxyls were
acetylated to give 13. N6-Benzoyladenine was successfully introduced at the 1β-position of 13, using
the usual Vorbrüggen glycosylation procedure with a silylated base and SnCl4 in MeCN to give adenyl
C-disaccharide 14 in 65% yield. The four acetyl groups of 14 were removed simultaneously, and the 600-

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Scheme 2. Reagents and conditions: (a) (1) NaOMe, THF/MeOH, rt; (2) NaH, MPMCl, HMPA/DMF, rt, 77%; (b) (1) PhSeH,
MS3Å, MeNO2, reflux; (2) NaOMe, THF/MeOH, rt, 65%; (c) (1) NaOCMe2Et, Ph3PMeBr, THF, rt; (2) TBAF, THF, rt, 80%;
(d) (1) Me2SiCl2, BuLi, THF, −78°C–rt; (2) 5, Et3N, THF, 0°C–rt, 67%; (e) (1) Bu3SnH, AIBN, benzene, reflux; (2) TBAF,
THF, 50%; (f) BnBr, NaH, HMPA/DMF/THF, 0°C–rt, 72%; (g) (1) 90% TFA, 0°C–rt; (2) NaOMe, MeOH, rt; (3) Ac2O,
Et3N, DMAP, MeCN, 70%; (h) silylated N6-benzoyladenine, SnCl4, MeCN, 0°C–rt, 65%; (i) (1) NaOMe, MeOH; (2) TrCl,
py, 0–50°C, 95%; (j) XEPA, CH2Cl2, −40°C, then m-CPBA, −40°C–rt, 92%; (k) (1) NH3, aq. dioxane, rt; (2) H2, Pd-black,
aqueous MeOH, rt, 89%
primary hydroxyl was selectively protected by a trityl group to give 15. Phosphate units were introduced,
using the phosphoramidite method with o-xylene N,N-diethylphosphoramidite (XEPA) developed by
Watanabe and co-workers.15 Thus, 15 was treated with XEPA and tetrazole in CH2Cl2, followed by
oxidation with m-CPBA to give the desired 20,300,400-trisphosphate derivative 16 in 92% yield. The N6-
benzoyl group was removed with NH3/aq. dioxane. Finally, the trityl- and benzyl-protecting groups were
all removed in one step by catalytic hydrogenation with Pd-black in aqueous MeOH to give the target
compound 3 in 89% yield as a sodium salt, after treatment with ion-exchange resin.
In summary, we have successfully synthesized the C-glycosidic analog 3 of adenophostin A, using a
temporary silicon-tethered reductive coupling reaction as the key step.16 Biological evaluation of 3 is
under investigation and will be reported elsewhere.
Acknowledgements
This investigation was supported in part by a Grant from the Ministry of Education, Science, Sports
and Culture of Japan. We acknowledge useful discussions with Prof. B. V. L. Potter and Dr. A. M. Riley.

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1
16. Physical data of 3: H NMR (500 MHz, D2O) δ: 8.29 (1H, s, H-2), 8.17 (1H, s, H-8), 6.35 (1H, s, H-10), 5.00 (1H, dd,
H-20, J=4.9, 7.6 Hz), 4.21 (3H, m, H-40, H-400, H-100), 4.07 (1H, dd, H-600, J=6.8, 12.9 Hz), 3.92 (1H, ddd, H-300, J=5.7,
5.7, 10 Hz), 3.82 (1H, dd, H-50 , J=13.0, 1.4 Hz), 3.79 (2H, m, H-200, H-500), 3.65 (1H, dd, H-50 , J=3.7, 13.0 Hz), 3.57
a
b
(1H, dd, H-600, J=3.2, 12.9 Hz), 2.71 (1H, m, H-30), 2.02 (1H, m, C-glycosidic CHaHb), 1.80 (1H, m, C-glycosidic CHaHb);
31P NMR (67.5 MHz, D2O, H-decoupled) δ: 4.68, 4.20, 4.14; FAB-HRMS (triethylammonium salt, negative) calcd for
C17H27O17N5P3: 666.0615; found: 660.0615 (M−).