Construction of a chiral quaternary carbon center by a radical cyclization/ring-enlargement reaction: Synthesis of 4α-azidoethyl carbocyclic ribose, a key unit for the synthesis of cyclic ADP-ribose derivatives of biological importance

Article abstract of DOI:10.1016/j.tet.2015.05.084

As a stable analog of the second messenger cyclic ADP-ribose (cADPR), we designed 4″-azidoethyl-cyclic ADP-carbocylic-ribose (N₃-cADPcR). For the synthesis of N₃-cADPcR, 1β-amino-2,3-O-isoproplylidene-4α-azidoethyl carbocyclic-ribose (4) having a chiral quaternary stereogenic center is required as the key unit. We successfully synthesized the desired unit 4 via construction of the quaternary stereogenic center by a radical cyclization/ring-enlargement reaction with a silicon-tethered substrate as the key step.

Full text of DOI:10.1016/j.tet.2015.05.084

Tetrahedron 71 (2015) 5407e5413
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Construction of a chiral quaternary carbon center by a radical
cyclization/ring-enlargement reaction: synthesis of 4a-azidoethyl
carbocyclic ribose, a key unit for the synthesis of cyclic ADP-ribose
derivatives of biological importance
a
a
a
a
a
Takatoshi Sato , Takayoshi Tsuzuki , Satoshi Takano , Kohtaro Kato , Hayato Fukuda ,
a,
y
a,b,
*
Mitsuhiro Arisawa , Satoshi Shuto
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan
a
b
Center for Research and Education on Drug Discovery, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan
a r t i c l e i n f o
a b s t r a c t
0
0
Article history:
As a stable analog of the second messenger cyclic ADP-ribose (cADPR), we designed 4 -azidoethyl-cyclic
ADP-carbocylic-ribose (N -cADPcR). For the synthesis of N -cADPcR, 1 -amino-2,3-O-isoproplylidene-
-azidoethyl carbocyclic-ribose (4) having a chiral quaternary stereogenic center is required as the key
Received 16 February 2015
Received in revised form 22 May 2015
Accepted 24 May 2015
3
3
b
4
a
unit. We successfully synthesized the desired unit 4 via construction of the quaternary stereogenic center
by a radical cyclization/ring-enlargement reaction with a silicon-tethered substrate as the key step.
Ó 2015 Elsevier Ltd. All rights reserved.
Available online 9 June 2015
Keywords:
Cyclic ADP-ribose
Radical reaction
Silicon tether
Quaternary carbon center
Carbocyclic ribose
Ring-enlargement
1. Introduction
pathway that uses cADPR are needed, but the biological and
chemical instability of cADPR due to its positively-charged N1-
8
Stereocontrolled construction of chiral quaternary carbon cen-
riboside structure limits further studies of its physiological role.
We previously designed and synthesized cyclic ADP-carbocyclic
1
ters is a challenging issue in organic synthesis. In our continuing
2
2c
medicinal chemical studies on cyclic ADP-ribose (cADPR, 1, Fig. 1),
ribose (cADPcR, 2), which is chemically and biologically stable
which is a Ca2 -mobilizing second messenger, we designed 4
00
a-
þ
3,4
azidoethyl-cADP-carbocyclic-ribose (N
quaternary carbon center as a synthetic target. Here we describe
the synthesis of 4 -azidoethyl carbocyclic-ribose 4 (Fig. 2), a key
unit for the synthesis of N -cADPcR, in which the quaternary carbon
3
-cADPcR, 3) having a chiral
a
3
center at the 4-position was effectively constructed by a radical
cyclization/ring-enlargement reaction.5
Analogs of cADPR have been extensively designed and synthe-
sized due to their potential usefulness for investigating the mech-
2
þ
3,6,7
anism of cADPR-mediated Ca release.
Because of its
physiological importance, intensive studies of the signaling
*
Corresponding author. Tel./fax: þ81 11 706 3769; e-mail address: shu@pharm.
hokudai.ac.jp (S. Shuto).
y
3
Fig. 1. cADPR (1), cADPcR (2), and N -cADPcR (3).
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka,
Suita, Osaka 565-0871, Japan.
http://dx.doi.org/10.1016/j.tet.2015.05.084
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

5408
T. Sato et al. / Tetrahedron 71 (2015) 5407e5413
2. Results and discussion
We previously developed a regio- and stereoselective method
for introducing hydroxyethyl group at the -position of a hydroxyl
group in halohydrins or -phenylselenoalkanols using an intra-
b
a
molecular radical cyclization reaction with a dimethyl- or diphe-
nylvinylsilyl group as a temporary connecting radical-acceptor
5
tether (Scheme 1). In this reaction, the kinetically favored 5-exo-
cyclized radical C, formed from the radical B, is rearranged into
a more stable ring-enlarged radical E via pentavalent silicon radical
5
b
3
D, which is subsequently trapped with Bu SnH to give F. Tamao-
Fig. 2. Synthetic plan for N
key unit.
3
-cADPcR (3) with 4
a-azidoethyl carbocyclic-ribose 4 as the
Fleming oxidation of the radical reaction product F allows us to
stereoselectively introduce a hydroxyethyl group adjacent to the
5
hydroxyl group. We planned to construct the quaternary center at
the 4-position of the carbocyclic-ribose unit 4 using this radical
cyclization/ring-enlargement reaction.
and effectively mobilizes Ca2þ in various biological systems.2d,e
Therefore, cADPcR can be used as a lead structure for developing
biological tools for investigating the cADPR-related Ca -mobiliz-
ing signaling pathway.
Thus, we expected to obtain the carbocyclic amine II having the
desired quaternary carbon center at the 4-position by the radical
cyclization/ring-enlargement reaction and subsequent oxidation
with the substrate I (Scheme 2). After various attempts to prepare
substrate having the structure I, we reached substrates 11 and 12
for the radical reaction, which were synthesized from commercially
available (1R)-2-azabicyclo[2.2.1]-hept-5-en-3-one (5) (Scheme 3).
2
þ
Previous findings from structureeactivity relationship (SAR)
2
studies of cADPR revealed that the 6-NH and pyrophosphate
2
b,6e
00
whereas the 3 -
moieties are essential for its biological activity,
hydroxyl is not.2 Based on the structureeactivity relationship
e
9
The bicyclic lactam 6, prepared from 5 by a known procedure, was
findings and the three-dimensional structure of cADPcR predicted
converted to the aldehyde 8 via the alcohol 7. Introduction of
a phenylseleno group at the 4-position of 8 via its silyl enol ether
2
g
by NOE-based molecular dynamics study, we expected that the
0
0
a
4
-position would not be important for recognition by the target
biomolecules, because the position is rather distant from the es-
sential 6-NH and pyrophosphate moieties and near the un-
important 3 -hydroxyl in the three-dimensional cADPcR structure.
Thus, we designed N -cADPcR (3) as a synthetic target, in which the
10
gave 9. Reduction of the formyl group of 9 and subsequent pro-
tecting group manipulation gave 10. Introduction of the silicon
tether selectively at the 3-hydroxyl was unsuccessful. When 10 was
treated with CH ]CHSiPh2Cl, Et N, and DMAP in toluene, how-
2 3
ever, it afforded a mixture of the 2-O-tethered product 11 and the 3-
O-tethered product 12 (99%) in a ratio of 1.4:1.
The key radical reaction was investigated next, and the results
3
are summarized in Scheme 4. When a solution of Bu SnH and AIBN
in benzene was added slowly to a solution of 11 and 12 (1.4:1), the
reaction gave the cyclization product 13 with the desired quater-
nary stereogenic center as a major product (71%) along with the
reduction product 14 (24%) with the unreacted 2-O-silyl group
2
0
0
3
azido group could be effectively used for conjugating various
functional groups by a H u€ isgen reaction to prepare useful biological
tools.
In the synthesis of N
structure would be constructed with 4
3
-cADPcR, the N1-carbocyclic adenosine
-azidoethyl carbocyclic ri-
a
bose (4) as a key unit and the characteristic 18-membered cyclic
pyrophosphate ring would be constructed by previously developed
procedures.2 Thus, if the carbocyclic ribose unit 4 was available,
b,c
(
entry 1). The stereochemistry of the products 13 and 14 was
synthesis of the target N
3
-cADPcR could be achieved (Fig. 2).
11
confirmed by NOE experiments (Fig. 3). Purified 11 or 12 was then
treated under the same radical reaction conditions. Thus, the re-
action of 3-O-tethered 12 gave exclusively 13 (84%) (entry 2). In-
terestingly, when the 2-O-tethered 11 was subjected to the same
Therefore, we initiated our study for providing the key carbocyclic-
ribose unit 4, and in this report, we describe the details of the
synthesis of 4 with a chiral quaternary carbon center.
Scheme 1. Radical cyclization/ring-enlargement with a vinylsilyl group and subsequent oxidation to stereoselectively introduce a hydroxyethyl group.

T. Sato et al. / Tetrahedron 71 (2015) 5407e5413
5409
Scheme 2. Plan for constructing the quaternary carbon center via the radical cyclization/ring-enlargement reaction.
Scheme 3. Synthesis of the radical reaction substrates 11 and 12.
reaction, the desired cyclization product 13 was obtained as the
major product with the reduction product 14 (34%). Thus, in this
reaction, not only the 3-O-tethered 12, but also the 2-O-tethered 11
unexpectedly worked as a substrate for the reaction forming the
product 13 with the desired quaternary stereogenic center.
To investigate the reaction mechanism, we performed a deute-
rium-labeling reaction. When the mixture 11 and 12 (1.4:1) was
O-tethered 12, was formed. These results suggested that the desired
cyclization product 13 formed via the exo-cyclization/ring-en-
largement reaction from both 11 and 12. In the case with the 2-O-
tethered substrate 11, migration of the silicon tether from the 2-
hydroxyl to the 3-hydroxyl occurred, probably after the radical
cyclization due to the steric demand of the cyclization product, as
shown in Scheme 5. Thus, in accordance with previous cases, the
exo-cyclization and subsequent ring-enlargement reaction effec-
tively occurred in the radical reaction course to afford the desired
product with the quaternary stereogenic center.
treated with Bu
conditions, cyclization product 13D, in which the position
3
SnD instead of Bu
3
SnH under the same reaction
to the
b
silicon was exclusively deuterated, was produced in 61% isolated
yield. In addition, when the 2-O-tethered substrate 11 was heated
under reflux in benzene, none of the migration product, i.e., the 3-
Thus, the stereogenic center was successfully constructed, and
the product 13 was next converted into the carbocyclic-ribose unit

5410
T. Sato et al. / Tetrahedron 71 (2015) 5407e5413
Scheme 4. Radical cyclization/ring-enlargement reaction of the substrate 11 and/or 12.
4. When 13 was treated with m-CPBA and KF in DMF, oxidative
cleavage of the oxasilacyclohexane ring proceeded to afford 4a-
hydroxyethyl carbocyclic-ribose derivative 15 in 71% yield. Pro-
tecting the 2,3-cis-diol of 15 with an isopropylidene group and
subsequent introduction of the azido group at the terminal position
of the 4
group produced the desired 1
azidoethyl carbocyclic-ribose (4) (Scheme 6)..
In summary, we successfully prepared 4
clic-ribose 4, an essential unit for the synthesis of 4
cyclic ADP-carbocylic-ribose (N -cADPcR) of significant biological
a-branched-chain, followed by removal of the phthaloyl
b-amino-2,3-O-isopropyliden-4a-
a
-azidoethyl carbocy-
0
0
a-azidoethyl-
3
importance. For the synthesis of 4, the key chiral quaternary ster-
eogenic center was effectively constructed by a radical cyclization/
ring-enlargement reaction with the silicon-tethered substrates.
Fig. 3. NOE data of 13 and 14.
3
Synthesis of the target N -cADPcR (3) is now under investigation.
Scheme 5. The presumed radical reaction mechanism.

T. Sato et al. / Tetrahedron 71 (2015) 5407e5413
5411
Scheme 6. Synthesis of 4
a
-azidoethyl carbocyclic-ribose 4.
3
3
. Experimental section
3.3. (1R,2S,3R,4S)-4-Formyl-2,3-O-isopropylidenedioxy-1-
phthaloylaminocyclopentane (8)
.1. General methods and materials
1H NMR spectra were recorded in CDCl
A mixture of 7 (1.93 g, 6.08 mmol) and Dess-Martin periodinane
ꢁ
2 2
Cl (61 mL) was stirred at 0 C for
3
at ambient temperature
(DMP, 3.20 g, 7.54 mmol) in CH
30 min and then at room temperature for 1 h. After addition of
aqueous saturated Na , the resulting mixture was partitioned
between AcOEt and H O, and the organic layer was washed with
O and brine, dried (Na SO ), and evaporated. The residue was
purified by column chromatography (SiO , AcOEt/hexane, 1:2e2:3)
to give 8 (1.55 g, 4.92 mmol, 81%) as a colorless oil: H NMR
(400 MHz, CDCl 9.84 (1H, s), 7.86e7.72 (4H, m), 5.28 (1H, dd,
J¼7.7 Hz, 3.6 Hz), 5.04 (1H, dd, J¼6.3 Hz, 3.6 Hz), 4.78e4.73 (1H, m),
unless otherwise noted, at 400 or 500 MHz, with TMS as an internal
standard. 13C NMR spectra were recorded in CDCl
at ambient
temperature at 100 or 125 MHz. Silica gel column chromatography
was performed with silica gel 60 N (spherical, neutral, 63e210 m,
Kanto Chemical Co., Inc.). Flash column chromatography was per-
formed with silica gel 60 N (spherical, neutral, 40e50 m, Kanto
Chemical Co., Inc.). Structures of synthesized compounds were
3
2 2 3
S O
2
m
H
2
2
4
2
1
m
3
) d
1
13
confirmed by H NMR, C NMR, and HRMS spectra.
13
3
.03e2.98 (1H, m), 2.48e2.42 (2H, m), 1.55 (3H, s), 1.34 (3H, s);
NMR (100 MHz, CDCl 200.4, 167.9, 134.2, 131.6, 123.4, 112.3, 83.2,
NNa
C
3
) d
3
.2. (1R,2S,3R,4R)-4-Hydroxymethyl-2,3-O-iso-
8
3
0.8, 58.2, 55.3, 29.1, 27.1, 24.7; HRMS (ESI) calcd for C17
38.1014 (MþNa) , found 338.1004.
H
17
O
5
propylidenedioxy-1-phthaloylaminocyclopentane (7)
þ
A mixture of 6 (2.01 g, 8.26 mmol), Me
2.4 mmol), and TsOHꢀH O (318 mg, 1.67 mmol) in acetone (82 mL)
was stirred at room temperature for 1 h, then neutralized with
saturated aqueous NaHCO and concentrated. The residue was
partitioned between AcOEt and H O, and the organic layer was
washed with brine, dried (Na SO ), and evaporated. A mixture of
the residue and NaBH (635 mg, 16.8 mmol) in MeOH (82 mL) was
2 2
C(OMe) (1.52 mL,
1
2
3.4. (1R,2S,3R,4S)-4-Formyl-2,3-O-isopropylidenedioxy-4-
phenylseleno-1-phthaloylaminocyclopentane (9)
3
2
2
4
A mixture of 8 (1.25 g, 3.95 mmol), Et
3
N (0.94 mL, 6.7 mmol),
(151 mL) was stirred
4
and Me SiCl (0.75 mL, 5.9 mmol) in CH Cl
3
2
2
stirred at room temperature for 10 h, then neutralized with AcOH
and evaporated. The residue was partitioned between AcOEt and
at room temperature for 10 h, and then to which PhSeCl (774 mg,
4.04 mmol) was added. The resulting mixture was stirred at
room temperature for 1 h and then partitioned between AcOEt
H
2
O, and the organic layer was washed with brine, dried (Na
2 4
SO ),
and evaporated. A mixture of the residue in H O (82 mL) was
2
and H O. The organic layer was washed with brine, dried
4
(Na SO ), and evaporated. The residue was purified by column
chromatography (silica gel; hexane/AcOEt, 4:1e2:1) to give 9
2
heated under reflux for 16 h and evaporated. A mixture of the
residue and phthalic anhydride (1.19 g, 8.01 mmol) in toluene was
heated under reflux for 12 h and evaporated. The residue was pu-
2
(1.70 g, 3.61 mmol, two steps 90%) as white amorphous powder
1
1
rified by column chromatography (SiO
2
, AcOEt/hexane, 1:1e1:2) to
(
a
/
b
diastereomer ratio, about 45:1 on the H NMR): H NMR
give 7 (2.30 g, 7.25 mmol, four steps 88%) as a white amorphous
(500 MHz, CDCl 9.38 (1H, s, H-5), 7.77e7.24 (9H, m), 5.26 (1H,
3
) d
1
powder: H NMR (400 MHz, CDCl
3
)
d
7.83e7.72 (4H, m), 5.07 (1H,
dd, J¼6.3 Hz, 2.3 Hz), 5.24 (1H, d, J¼6.3 Hz), 4.99 (1H, dd,
dd, J¼7.2 Hz, 5.9 Hz), 4.75e4.68 (1H, m), 4.62 (1H, dd, J¼6.9 Hz,
J¼7.5 Hz, 5.2 Hz, 2.3 Hz), 2.61 (1H, dd, J¼14.3 Hz, 5.2 Hz), 2.47
13
5
2
.9 Hz), 3.82e3.75 (2H, m), 2.41e2.32 (1H, m), 2.32 (1H, s),
.20e2.15 (2H, m), 1.56 (3H, s),1.30 (3H, s); C NMR (100 MHz,
(1H, H-6, J¼14.3 Hz, 7.5 Hz), 1.68 (3H, s), 1.38 (3H, s); C NMR
13
3
(125 MHz, CDCl ) d 189.5, 168.0, 138.0, 134.2, 131.6, 129.6, 129.1,
CDCl
3
)
d
168.1, 134.1, 131.7, 123.2, 113.3, 81.9, 64.2, 55.2, 46.2, 31.3,
125.3, 123.3, 113.4, 83.0, 81.3, 66.8, 54.8, 35.2, 25.7, 24.5; HRMS
þ
þ
27.6, 25.2; HRMS (ESI) calcd for C17
H
19
O
5
NNa 340.1177 (MþNa) ,
(ESI) calcd for
494.0489.
C
16
H
21
O
5
NNaSe 494.0484 (MþNa) , found
found 340.1155.

5412
T. Sato et al. / Tetrahedron 71 (2015) 5407e5413
3
.5. (1R,2S,3R,4S)-4-Benzoyloxymethyl-2,3-O-iso-
3.7. General procedure for the radical reactions
propylidenedioxy-4-phenylseleno-1-
phthaloylaminocyclopentane (10)
To a solution of substrate (37 mg, 0.050 mmol) in benzene
ꢁ
(
5 mL) at 80 C, a solution of Bu
3
SnH (53
mL, 0.15 mmol) and AIBN
A mixture of 9 (1.60 g, 3.40 mmol,
5:1), NaBH CN (544 mg, 8.66 mmol), and AcOH (2.3 mL) in THF
34 mL) was stirred at room temperature for 24 h and then parti-
tioned between AcOEt and H O, and the organic layer was washed
with brine, dried (Na SO ), and evaporated. The residue was puri-
a
/
b
diastereomer ratio, about
(8 mg, 0.050 mmol) in benzene (2 mL) was added slowly over a 1 h
period. The solvent was evaporated, and the residue was purified by
silica gel column chromatography (silica gel; hexane/AcOEt,
4
(
3
2
9:1e4:1) to give 13, or 13 and 14, as white amorphous powder
1
2
4
(yields are shown in Fig. 3). 13: H NMR (400 MHz, CDCl
3
)
fied by column chromatography (silica gel; hexane/AcOEt, 2:1) to
give the 5-hydroxy reduction product (1.44 g, 3.05 mmol, 90%) as
d
7.37e7.93 (19H, m), 5.01 (1H, ddd, J¼10.4 Hz, 10.0 Hz, 5.0 Hz), 4.86
(1H, dd, J¼10.4 Hz,10.0 Hz, 9.5 Hz), 4.45 (1H, d, J¼11.3 Hz), 4.36 (1H,
d, J¼5.0 Hz), 4.28 (1H, d, J¼11.3 Hz), 2.98 (1H, d, J¼10.4 Hz), 2.38
(1H, dd, J¼13.6 Hz, 10.4 Hz), 2.27e2.22 (1H, m), 2.02 (1H, dd,
white amorphous, where the minor
was removed: A mixture of the obtained reduction product
406 mg, 0.859 mmol), BzCl (0.13 mL, 1.1 mmol) in pyridine (8.6 mL)
b-phenylseleno diastereomer
13
(
J¼13.6 Hz, 9.5 Hz), 1.99e1.95 (1H, m), 1.33e1.29 (2H, m); C NMR
was stirred at room temperature for 36 h and then evaporated. A
(100 MHz, CDCl
3
) d 168.5, 166.4, 134.3, 134.0, 133.1, 133.0, 131.9,
mixture of the residue and aqueous HCl (1 M, 1.8 mL) in MeOH
130.7, 130.5, 129.7, 129.6, 128.4, 128.3, 128.2, 123.2, 75.9, 73.4, 69.6,
ꢁ
(
24 mL) and THF (12 mL) was stirred at 50 C for 10 h, and then
55.2, 43.8, 33.0, 28.1, 5.6; HRMS (ESI) calcd for C35
H
31
O
6
NNaSi
þ
partitioned between AcOEt and H
with brine, dried (Na SO ), and evaporated. The residue was puri-
fied by column chromatography (silica gel; hexane/AcOEt, 3:2e1:1)
2
O. The organic layer was washed
612.1806 (MþNa) , found 612.1813; NOE irradiation of H-5a/ob-
served at H-6b (4.4%), irradiation of H-5b/observed at H-6b (6.2%),
irradiation of H-6b/observed at H-2 (5.3%), H-5a (3.5%), H-5b (3.9%),
2
4
1
to give 10 (1.53 g, 80% from 9) as white amorphous powder:
H
irradiation of H-2/observed at H-5a (2.8%), irradiation of H-7a/ob-
1
NMR (400 MHz, CDCl 7.33e8.10 (14H, m), 4.99 (1H, ddd,
3
)
d
served at H-3 (1.7%), H-5a (2.3%). 14: H NMR (400 MHz, CDCl
3
)
J¼10.8 Hz, 8.6 Hz, 5.9 Hz), 4.76 (1H, d, J¼11.8 Hz), 4.70e4.67 (1H, m,
H-2), 4.59e4.56 (1H, m, H-3), 4.47 (1H, d, H-5, J¼11.8 Hz), 3.22 (1H,
s, OH), 2.95 (1H, s, OH), 2.44 (1H, dd, J¼13.9 Hz, 10.8 Hz), 1.81 (1H,
d
8.04e7.07 (19H, m), 6.35 (1H, dd, J¼20.4 Hz, 15.0 Hz), 6.10 (1H, dd,
J¼15.0 Hz, 3.6 Hz), 5.79 (1H, dd, J¼20.4 Hz, 3.6 Hz), 5.00 (1H, dd,
J¼7.7 Hz, 3.6 Hz), 4.91e4.85 (1H, H-1), 4.57 (1H, H-5, J¼10.9 Hz,
8.6 Hz), 4.38 (1H, dd, J¼10.9 Hz, 6.8 Hz), 4.19 (1H, dd, J¼3.6 Hz,
3.6 Hz), 2.94e2.88 (1H, m), 2.77 (1H, s), 2.15 (1H, dd, J¼13.6 Hz,
13
dd, J¼13.9 Hz, 8.6 Hz); C NMR (100 MHz, CDCl
3
) d 168.0, 166.3,
1
7
5
38.0, 134.1, 133.2, 131.7, 129.8, 129.7, 129.6, 129.5, 128.5, 123.3, 73.9,
13
3.2, 67.3, 59.0, 55.9, 31.4; HRMS (ESI) calcd for C27
H
23
O
6
NNaSe
10.0 Hz), 2.00 (1H, ddd, J¼13.6 Hz, 8.4 Hz, 5.2 Hz); C NMR
þ
60.0586 (MþNa) , found 560.0583.
(100 MHz, CDCl
3
) d 167.9, 166.5, 137.9, 134.9, 134.8, 134.8, 133.6,
32.9,132.5,131.8,130.3,129.9,129.6,128.3,127.9,127.7,127.7,127.6,
1
1
C
23.0, 77.1, 73.2, 64.0, 54.5, 39.4, 29.1, 21.0; HRMS (ESI) calcd for
þ
3
.6. (1R,2S,3R,4S)-4-Benzoyloxymethyl-2-
H
35 31
O
6
NNaSi 612.1806 (MþNa) , found 612.1813; NOE irradia-
diphenylvinylsiloxy-3-hydroxy-4-phenylseleno-1-
tion of H-4/observed at H-6b (5.7%), H-3 (8.4%), H-2 (5.7%).
phthaloylaminocyclopentane (11) and (1R,2S,3R,4S)-4-
benzoyloxymethyl-3-diphenylvinylsiloxy-2-hydroxy-4-
phenylselenyl-1-phthaloylaminocyclopentane (12)
3.8. Deuterium labeling reaction
To a solution of a mixture of 11 and 12 (25 mg, 0.034 mmol, 1.4:
ꢁ
A mixture of 10 (365 mg, 0.680 mmol), Et
DMAP (44 mg, 0.36 mmol), and diphenylvinylchlorosilane (185 mL,
.82 mmol) in toluene (6.8 mL) was stirred at room temperature for
O. The organic
), and evaporated. The
3
N (110
m
L, 0.81 mmol),
1.0) in benzene (3.4 mL) at 80 C, a solution of Bu
3
SnD (18
m
L,
0.068 mmol) and AIBN (4 mg, 0.025 mmol) in benzene (1 mL) was
added slowly over a 1 h period. The solvent was evaporated, and the
residue was purified by silica gel column chromatography (silica
gel; hexane/AcOEt, 9:1e3:1) to give 13D (12 mg, 0.0208 mmol, 61%)
as white amorphous powder:
0
1
2 h, and then partitioned between AcOEt and H
2
layer was washed with brine, dried (Na
2
SO
4
1
residue was purified by column chromatography (silica gel; hex-
ane/AcOEt, 2:1) to give a mixture of 11 and 12 (500 mg, 0.671 mmol,
3
H NMR (400 MHz, CDCl )
d
7.93e7.37 (19H, m, AreH), 5.01 (1H, ddd, H-2, J¼10.4 Hz, 10.0 Hz,
9
9%, 11/12¼1.4:1.0) as white amorphous solid. The mixture
250 mg) was subjected to column chromatography again (silica
gel; hexane/AcOEt, 4:1e2:1) to give pure 11 (58 mg) and 12 (35 mg)
5.0 Hz), 4.86 (1H, dd, H-1, J¼10.4 Hz, 10.0 Hz, 9.5 Hz), 4.45 (1H, d, H-
5, J¼11.3 Hz), 4.36 (1H, d, H-3, J¼5.0 Hz), 4.28 (1H, d, H-5,
J¼11.3 Hz), 2.98 (1H, d, OH, J¼10.4 Hz), 2.38 (1H, dd, H-6, J¼13.6 Hz,
10.4 Hz), 2.24 (1H, dd, H-7, J¼4.0 Hz, 8.6 Hz), 2.02 (1H, dd, H-6,
J¼13.6 Hz, 9.5 Hz),1.30 (1H, dd, H-8, J¼14.3 Hz, 4.0 Hz),1.25 (1H, dd,
(
1
3
together with their mixture. 11: H NMR (500 MHz, CDCl )
d
8.07e7.06 (24H, m), 6.40 (1H, dd, J¼20.6 Hz, 15.5 Hz), 6.17 (1H, dd,
J¼15.5 Hz, 3.4 Hz), 5.93 (1H, dd, J¼20.6 Hz, 3.4 Hz), 5.16 (1H, ddd,
J¼11.5 Hz, 8.0 Hz, 6.9 Hz), 5.11 (1H, dd, J¼6.9 Hz, 6.9 Hz), 4.67 (1H, d,
J¼11.5 Hz), 4.51 (1H, dd, J¼6.9 Hz, 6.9 Hz), 4.44 (1H, d, J¼11.5 Hz),
H-8, J¼14.3 Hz, 6.9 Hz); HRMS (ESI) calcd for C35
6
H30DO NNaSi
þ
613.1874 (MþNa) , found 613.1876.
3
.41 (1H, d, J¼6.9 Hz), 2.28 (1H, dd, J¼13.7 Hz, 11.5 Hz), 1.76 (1H, dd,
3.9. (1R,2S,3R,4S)-4-Benzoyloxymethyl-2,3-dihydroxy-4-(2-
hydroxyethyl)-1-phthaloylaminocyclopentane (15)
13
J¼13.7 Hz, 8.0 Hz); C NMR (125 MHz, CDCl
3
);
d
167.9, 165.7, 138.6,
1
38.3, 135.1, 134.0, 133.0, 132.5, 131.8, 130.4, 130.4, 129.7, 129.5,
1
28.3, 128.0, 128.0, 123.2, 74.0, 74.0, 65.8, 59.3, 56.6, 29.9; HRMS
A mixture of 13 (492 mg, 0.83 mmol), m-CPBA (585 mg,
3.34 mmol), and KF (194 mg, 3.3 mmol) in DMF (8.3 mL) was stirred
þ
(
ESI) calcd for C41
H O
35 6
NNaSi 768.1295 (MþNa) , found 768.1291.
1
12: H NMR (500 MHz, CDCl
3
)
d
7.94e7.28 (24H, m), 6.53 (1H, dd,
at room temperature for 4 h, and then saturated aqueous Na
was added. The resulting mixture was partitioned between CHCl
and H
(Na SO
2
S
2
O
3
J¼20.6 Hz, 14.9 Hz), 6.28 (1H, dd, J¼14.9 Hz, 3.4 Hz), 6.00 (1H, dd,
3
J¼20.6 Hz, 3.4 Hz), 5.13e5.09 (1H, m), 5.07 (1H, d, J¼8.0 Hz),
2
O, and the organic layer was washed with brine, dried
4
), and evaporated. The residue was purified by column
4
2
.51e4.49 (1H, m), 4.41 (2H, d, J¼11.5 Hz), 3.17 (1H, d, J¼8.6 Hz),
2
13
.35 (1H, dd, J¼14.4 Hz,11.5 Hz),1.55 (1H, dd, J¼14.4 Hz, 8.6 Hz);
167.6, 166.1, 138.5,138.1,134.9,134.8,133.7,
33.0, 132.3, 131.7, 130.2, 130.0, 129.7, 129.2, 129.2, 128.4, 127.9,
C
chromatography (silica gel; hexane/AcOEt, 1:1e1:2) to give 15
1
NMR (125 MHz, CDCl
1
3
)
d
(252 mg, 0.59 mmol, 71%) as white amorphous powder: H NMR
(400 MHz, CDCl
3
)
d
8.07e7.42 (9H, m), 4.92 (1H, ddd, J¼9.1 Hz,
127.8, 123.0, 73.1, 72.8, 67.6, 57.9, 55.9, 31.4; HRMS (ESI) calcd for
8.6 Hz, 5.0 Hz), 4.80 (1H, ddd, J¼10.0 Hz, 10.0 Hz, 8.6 Hz), 4.56 (1H,
d, J¼11.3 Hz), 4.40 (1H, s), 4.40 (1H, d, J¼11.3 Hz), 4.08 (1H, d,
þ
C
H O
41 35 6
NNaSi 768.1297 (MþNa) , found 768.1296.

T. Sato et al. / Tetrahedron 71 (2015) 5407e5413
5413
J¼5.0 Hz), 3.92 (1H, ddd, J¼10.9 Hz, 10.4 Hz, 2.7 Hz), 3.83 (1H, ddd,
References and notes
J¼10.9 Hz, 6.3 Hz, 4.5 Hz), 3.00 (1H, d, J¼9.1 Hz), 2.64 (1H, s), 2.43
1. For example: (a) Quaternary Stereocenters: Challenges and Solutions for Organic
(
4
1H, dd, J¼13.6 Hz, 10.0 Hz), 2.25 (1H, ddd, J¼15.0 Hz, 10.4 Hz,
Synthesis; Christophers, J., Baro, A., Eds.; WileyeVCH: Weinheim, 2006; (b)
Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969e5994; (c)
Fujimoto, T.; Endo, K.; Tsuji, H.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc.
13
3
.5 Hz),1.91e1.85 (2H, m); C NMR (100 MHz, CDCl ) d 168.5,166.5,
134.0, 133.2, 131.9, 129.8, 129.7, 128.5, 123.2, 74.1, 73.6, 68.0, 58.8,
2
008, 130, 4492e4496.
2. (a) Shuto, S.; Shirato, M.; Sumita, Y.; Ueno, Y.; Matsuda, A. J. Org. Chem. 1998, 63,
986e1994; (b) Fukuoka, M.; Shuto, S.; Minakawa, N.; Ueno, Y.; Matsuda, A. J.
5
4.8, 45.7, 35.0, 34.7; HRMS (ESI) calcd for C23
23
H O
7
NNa 448.1383
þ
(
MþNa) , found 448.1367.
1
Org. Chem. 2000, 65, 5238e5248; (c) Shuto, S.; Fukuoka, M.; Manikowsky, A.;
Ueno, Y.; Nakano, T.; Kuroda, R.; Kuroda, H.; Matsuda, A. J. Am. Chem. Soc. 2001,
3
.10. (1R,2S,3R,4S)-1-Amino-4-(2-azidoethyl)-2,3-
123, 8750e8759; (d) Shuto, S.; Fukuoka, M.; Kudoh, T.; Garnham, C.; Galione,
isopropylidenedioxy-4-hydroxymethylcyclopentane (4)
A.; Potter, B. V. L.; Matsuda, A. J. Med. Chem. 2003, 46, 4741e4749; (e) Kudoh, T.;
Fukuoka, M.; Ichikawa, S.; Murayama, T.; Ogawa, Y.; Hashii, M.; Higashida, H.;
Kunerth, S.; Weber, K.; Guse, A. H.; Potter, B. V. L.; Matsuda, A.; Shuto, S. J. Am.
Chem. Soc. 2005, 127, 8846e8855; (f) Sakaguchi, N.; Kudoh, T.; Tsuzuki, T.;
Murayama, T.; Sakurai, T.; Arisawa, M.; Shuto, S. Bioorg. Med. Chem. Lett. 2008,
A mixture of 15 (33 mg, 0.077 mmol), Me
.085 mmol), and TsOHꢀH O (1.4 mg, 7.4 mol) in acetone (3.0 ml)
was stirred at room temperature for 1 h, then neutralized with satd
aqueous NaHCO and evaporated. The residue was partitioned be-
tween AcOEt and H O, and the organic layer was washed with
brine, dried (Na SO ), and evaporated. A mixture of the residue,
TsCl (18 mg, 0.097 mmol), DMAP (4.0 mg, 0.033 mmol), Et N (21 L,
.15 mmol) in CH Cl (1.0 mL) was stirred at room temperature for
.5 h, and then neutralized with satd aqueous NH Cl and concen-
trated. The resulting mixture was partitioned between AcOEt and
O, and the organic layer was washed with brine, dried (Na SO ),
and evaporated. A mixture of the residue and NaN (8.6 mg,
.132 mmol) in DMF (1.0 mL) was stirred at room temperature for
0 h, and then partitioned between AcOEt and H O. The organic
SO ), and evaporated. A
O (19 L, 0.39 mmol) in
2 2
C(OMe) (10 mL,
0
2
m
18, 3814e3818; (g) Tsuzuki, T.; Sakaguchi, N.; Kudoh, T.; Takano, S.; Uehara, M.;
Murayama, T.; Sakurai, T.; Hashii, M.; Higashida, H.; Weber, K.; Guse, A. H.;
Kameda, T.; Hirokawa, T.; Kumaki, Y.; Potter, B. V. L.; Fukuda, H.; Arisawa, M.;
Shuto, S. Angew. Chem., Int. Ed. 2013, 52, 6633e6637; (h) Swarbrick, J. M.; Potter,
B. V. L. J. Org. Chem. 2012, 77, 4191e4197.
3
2
2
4
m
3. Clapper, D. L.; Walseth, T. F.; Dargie, P. J.; Lee, H. C. J. Biol. Chem. 1987, 262,
3
9
561e9568.
. (a) Galione, A. Science 1993, 259, 325e326; (b) Guse, A. H. Cell. Signalling 1999,
1, 309e316; (c) Lee, H. C. J. Biol. Chem. 2012, 287, 31633e31640.
5. (a) Shuto, S.; Kanazaki, M.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 1997, 62,
0
2
2
4
1
4
1
5676e5677; (b) Shuto, S.; Sugimoto, I.; Abe, H.; Matsuda, A. J. Am. Chem. Soc.
H
2
2
4
2000, 122, 1343e1351; (c) Sukeda, M.; Ichikawa, S.; Matsuda, A.; Shuto, S. An-
3
gew. Chem., Int. Ed. 2002, 41, 4748e4750.
6. For examples see: (a) Lee, H.; Aarhus, R.; Walseth, T. Science 1993, 261,
0
2
352e355; (b) Walseth, T. F.; Lee, H. C. Biochim. Biophys. Acta 1993, 1178,
2
235e242; (c) Aarhus, R.; Graeff, R. M.; Dickey, D. M.; Walseth, T. F.; Lee, H. C. J.
layer was washed with brine, dried (Na
mixture of the residue and NH NH $H
2
4
Biol. Chem. 1995, 270, 30327e30333; (d) Ashamu, G. A.; Sethi, J. K.; Galione, A.;
Potter, B. V. L. Biochemistry 1997, 36, 9509e9517; (e) Xu, L.; Walseth, T. F.;
Slama, J. T. J. Med. Chem. 2005, 48, 4177e4181; (f) Moreau, C.; Kirchberger, T.;
Zhang, B.; Thomas, M. P.; Weber, K.; Guse, A. H.; Potter, B. V. L. J. Med. Chem.
2
2
2
m
EtOH (1.0 mL) was heated under reflux for 9 h, and then evaporated.
The residue was purified by silica gel column chromatography
2012, 55, 1478e1489; (g) Yu, P.-L.; Zhang, Z.-H.; Hao, B.-X.; Zhao, Y.-J.; Zhang, L.-
(
6
3
silica gel; CHCl /MeOH, 9:1e4:1) to give 4 (13 mg, 0.0492 mmol,
H.; Lee, H. C.; Zhang, L.; Yue, J. J. Biol. Chem. 2012, 287, 24774e24783.
7. Reviews on cADPR analogs: (a) Guse, H. Cell. Signalling 1999, 11, 309e316; (b)
Shuto, S.; Matsuda, A. Curr. Med. Chem. 2004, 11, 827e845; (c) Potter, B. V. L.;
Walseth, T. F. Curr. Mol. Med. 2004, 4, 303e311.
1
4%) as white amorphous powder: H NMR (400 MHz, CD
3
OD)
d
4.40 (1H, d, J¼5.4 Hz), 4.30 (1H, d, J¼5.4 Hz), 3.46 (1H, d,
J¼10.9 Hz), 3.38 (1H, d, J¼10.9 Hz), 3.36e3.30 (1H, m), 3.28e3.21
1H, m), 3.17e3.20 (1H, m), 2.08 (1H, dd, J¼14.6 Hz, 7.7 Hz),
.76e1.61 (2H, m), 1.48 (1H, d, J¼14.6 Hz), 1.33 (3H, s), 1.19 (3H, s);
8
. Lee, H. C.; Aarhus, R. Biochim. Biophys. Acta 1993, 1164, 68e74.
9. Hutchinson, E. J.; Taylor, B. F.; Blackburn, G. M. Chem. Commun. 1997,
859e1860.
0. When the phenylseleno group was introduced, a trace of the 4
produced, and the 4 -product 8 was obtained in a pure form after silica gel
column chromatography.
(
1
1
1
b-isomer was
1
3
3
C NMR (100 MHz, CD OD) d 111.5, 89.0, 86.6, 68.3, 58.2, 51.0, 48.9,
a
4
2.5, 33.9, 26.9, 24.2; HRMS (ESI) calcd for C11
H
21
ꢂ1
O
3
N
4
257.1605
).
þ
11. When the mixture of 11 and 12 was subjected to silica gel column chroma-
tography, 11 and 12 were obtained in a pure form, respectively, together with
the mixture.
(
MþH) , found 257.1608; IR (CHCl
3
)
n
max 2096 cm (N
3
Supplementary data
1
Supplementary data ( H NMR charts of compounds) related to
this article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2015.05.084.