Rapid methylation for the synthesis of a 11C-labeled tolylisocarbacyclin imaging the IP2 receptor in a living human brain

Article abstract of DOI:10.1016/S0040-4020(00)00734-1

A rapid method for Pd-promoted cross-coupling of methyl iodide and tributyltin derivatives of tolylisocarbacyclins was developed with the objective of applying to the PET study on the IP₂ receptor in a living human brain. The high efficiency is obtainable for both of the one-pot operation using a large excess of CuCl and the stepwise operation consisting of the initial preparation of a methylpalladium complex followed by mixing with the remaining requisite materials for the cross-coupling. The latter protocol allowed for the highly reproducible synthesis of an actual PET tracer with total radioactivity of several GBq. Several stannanes could be employed as precursors of PET tracers in this rapid cross-coupling reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00734-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8263±8273
11
Rapid Methylation for the Synthesis of a C-Labeled
Tolylisocarbacyclin Imaging the IP2 Receptor
in a Living Human Brain
b
b
c
c
Masaaki Suzuki,a, Hisashi Doi, Koichi Kato, Margareta Bjorkman, Bengt Langstrom,
*
Ê
È
È
Yasuyoshi Watanabed,e and Ryoji Noyorib,
*
aDepartment of Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan
bDepartment of Chemistry and Research Center for Materials Science, Nagoya University, Nagoya 464-8602, Japan
cUppsala University PET Centre, UAS, SE-751 85 Uppsala, Sweden
dDepartment of Neuroscience, Osaka Bioscience Institute, Osaka 565-0874, Japan
eDepartment of Physiology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
Received 24 July 2000; accepted 23 August 2000
AbstractÐA rapid method for Pd-promoted cross-coupling of methyl iodide and tributyltin derivatives of tolylisocarbacyclins was
developed with the objective of applying to the PET study on the IP2 receptor in a living human brain. The high ef®ciency is obtainable
for both of the one-pot operation using a large excess of CuCl and the stepwise operation consisting of the initial preparation of a
methylpalladium complex followed by mixing with the remaining requisite materials for the cross-coupling. The latter protocol allowed
for the highly reproducible synthesis of an actual PET tracer with total radioactivity of several GBq. Several stannanes could be employed as
precursors of PET tracers in this rapid cross-coupling reaction. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
studies, the newly devised rapid methylation reaction6
played a crucial role to realize the synthesis of a PET tracer,
15R-[11C]TIC methyl ester [11C]-6. However, there remains
a room for further improvement to satisfy the applicable
level required for a living human brain whose volume is
ca. 10 times larger than that of monkey. This paper
describes an advanced rapid Stille methylation7 using a
model nonradiolabeled system and the synthesis of stannyl
precursor 7 and related compounds, which represent key
intermediates for the real PET study. The facile 13C-incor-
poration into TICs is also described.
The role of prostaglandins (PGs) in brain function has
attracted intense attention in recent years, because the
neuroscience is expected to represent a leading criterion in
the area of PG life science in the next decades.1 Accord-
ingly, the development of PG molecular probes, which serve
speci®cally for brain research, has become increasingly
important. In this context, we recently developed some
novel PG probes 1±3.1,2 15R-TIC 1 and 15-deoxy-TIC 3
bind selectively to a PGI2 receptor (IP2) in the central
nervous system (CNS),2a,b while 15S-TIC 2 shows a dual
binding af®nity for both of the IP1 (a peripheral nervous
system (PNS)-type PGI2 receptor) and IP2.2a Thus, the 15R
and 15-deoxy derivatives 1 and 3, and the 15S compound 2
will serve as good ligands for the CNS-speci®c and PNS-
type PGI2 receptor in the brain, respectively. Furthermore,
the speci®c location of the IP2 receptor was visualized by an
in vitro autoradiography of rat brain slices using the tritium-
labeled ligand [3H]-43 and also by an in vivo positron
emission tomography (PET) of a rhesus monkey1,4 using
the 11C-labeled ligand [11C]-55. In the latter challenging
Keywords: labeling; palladium and compounds; prostacyclins; tin and
compounds.
* Corresponding authors. Fax: 158-293-2635;
e-mail: suzukims@biomol.gifu-u.ac.jp;
Fax: 152-783-4177; e-mail: noyori@chem3.chem.nagoya-u.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00734-1

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M. Suzuki et al. / Tetrahedron 56 (2000) 8263±8273
Rapid Methylation for the Synthesis of a 11C-Labeled
Tolylisocarbacyclin
Conventional organic synthesis appreciates high produc-
tivity and selectivity. The criteria of synthetic ef®ciency in
an in vivo PET study using 11C as a positron nuclide are
different. The investigation needs the rapid chemical reac-
tion for the incorporation of 11C into bioactive organic
compounds, because of the time-limitation of the short-
lived positron emitter (half-life 20.3 min).8 Furthermore,
the reaction uses a very small amount of a 11C source,
requiring special operational condition.8 The synthesis of
[11C]TIC methyl esters, [11C]-6 and [11C]-8, was previously
accomplished based on our modi®ed Stille reaction.5 The
reaction was promoted with a Pd(0) complex generated in
situ from Pd2(dba)3 (dbaˆdibenzylideneacetone) and P(o-
CH3C6H4)3 (1:4) in the absence of Cu(I) salt and K2CO3 at
1308C for 7 min in DMF to give the desired compounds in
33±45% yield4 and with the total amount of radioactivity of
150±250 MBq. The resulting [11C]-labeled compound
[11C]-6 was subjected to intravenous administration to
achieve the clear imaging of the IP2 receptor in a living
monkey brain.1,9 In order to realize the imaging of the recep-
tor in a human brain, however, 15R-[11C]TIC methyl ester
[11C]-6 with a total radioactivity even higher than several
GBq is required. This strict requirement prompted us to
further pursue a rapid, more ef®cient Stille methylation.
For the synthesis of the actual TIC structure systems, we
intended to apply our previously optimized methylation of
tributylphenylstannane for a model reaction, which is
characterized by the use of Pd2(dba)3 and P(o-CH3C6H4)3
(1:4) together with a Cu(I) salt and K2CO3 at 608C.6
In the search for optimized conditions of a rapid Stille
methylation, the 15S stannane 9 was selected as a standard
tin substrate because of the structural resemblance to the
more valuable 15R precursor 7 (Scheme 1). The previous
coupling reaction between tributylphenylstannane and
methyl iodide was conducted with a ratio of 40:1.6
However, tributyltin derivatives of tolylisocarbacyclins are
precious compounds, therefore the coupling reaction was
performed for 5 min using 5 equiv. of 9 relative to methyl
iodide (Scheme 1). The reaction product was puri®ed by
silica gel column chromatography, and the yields of the
15S-TIC methyl ester [12C]-8 were determined by HPLC
using its authentic sample and anisole as an internal
standard. The results are summarized in Table 1. Unex-
pectedly, the simple application of the same ratio between
methyl iodide and metallic reagents as optimized for the
model methylation of tributylphenylstannane in the one-
pot operation6 (method A) was not successful (entries 1
and 2 in Table 1). Such a discrepancy between a functional-
ized substrate and a simple nonpolar model compound is
often observed. Reaction with modulating the ratio of
metallic reagents to the tin substrate 9 was revealed that
the addition of excess CuCl markedly increased the yield
up to 93% (entries 3±5). We then attempted immediately to
apply this method to the synthesis of the PET tracer [11C]-6
using 11CH3I10 and stannane 7. However, the reaction using
the above conditions lacked reproducibility for some
unknown reasons. During the investigation to overcome
this dif®culty in harmony with the actual PET tracer syn-
thesis, we obtained signi®cant information from a negative

M. Suzuki et al. / Tetrahedron 56 (2000) 8263±8273
8265
Scheme 1. Rapid cross-coupling reaction of methyl iodide and stannane 9 to [12C]-8. (1:5 mol ratio)
experiment on the model system6 that use of CuI in place of
CuCl severely retarded the methylation of tributylphenyl-
stannane. In order to minimize this inhibitory effect of CuI
which is also produced in the actual reaction system, we
changed the one-pot operation (method A) (entry 5 in
Table 1) to a stepwise procedure (method B) (entry 9 in
Table 1). The stepwise procedure consists of independent
syntheses of a methylpalladium complex and a phenyl±
copper complex at low temperatures, followed by the
mixing of these species in one portion at a higher tempera-
ture. Thus, a solution of Pd2(dba)3 and P(o-CH3C6H4)3 in
DMF was prepared in a dry Schlenk tube under argon
atmosphere at room temperature. In another dry Schlenk
tube, a solution of stannane 9, CuCl, and K2CO3 in DMF
was prepared under argon at room temperature. Methyl
iodide was added to the solution in the ®rst Schlenk tube
and, after the color of the solution had changed to pale
orange, the resulting solution containing a methylpalladium
compound was transferred to the solution in the second
Schlenk tube containing a phenylcopper species, after
which the mixture was heated to 608C for 5 min. This step-
wise procedure gave the desired methylated derivative
[12C]-8 in 74% yield using 8 equiv. of CuCl (entry 9 in
Table 1). The use of higher temperatures and larger excesses
of CuCl (22 equiv.) results in negative effects (entries 10
and 11 in Table 1). The methylation of the stannyl pre-
cursors 7 and 10, by the same procedure as that in entry 9
proceeded well in 5 min, giving 15R-TIC methyl ester [12C]-
6 and 15-deoxy-TIC methyl ester [12C]-112b in 79 and 80%
yield, respectively (Scheme 2).11 Notably, this stepwise
procedure was very ef®cient for the actual PET tracer syn-
thesis, giving [11C]-6 with the total radioactivity of several
giga-Becquerel with a high reproducibility.12 The PET
tracer synthesis is conducted at an extremely low concen-
tration of a positron source and therefore, the reaction is
substantially slow. Under such conditions, the in¯uence of
undesired secondary reactions becomes inevitably large.
The use of a trapping substrate in a large excess at high
temperature accelerates the reaction to compensate such
disadvantages to some extent, as usually seen in a PET
study.8 The stepwise procedure (method B) elaborated in
this study will therefore provide an expedient way to over-
come a problem encountered in complicated organometallic
Table 1. Rapid cross-coupling of methyl iodide and stannane 9 to [12C]-8
Entry
CH3I:9:Pd:Cua
(molar ratio)
Operation
protocolb
T
(8C)
15S-TIC methyl ester
[12C]-8 yield (%)c
1
2
3
4
5
6
7
8
1:5:1:2
1:5:2:2
1:5:2:8
1:5:2:8
1:5:2:22
1:1:2:8
1:5:2:2
1:5:2:4
1:5:2:8
1:5:2:8
1:5:2:22
A
A
A
A
A
B
B
B
B
B
B
60
60
60
100
60
60
60
60
60
100
60
0
0
25
23
93
8
10
55
74
24
66
9
10
11
a Pdˆa Pd(0) complex generated in situ from Pd2(dba)3 and P(o-
CH3C6H4)3 (1:4). CuˆCuCl.
b Method A: one-pot operation. Method B: stepwise procedure (see text).
c Yield based on methyl iodide and determined by HPLC analysis.
Scheme 2. Rapid cross-coupling of methyl iodide and stannane 7 or 10 by the stepwise procedure. [CH3I:tin substrate (7 or 10)ˆ1:5 mol ratio. Yield was based
on methyl iodide.]

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M. Suzuki et al. / Tetrahedron 56 (2000) 8263±8273
Scheme 3. Synthesis of the phosphonate 14: (a) [(n-C4H9)3Sn]2, Pd(PPh3)4, 1,4-dioxane, 908C, 24 h, 52%; (b) (CH3O)2P(O)CH3, n-C4H9Li, THF, 2788C, 54%.
reactions conducted by a one-pot operation at an extremely
low concentration.
the corresponding [13C]tolylisocarbacyclin methyl esters
[13C]-6, [13C]-8, and [13C]-11, in 78, 82, and 83% yield,
respectively. These isotope-labeled TIC derivatives can be
used for a study on biometabolism of TICs.
Thus, we devised a rapid, high-yield methylation method
which is applicable to the synthesis of a PET tracer with a
suf®cient total radioactivity for in vivo imaging of the IP2
receptor in a human brain.13
Synthesis of Stannyl Precursors 7, 9, and 10
Synthesis of the phosphonate 14 (Scheme 3)
Synthesis of 13C-Labeled Tolylisocarbacyclins
13C is a stable isotope and 14C has a long half-life and,
therefore, the coupling does not require the reaction-accel-
erating additives such as a Cu(I) salt and K2CO3. Thus, the
coupling between [13C]methyl iodide and a stoichiometric
amount of the stannane 7, 9, or 10, is performed in the
presence of the Pd(0) complex generated in situ from
Pd2(dba)3 and P(o-CH3C6H4)3 (1:4) at 508C for 15 h, giving
The cross-coupling of methyl 3-bromophenylacetate 12
with hexa-n-butylditin in the presence of a catalytic amount
of tetrakis(triphenylphosphine)palladium(0)14 gave the tri-
n-butyltin-substituted derivative 13 in 52% yield. The
resulting methyl ester 13 was condensed with the anion of
dimethyl methylphosphonate to afford the b-ketophospho-
nate 14, a Horner±Emmons reagent, in 54% yield.
Scheme 4. Synthesis of (15R)-16-[3-(tri-n-butylstannyl)phenyl]-17,18,19,20-tetranorisocarbacyclin methyl ester 7 and its 15-epimer 9: (a) NaH, DME, 91%;
(b) NaBH4, CeCl3´7H2O, CH3OH, 87%; (c) separation of the C(15) epimers.
Scheme 5. Synthesis of the sulfone 20: (a) PhSH, (CH3)3SiCl, CHCl3, 99%; (b) 30% H2O2, CH3COOH, (CH3CO)2O, 70%; (c) [(n-C4H9)3Sn]2, Pd(PPh3)4, 1,4-
dioxane, 908C, 17 h, 44%.

M. Suzuki et al. / Tetrahedron 56 (2000) 8263±8273
8267
Scheme 6. Synthesis of 15-deoxy-16-[3-(tri-n-butylstannyl)phenyl]-17,18,19,20-tetranorisocarbacyclin methyl ester 10: (a) (C6H5)3PCHCHO, benzene,
re¯ux, 66%; (b) NaBH4, CH3OH; (c) ClCOOCH3, 4-(dimethylamino)pyridine, CH2Cl2, 91% (2 steps); (d) Pd2(dba)3´CHCl3, dppe, 3-[(n-
C4H9)3Sn]C6H4CH(SO2C6H5)2 (20), THF, 608C, 98%; (e) Mg, CH3OH; (f) pyridinium p-toluenesulfonate, CH3OH, 69% (2 steps).
Synthesis of 7 and 9 (Scheme 4)
NaBH4, followed by methoxycarbonylation of the alcohol
with ClCOOCH3 gave the allyl carbonate 23 in 91% overall
yield. The cross-coupling reaction between 23 and the sul-
fone 20 with Pd2(dba)3´CHCl3/1,2-bis(diphenylphos-
phino)ethane (1:3)18 gave the sulfone 24 in 98% yield.
Reductive removal of the C6H5SO2 group in 24 with Mg
metal in CH3OH and subsequent removal of the tetrahydro-
pyranyl group gave the stannane 10 in 69% overall yield,
leaving the tri-n-butyltin substituent intact.
The Horner±Emmons reaction of the aldehyde 1515 and the
phosphonate 14 gave the enone 16 in 91% yield. The
chemoselective 1,2-reduction of the C(15) keto group with
NaBH4 in the presence of cerium(III) chloride16 gave a 1:1
mixture of the stereoisomeric diol 7 (less polar), and 9 (more
polar) in 87% yield, accompanied by a small amount of the
destannylated compound. The C(15) stereoisomers were
separated by conventional silica gel column chroma-
tography.
Conclusions
Reaction of methyl iodide and a stannyl precursor 9 was
accomplished by the stoichiometric use of the Pd(0)
complex generated in situ from Pd2(dba)3 and P(o-
CH3C6H4)3 (1:4) in DMF, giving [12C]-8 in 73% yield, iden-
tical with an authentic sample. The alcohol 9 has the S
con®guration at the C(15) stereocenter, while 7 possesses
the R con®guration.
We developed a rapid procedure for the Stille methylation
of arylstannanes 7, 9, or 10 by a novel stepwise procedure
using a Pd(0) complex generated from Pd2(dba)3 and P(o-
CH3C6H4)3 (1:4) in the presence of CuCl and K2CO3. This
protocol is useful for the synthesis of 11C-incorporated TIC
derivatives with the high radioactivity suf®cient for the
imaging of a living human brain. The stable 13CH3 group
is readily incorporated into a TIC derivative conveniently
by the Pd(0)-mediated reaction using 13CH3I without a Cu(I)
salt.
Synthesis of the sulfone 20 (Scheme 5)
Reaction of 3-bromobenzaldehyde 17 with benzenthiol in
the presence of chlorotrimethylsilane afforded the dithio-
acetal 18 in 99% yield. Oxidation of 18 with hydrogen per-
oxide under acidic conditions gave the sulfone 19 in 70%
yield. Condensation of 19 with hexa-n-butylditin in the
presence of a catalytic amount of tetrakis(triphenylphos-
phine)palladium(0) gave the stannane 20 in 44% yield.14
Experimental
General
1H NMR spectra were recorded on a JEOL GSX-270
(270 MHz), JMN-GX-500 (500 MHz), or JNM-A600
(600 MHz) spectrometer. Chemical shifts are reported in
parts per million from tetramethylsilane with the solvent
resonance as the internal standard (CHCl3: d 7.26 ppm).
Data are reported as follows: chemical shift, multiplicity
Synthesis of 10 (Scheme 6)
The Wittig reaction of the aldehyde 2115 with (formyl-
methylene)triphenylphosphorane gave (E)-a,b-unsaturated
aldehyde 22 in 66% yield.17 Carbonyl reduction of 22 using

8268
M. Suzuki et al. / Tetrahedron 56 (2000) 8263±8273
(sˆsinglet, dˆdoublet, tˆtriplet, qˆquartet, brˆbroad,
mˆmultiplet), integration, coupling constants, and assign-
ment. 13C NMR spectra were recorded on a JEOL GSX-270
(270 MHz), JMN-GX-500 (500 MHz), or JNM-A600
(600 MHz) spectrometer with complete proton decoupling.
Chemical shifts are reported in parts per million from tetra-
methylsilane with the solvent resonance as the internal
standard (CHCl3: d 77.0 ppm). High-resolution mass spec-
tra were recorded on a JEOL JMS-700 instrument. Infrared
(IR) spectra was recorded on a Perkin±Elmer PARAGON
1000 spectrometer. HPLC analysis was performed using a
JASCO PU-980 pump, a JASCO UV-970 UV detector, a
JASCO DG-980-50 degasser, and a JASCO CO-965 column
oven. The analytical column was a Wakopak Wakosil
5C18-200T (250£4.6 mm). The apparatus (test tubes, ¯asks,
and Schlenk tubes) used for all air and/or moisture sensitive
reactions were evacuated by heating with a heat gun under
high vacuum and then ®lled with dry argon before use.
Solvents and solutions were transferred by syringe-septum
and cannula techniques. Tetrahydrofuran (THF), dimethoxy-
ethane (DME), and 1,4-dioxane were used after fresh distil-
lation over sodium-benzophenone ketyl under argon. N,N-
dimethylformamide (DMF), dichloromethane, and chloro-
form were used after distillation over CaH2 under argon.
Methanol was used after distillation over activated Mg
under argon. Tetrakis(triphenylphosphine)palladium(0)
(Aldrich), tris(dibenzylideneacetone)dipalladium(0)-chloro-
form adduct (Kanto Chemicals), tris(dibenzylideneacetone)-
dipalladium(0) (Aldrich), hexa-n-butylditin (Merck), tri-o-
tolylphosphine (Aldrich), copper(I) chloride (WAKO),
potassium carbonate (WAKO), [13C]methyl iodide
(ISOTEC), (formylmethylene)triphenylphosphorane (Aldrich),
Methyl chloroformate (Tokyo Kasei), 1,2-bis(diphenyl-
phosphino)ethane (Kanto Chemicals), n-butyllithium
(1.6 M in hexane), sodium hydride (60% oil dispersion),
sodium borohydride, 4-(dimethylamino)pyridine, cerium-
(III) chloride heptahydrate, benzenethiol, 30% aqueous
H2O2, magnesium turnings, and pyridinium p-toluenesulfo-
nate (all from Nacalai) were commercial grade. Chloro-
trimethylsilane (Tokyo Kasei) and dimethyl methyl-
phosphonate (Tokyo Kasei) were used after distillation.
The molarity of a solution of n-butyllithium in hexane
was determined by titration. Methyl iodide was distilled
over P4O10 prior to use. Methyl 3-bromophenylacetate 12
was prepared by methyl esteri®cation of commercially
available 3-bromophenylacetic acid (Tokyo Kasei). Rf
values on TLC were recorded on precoated silica gel
(Merck Kieselgel 60 F254 plates). Column chromatography
was conducted using Kanto Chemical silica gel 60 (spheri-
cal), 40±50 mm and Kanto Chemical silica gel 60N
(spherical, neutral), 40±50 mm. Literature procedures
were used to prepare the aldehyde intermediates, 15 and
21.15a
408C, retention time 29.8±30.2 min; 15-deoxy-16-m-tolyl-
17,18,19,20-tetranorisocarbacyclin methyl ester [12C]-11:
mobile phase CH3OH-H2O (83/17 v/v), ¯ow rate
1.0 mL min21, detection 246 nm, column temperature
408C, retention time 14.7±14.9 min.
Reaction of methyl iodide and stannane 9 leading to
[12C]-8 (entry 5 in Table 1, Method A: one-pot opera-
tion). In a dry Schlenk tube (10 mL), tris(dibenzylidene-
acetone)dipalladium(0) (1.2 mg, 1.3 mmol), tri-o-tolyl-
phosphine (1.6 mg, 5.2 mmol), copper(I) chloride (2.6 mg,
26.2 mmol), and potassium carbonate (3.6 mg, 26.0 mmol)
were placed under argon. After addition of DMF (0.4 mL),
the mixture was stirred for 5 min at room temperature
followed by successive additions of solutions of 9
(4.4 mg, 6.5 mmol) in DMF (0.4 mL) and methyl iodide in
DMF (0.2 M, 6 mL, 1.2 mmol). The resulting mixture was
stirred under argon at 608C for 5 min, and rapidly cooled
(ice bath). The reaction mixture was ®ltered and concen-
trated under reduced pressure by azeotropic removal of
DMF with toluene. The residue was puri®ed by chroma-
tography on silica gel (0.77 g) using 2:1, 1:1, and 2:3
mixtures of hexane and ethyl acetate as eluents. The
products were analyzed by HPLC with anisole as an internal
standard. Yield of 15S-TIC methyl ester [12C]-8: 93%. The
product was identi®ed by HPLC with an added authentic
reference compound.
Reaction of methyl iodide and stannane 7 leading to
[12C]-6.11 Reaction was conducted using 7 (4.4 mg,
6.5 mmol) by the same procedure as described above. The
residue was puri®ed by chromatography on silica gel
(0.77 g) using 4:1, 5:2, and 3:2 mixtures of hexane and
ethyl acetate as eluents. The products were analyzed by
HPLC with anisole as an internal standard. Yield of 15R-
TIC methyl ester [12C]-6: 82%.
Reaction of methyl iodide and stannane 10 leading to
[12C]-11.11 Reaction was conducted using 10 (4.0 mg,
6.1 mmol) by the same procedure as described above.
Chromatography of the product on silica gel (0.5 g) using
a 12:1 mixture of hexane and ethyl acetate as an eluent gave
a yellow oil. The oil was further puri®ed by chromatography
on silica gel (0.6 g) using a 15:1 mixture of hexane and ethyl
acetate as an eluent. HPLC analysis with anisole as an
internal standard showed the yield of 15-deoxy-TIC methyl
ester [12C]-11 to be 92%.
Reaction of methyl iodide and stannane 9 leading to
[12C]-8 (entry 9 in Table 1, Method B: stepwise pro-
cedure). In a dry Schlenk tube A (10 mL), a solution of
tris(dibenzylideneacetone)dipalladium(0) (1.0 mg, 1.1 mmol)
and tri-o-tolylphosphine (1.3 mg, 4.4 mmol) in DMF
(250 mL) was placed under argon. While in another dry
Schlenk tube B (10 mL), a solution of 9 (4.2 mg,
6.2 mmol), copper(I) chloride (1.0 mg, 10 mmol), and potas-
sium carbonate (1.4 mg, 10 mmol) in DMF (250 mL) was
placed under argon. After addition of a solution of methyl
iodide in DMF (0.2 M, 6 mL, 1.2 mmol) to the solution of
the Schlenk tube A, the mixture was stirred for 3 min at
room temperature and the color of the solution changed to
pale orange. This solution was transferred to the Schlenk
tube B washing the inside of the Schlenk tube A with DMF
Product analysis
(15R)-16-m-Tolyl-17,18,19,20-tetranorisocarbacyclin methyl
ester [12C]-6: mobile phase CH3OH±H2O (65/35 v/v), ¯ow
rate 1.0 mL min21, detection 254 nm, column temperature
408C, retention time 28.4±28.6 min; (15S)-16-m-tolyl-
17,18,19,20-tetranorisocarbacyclin methyl ester [12C]-8:
mobile phase CH3OH-H2O (68/32 v/v), ¯ow rate
1.0 mL min21, detection 254 nm, column temperature

M. Suzuki et al. / Tetrahedron 56 (2000) 8263±8273
8269
(100 mL) and then the mixture was heated at 608C for 5 min.
The reaction mixture was ®ltered and concentrated under
reduced pressure by azeotropic removal of DMF with
toluene. The residue was puri®ed by chromatography on
silica gel (0.77 g) using 2:1, 1:1, and 2:3 mixtures of hexane
and ethyl acetate as eluents. The yield of 15S-TIC methyl
ester [12C]-8 was determined by HPLC with anisole as an
internal standard to be 74%. The product was identi®ed by
HPLC by co-injection with the authentic reference
compound.
(FAB, NBA/NaI), m/z calcd for C2413CH34O4Na (M11Na)
422.2388, found 422.2380.
Cross-coupling reaction of [13C]methyl iodide and 9
leading to [13C]-8. Reaction was conducted using tris(di-
benzylideneacetone)dipalladium(0) (5.0 mg, 5.5 mmol), tri-
o-tolylphosphine (6.7 mg, 22 mmol), [13C]methyl iodide in
DMF (0.8 M, 11.5 mL, 9.2 mmol), and 9 (5.6 mg, 8.3 mmol)
by the same procedure as that described for the synthesis of
[13C]-6. The residue was subjected to silica gel column
chromatography (1.3 g) using 2:1, 1:1, and 2:3 mixtures of
hexane and ethyl acetate as eluents to give a slightly yellow
oil. Further puri®cation by silica gel column chroma-
tography (0.7 g) using 2:1, 1:1, and 2:3 mixtures of hexane
and ethyl acetate as eluents gave [13C]-8 (2.7 mg,
6.78 mmol, 82% yield) as a colorless oil. TLC Rf 0.41 (1:4
hexane/ethyl acetate); 1H NMR (CDCl3, 500 MHz) d 1.20±
1.85 (m, 7, 2 CH2, CH, and 2 OH), 1.85±2.10 (m, 4, 2 CH2),
2.2±2.5 (m, 5, 2 CH2 and CH), 2.33 (d, 3, 1JC-Hˆ126.5 Hz,
13CH3), 2.77 (dd, 1, Jˆ7.8 and 13.2 Hz, benzylic CHH),
2.85 (dd, 1, Jˆ5.4 and 13.2 Hz, benzylic CHH), 2.95±
3.05 (br, 1, allylic CH in ring), 3.6±3.8 (m, 1, CHO), 3.67
(s, 3, OCH3), 4.34 (q, 1, Jˆ6.3 Hz, CHO), 5.28 (s, 1, vinylic
in ring), 5.49 (dd, 1, Jˆ8.3 and 15.4 Hz, vinylic in chain),
5.63 (dd, 1, Jˆ6.3 and 15.4 Hz, vinylic in chain), 6.95±7.10
(m, 3, aromatic), 7.19 (t, 1, Jˆ7.4 Hz, aromatic); 13C NMR
(CDCl3, 125 MHz) d 21.4, 24.7, 27.2, 30.6, 33.9, 39.5, 39.7,
44.0, 44.3, 45.6, 51.5, 58.2, 73.3, 77.2, 126.6, 127.3
(Jˆ2.8 Hz), 128.31, 128.34, 130.4 (Jˆ3.6 Hz), 132.7,
134.2, 137.6 (Jˆ3.6 Hz), 138.0 (Jˆ44.0 Hz), 141.4, 174.1;
HRMS (FAB, NBA/NaI), m/z calcd for C2413CH34O4Na
(M11Na) 422.2388, found 422.2385.
Reaction of methyl iodide and stannane 7 leading to
7 (4.2 mg,
[12C]-6. Reaction was conducted using
6.2 mmol) by the same procedure as described above. The
product was puri®ed by chromatography on silica gel
(0.77 g) using 4:1, 5:2, and 3:2 mixtures of hexane and
ethyl acetate as eluents, and analyzed by HPLC using
anisole as an internal standard. Yield of 15R-TIC methyl
ester [12C]-6: 79%.
Reaction of methyl iodide and stannane 10 leading to
[12C]-11. Reaction was conducted using 10 (4.1 mg,
6.2 mmol) by the same procedure as described above. The
product was puri®ed by chromatography on silica gel
(0.77 g) using 15:1 and 12:1 mixtures of hexane and ethyl
acetate as eluents, and analyzed by HPLC using anisole as
an internal standard. Yield of 15-deoxy-TIC methyl ester
[12C]-11: 80%.
Cross-coupling reaction of [13C]methyl iodide and 7
leading to [13C]-6. In a dry Schlenk tube (10 mL), tris(di-
benzylideneacetone)dipalladium(0) (4.4 mg, 4.8 mmol) and
tri-o-tolylphosphine (5.8 mg, 19.2 mmol) were placed under
argon. After addition of DMF (1.5 mL), the mixture was
stirred for 5 min at room temperature and then a solution
of [13C]methyl iodide in DMF (0.8 M, 10 mL, 8 mmol) was
added. The mixture was further stirred for 3 min at room
temperature followed by successive addition of a solution of
a tributyltin derivative 7 (5.0 mg, 7.42 mmol) in DMF
(1.5 mL). The resulting mixture was stirred under argon at
508C for 15 h. The whole mixture was ®ltered and concen-
trated under reduced pressure by azeotropic removal of
DMF with toluene. The residue was subjected to silica gel
column chromatography (1.3 g) using 5:2 and 1:1 mixtures
of hexane and ethyl acetate as eluents to give a slightly
yellow oil. Further puri®cation by silica gel column
chromatography (0.7 g) using 2:1 and 1:1 mixtures of
hexane and ethyl acetate as eluents gave [13C]-6 (2.3 mg,
5.76 mmol, 78% yield) as a colorless oil. TLC Rf 0.50 (1:4
Cross-coupling reaction of [13C]methyl iodide and 10
leading to [13C]-11. Reaction was conducted using tris(di-
benzylideneacetone)dipalladium(0) (5.4 mg, 5.9 mmol), tri-
o-tolylphosphine (7.2 mg, 23.6 mmol), [13C]methyl iodide
in DMF (0.8 M, 12.5 mL, 10 mmol), and 10 (5.8 mg,
8.8 mmol) by the same procedure as that described for the
synthesis of [13C]-6. The residue was subjected to silica gel
column chromatography (1.3 g) using 15:1, 10:1, and 7:1
mixtures of hexane and ethyl acetate as eluents to give a
slightly yellow oil. Further puri®cation by silica gel column
chromatography (0.7 g) using 15:1 and 7:1 mixtures of
hexane and ethyl acetate as eluents gave [13C]-11 (2.8 mg,
7.31 mmol, 83% yield) as a colorless oil. TLC Rf 0.44 (2:1
hexane/ethyl acetate); 1H NMR (CDCl3, 500 MHz) d 1.15±
2.10 (m, 10, 4 CH2, CH, and OH), 2.15±2.50 (m, 7, 3 CH2
and CH), 2.32 (d, 3, 1JC-Hˆ126.0 Hz, 13CH3), 2.60±2.75 (m,
2, benzylic CH2), 2.90±3.05 (m, 1, allylic CH in ring), 3.6±
3.7 (m, 1, CHO), 3.67 (s, 3, OCH3), 5.23 (dd, 1, Jˆ8.8 and
15.2 Hz, vinylic in chain), 5.27 (d, 1, Jˆ1.0 Hz, vinylic in
ring), 5.53 (dt, 1, Jˆ6.8 and 15.2 Hz, vinylic in chain),
6.95±7.05 (m, 3, aromatic), 7.17 (t, 1, Jˆ7.6 Hz, aromatic);
13C NMR (CDCl3, 125 MHz) d 21.4, 24.7, 27.2, 30.6, 33.9,
34.5, 35.8, 39.3, 39.7, 44.3, 45.6, 51.5, 58.7, 77.1, 125.6,
126.5 (Jˆ3.6 Hz), 128.1 (Jˆ3.4 Hz), 128.3, 129.4
(Jˆ3.8 Hz), 132.08, 132.13, 137.8 (Jˆ44.0 Hz), 141.4,
141.3 (Jˆ3.4 Hz), 174.1; HRMS (FAB, NBA/NaI), m/z
calcd for C2413CH34O3Na (M11Na) 406.2439, found
406.2436.
1
hexane/ethyl acetate); H NMR (CDCl3, 500 MHz) d 1.2±
1.7 (m, 7, 2 CH2, CH, and 2 OH), 1.8±2.1 (m, 4, 2 CH2),
2.2±2.5 (m, 5, 2 CH2 and CH), 2.33 (d, 3, 1JC-Hˆ126.4 Hz,
13CH3), 2.79 (dd, 1, Jˆ6.4 and 13.2 Hz, benzylic CHH),
2.85 (dd, 1, Jˆ7.4 and 13.2 Hz, benzylic CHH), 2.9±3.1
(br, 1, allylic CH in ring), 3.6±3.7 (m, 1, CHO), 3.67 (s,
3, OCH3), 4.35 (q, 1, Jˆ6.5 Hz, CHO), 5.28 (s, 1, vinylic in
ring), 5.45 (dd, 1, Jˆ8.6 and 15.4 Hz, vinylic in chain), 5.61
(dd, 1, Jˆ6.6 and 15.4 Hz, vinylic in chain), 6.95±7.10 (m,
3, aromatic), 7.20 (t, 1, Jˆ7.4 Hz, aromatic); 13C NMR
(CDCl3, 125 MHz) d 21.4, 24.7, 27.2, 30.6, 33.9, 39.4,
39.8, 44.1, 44.3, 45.7, 51.4, 58.2, 73.6, 77.1, 126.6, 127.3
(Jˆ2.8 Hz), 128.3, 128.4, 130.4 (Jˆ3.8 Hz), 133.0, 134.3,
137.8 (Jˆ3.6 Hz), 138.1 (Jˆ44.0 Hz), 141.5, 174.1; HRMS
Methyl 3-(tri-n-butylstannyl)phenylacetate 13. In a dry

8270
M. Suzuki et al. / Tetrahedron 56 (2000) 8263±8273
Schlenk tube (20 mL), tetrakis(triphenylphosphine)palla-
dium(0) (11.5 mg, 9.95 mmol) was placed under argon.
After addition of solutions of 12 (223 mg, 0.974 mmol) in
1,4-dioxane (3 mL) and hexa-n-butylditin (1.81 g,
3.13 mmol) in 1,4-dioxane (4 mL), the mixture was stirred
for 24 h at 908C. The reaction mixture was cooled to room
temperature. After addition of a 20% aqueous KF solution
(5 mL), the resulting mixture was ®ltered. The organic layer
was separated and the aqueous phase was extracted with
ethyl acetate (5 mL£3). The combined organic extracts
were washed with brine, dried over Na2SO4, ®ltered, and
concentrated under reduced pressure. The residue was
subjected to silica gel column chromatography (20 g)
using hexane, followed by a 50:1 mixture of hexane and
ethyl acetate as an eluent to give 13 (224.6 mg,
0.510 mmol, 52% yield). TLC Rf 0.74 (10:1 hexane/ethyl
then the mixture was stirred for 5 min at 08C, followed by
addition of a saturated NH4Cl aqueous solution (1 mL). The
organic layer was separated and the aqueous phase was
extracted with ethyl acetate. The combined organic extracts
were dried over Na2SO4, ®ltered, and concentrated under
reduced pressure. The residue was subjected to silica gel
column chromatography (13 g) using a 5:1 mixture of
hexane and ethyl acetate as an eluent to give 16 (55 mg,
81.9 mmol, 91% yield). TLC Rf 0.34 (2:1 hexane/ethyl
acetate); IR (neat, cm21) 3428, 1739, 1689, 1624, 1585;
1H NMR (CDCl3, 270 MHz) d 0.88 (t, 9, Jˆ7.4 Hz, 3
CH3), 0.9±1.0 (m, 6, 3 CH2), 1.2±1.7 (m, 18, 8 CH2, CH,
and OH), 1.85±2.2 (m, 4, 2 CH2), 2.25±2.5 (m, 5, 2 CH2 and
CH), 3.0±3.1 (br, 1, allylic CH), 3.65 (s, 3, OCH3), 3.81 (s,
2, CH2), 3.8±3.9 (m, 1, CHO), 5.28 (s, 1, vinylic in ring),
6.24 (d, 1, Jˆ15.8 Hz, vinylic in chain), 6.81 (dd, 1, Jˆ8.4
and 15.8 Hz, vinylic in chain), 7.1±7.4 (m, 4, aromatic); 13C
NMR (CDCl3, 67.5 MHz) d 9.6, 13.8, 24.7, 27.2, 27.4, 29.2,
30.6, 33.9, 40.0, 40.2, 44.4, 46.1, 48.2, 51.6, 58.2, 77.3,
128.2, 129.2, 130.2, 133.9, 135.1, 137.6, 141.6, 142.7,
148.6, 174.2, 197.5; HRMS (FAB, NBA/NaI), m/z calcd
for C36H56O4SnNa (M11Na) 695.3098, found 695.3072.
1
acetate); IR (neat, cm21) 1743, 1585; H NMR (CDCl3,
500 MHz) d 0.88 (t, 9, Jˆ7.3 Hz, 3 CH3), 1.05 (m, 6, 3
CH2), 1.35 (m, 6, 3 CH2), 1.55 (m, 6, 3 CH2), 3.59 (s, 2,
CH2), 3.66 (s, 3, OCH3), 7.2±7.4 (m, 4, aromatic); 13C NMR
(CDCl3, 125 MHz) d 9.6, 13.7, 27.4, 29.1, 41.4, 51.9, 128.1,
128.6, 128.7, 128.9, 135.2, 137.2, 142.4; HRMS (FAB,
NBA/NaI), m/z calcd for C21H36O2SnNa (M11Na)
463.1635, found 463.1618.
(15R)-16-[3-(Tri-n-butylstannyl)phenyl]-17,18,19,20-
tetranorisocarbacyclin methyl ester 7 and its 15-epimer
9. In a test tube (10 mL), a solution of 16 (30 mg, 44 mmol)
in CH3OH (1.2 mL) was placed at 2208C. Cerium(III)
chloride heptahydrate (16 mg, 43 mmol) was added and
the mixture was stirred for a few minutes at 2208C,
followed by successive addition of NaBH4 (2.5 mg,
66 mmol). The mixture was stirred for 30 min at 2208C.
A saturated NH4Cl aqueous solution (1 mL) was added to
the reaction mixture and the organic layer was separated.
The aqueous phase was extracted with ethyl acetate. The
combined organic extracts were dried over Na2SO4, ®ltered,
and concentrated under reduced pressure to give a crude
mixture of the C(15)-epimers, 7 and 9, which was subjected
to silica gel column chromatography (8 g) using 8:3 and 2:3
mixtures of hexane and ethyl acetate as eluents to give
stereochemically pure 7 (13.2 mg, 19.6 mmol, 44% yield)
and 9 (12.7 mg, 18.9 mmol, 43% yield) as the less and more
polar materials, respectively. 7: TLC Rf 0.41 (1:1 hexane/
1-(Dimethoxyphosphory)-3-[3-(tri-n-butylstannyl)phenyl]-
2-propanone 14. In a dry Schlenk tube (20 mL), a solution
of dimethyl methylphosphonate (296 mg, 2.4 mmol) in THF
(8 mL) was placed under argon at 2788C. After addition of
a solution of n-butyllithium in hexane (1.56 M, 1.54 mL,
2.4 mmol) over 10 min at 2788C, the mixture was stirred
for 30 min at 2788C to give a white suspension. This
mixture was transferred to
a round-bottomed ¯ask
(50 mL) containing a solution of 13 (528 mg, 1.2 mmol)
in THF (5 mL) kept at 2788C over 10 min. The resulting
mixture was further stirred at 2788C for 1 h, and poured
into a saturated NH4Cl aqueous solution (10 mL). The
organic layer was separated and the aqueous phase was
extracted with ethyl acetate. The combined organic extracts
were dried over Na2SO4, ®ltered, and concentrated under
reduced pressure. The residue was subjected to silica gel
column chromatography (25 g) using 3:1 and 1:2 mixtures
of hexane and ethyl acetate as eluents to give 14 (348 mg,
0.65 mmol, 54% yield). TLC Rf 0.34 (1:1 hexane/ethyl
acetate); IR (neat, cm21) 1719, 1633, 1586, 1258; 1H
NMR (CDCl3, 500 MHz) d 0.88 (t, 9, Jˆ7.3 Hz, 3 CH3),
1.05 (m, 6, 3 CH2), 1.32 (m, 6, 3 CH2), 1.53 (m, 6, 3 CH2),
3.10 (d, 2, JP±Hˆ22.5 Hz, CH2), 3.78 (d, 6, JP±Hˆ11.3 Hz, 2
OCH3), 3.86 (s, 2, CH2), 7.1±7.4 (m, 4, aromatic); 13C NMR
1
ethyl acetate); IR (neat, cm21) 3410, 1740, 1584; H NMR
(CDCl3, 270 MHz) d 0.89 (t, 9, Jˆ7.4 Hz, 3 CH3), 0.9±1.0
(m, 6, 3 CH2), 1.2±1.7 (m, 19, 8 CH2, CH, and 2 OH), 1.8±
2.1 (m, 4, 2 CH2), 2.2±2.5 (m, 5, 2 CH2 and CH), 2.7±2.9
(m, 2, benzylic CH2), 2.9±3.1 (m, 1, allylic CH), 3.5±3.8
(m, 1, CHO), 3.67 (s, 3, OCH3), 4.3±4.4 (m, 1, CHO), 5.28
(s, 1, vinylic in ring), 5.47 (dd, 1, Jˆ8.4 and 15.3 Hz, vinylic
in chain), 5.63 (dd, 1, Jˆ6.4 and 15.3 Hz, vinylic in chain),
7.1±7.4 (m, 4, aromatic); 13C NMR (CDCl3, 67.5 MHz) d
9.6, 13.8, 24.8, 27.3, 27.4, 29.2, 30.6, 34.0, 39.4, 39.9,
44.35, 44.40, 45.7, 51.6, 58.3, 73.8, 77.3, 128.0, 128.3,
129.3, 133.0, 134.3, 134.8, 137.4, 137.6, 141.5, 142.6,
174.2; HRMS (FAB, NBA/NaI), m/z calcd for
C36H58O4SnNa (M11Na) 697.3263, found 697.3232. 9:
(CDCl3, 125 MHz)
d
9.5, 13.6, 27.3, 29.0, 40.0
(Jˆ128.3 Hz), 51.1, 53.0 (Jˆ6.4 Hz), 128.2, 129.2, 132.7,
135.4, 137.4, 142.9, 199.5 (Jˆ5.5 Hz); HRMS (FAB, NBA/
NaI), m/z calcd C23H41O4PSnNa (M11Na) 555.1667, found
555.1660.
15-Dehydro-16-[3-(tri-n-butylstannyl)phenyl]-17,18,19,
20-tetranorisocarbacyclin methyl ester 16. In a dry
round-bottomed ¯ask (10 mL), a solution of 14 (98 mg,
184 mmol) in DME (2 mL) was placed at 08C under
argon. After addition of NaH (60% oil dispersion, 7.2 mg,
180 mmol), the mixture was stirred for 5 min at 08C to give a
white clear solution. A solution of the aldehyde 15 (24 mg,
90 mmol) in DME (1 mL) was added at 08C over 5 min and
TLC Rf 0.31 (1:1 hexane/ethyl acetate); IR (neat, cm21
)
1
3369, 1741, 1458; H NMR (CDCl3, 270 MHz) d 0.89 (t,
9, Jˆ7.4 Hz, 3 CH3), 1.0±1.1 (m, 6, 3 CH2), 1.2±1.7 (m, 19,
8 CH2, CH, and 2 OH), 1.8±2.1 (m, 4, 2 CH2), 2.2±2.5 (m,
5, 2 CH2 and CH), 2.7±2.9 (m, 2, benzylic CH2), 2.9±3.1
(m, 1, allylic CH), 3.6±3.8 (m, 1, CHO), 3.67 (s, 3, OCH3),
4.3±4.4 (m, 1, CHO), 5.28 (s, 1, vinylic in ring), 5.52 (dd, 1,

M. Suzuki et al. / Tetrahedron 56 (2000) 8263±8273
8271
Jˆ7.9 and 15.3 Hz, vinylic in chain), 5.65 (dd, 1, Jˆ5.4 and
15.3 Hz, vinylic in chain), 7.1±7.4 (m, 4, aromatic); 13C
NMR (CDCl3, 125 MHz) d 9.6, 13.7, 24.7, 27.2, 27.4,
29.1, 30.6, 33.9, 39.6, 39.8, 44.29, 44.32, 45.7, 51.5, 58.2,
73.4, 77.2, 127.9, 128.3, 129.3, 132.9, 134.1, 134.7, 137.2,
137.6, 141.4, 142.4, 174.2; HRMS (FAB, NBA/NaI), m/z
calcd for C36H58O4SnNa (M11Na) 697.3263, found
697.3259.
(CDCl3, 270 MHz) d 5.33 (s, 1, benzylic CH), 7.0±7.5
(m, 14, aromatic); 13C NMR (CDCl3, 67.5 MHz) d 59.9,
122.3, 126.5, 128.1, 128.9, 129.9, 130.9, 131.0, 132.8,
133.8, 141.9; HRMS (FAB, NBA/NaI), m/z calcd for
C19H1579BrS2Na (M11Na) 408.9696, found 408.9699; m/z
calcd for C19H1581BrS2Na (M11Na) 410.9676, found
410.9687.
3-[Bis(phenylsulfonyl)methyl]bromobenzene 19. In a
round-bottomed ¯ask (500 mL), a mixture of an aqueous
H2O2 solution (30%, 35 mL), acetic acid (32 mL), and
acetic anhydride (17 mL) were placed. This mixture was
heated to 708C and stirred for 5 min. After addition of a
solution of 18 (4.0 g, 10.3 mmol) in acetic acid (20 mL),
the resulting mixture was heated to re¯ux for 12 h. The
reaction mixture was cooled to room temperature and
poured into H2O to give a white precipitate. This precipitate
was washed with hexane and cold acetone, and dried under
vacuum to give 19 (3.26 g, 7.24 mmol, 70% yield). TLC Rf
0.54 (1:1 hexane/ethyl acetate); IR (KBr, cm21) 1584, 1447,
1335, 1163; 1H NMR (CDCl3, 270 MHz) d 5.36 (s 1,
benzylic CH), 7.0±7.9 (m, 14, aromatic); 13C NMR
(CDCl3, 67.5 MHz) d 87.8, 122.5, 127.8, 129.0, 129.8,
130.1, 133.5, 134.8, 137.5; HRMS (FAB, NBA/NaI), m/z
calcd for C19H15O479BrS2Na (M11Na) 472.9493, found
472.9491; m/z calcd for C19H15O481BrS2Na (M11Na)
474.9473, found 474.9479.
Determination of the C(15) stereochemistry of 9. In a dry
Schlenk tube (10 mL), tris(dibenzylideneacetone)dipalla-
dium(0) (4.4 mg, 4.8 mmol) and tri-o-tolylphosphine
(5.8 mg, 19.2 mmol) were placed under argon. After
addition of DMF (1.5 mL), the mixture was stirred for
5 min at room temperature and then a solution of methyl
iodide in DMF (0.8 M, 10 mL, 8 mmol) was added. The
mixture was further stirred for 3 min at room temperature
followed by successive addition of a solution of the tri-
butyltin derivative 9 (5.1 mg, 7.6 mmol) in DMF (1.5 mL).
The resulting mixture was stirred under argon at 508C for
15 h. The mixture was ®ltered and concentrated under
reduced pressure by azeotropic removal of DMF with
toluene. The residue was subjected to silica gel column
chromatography (1.3 g) using successively 2:1, 1:1, and
2:3 mixtures of hexane and ethyl acetate as eluents to give
a slightly yellow oil. Further puri®cation by silica gel
column chromatography (0.7 g) using successively 2:1,
1:1, and 2:3 mixtures of hexane and ethyl acetate as eluents
gave [12C]-8 (2.2 mg, 5.5 mmol, 73% yield) as a colorless
oil. TLC Rf 0.40 (1:4 hexane/ethyl acetate); 1H NMR
(CDCl3, 500 MHz) d 1.2±1.8 (m, 7, 2 CH2, CH, and 2
OH), 1.85±2.10 (m, 4, 2 CH2), 2.2±2.5 (m, 8, CH3, 2
CH2, and CH), 2.77 (dd, 1, Jˆ7.4 and 13.2 Hz, benzylic
CHH), 2.85 (dd, 1, Jˆ5.4 and 13.2 Hz, benzylic CHH),
2.95±3.05 (br, 1, allylic CH in ring), 3.6±3.8 (m, 1,
CHO), 3.67 (s, 3, OCH3), 4.34 (q, 1, Jˆ6.4 Hz, CHO),
5.28 (d, 1, Jˆ1.0 Hz, vinylic in ring), 5.49 (dd, 1, Jˆ8.3
and 15.3 Hz, vinylic in chain), 5.63 (dd, 1, Jˆ6.2 and
15.3 Hz, vinylic in chain), 6.95±7.10 (m, 3, aromatic),
7.19 (t, 1, Jˆ7.6 Hz, aromatic); HRMS (FAB, NBA/NaI),
m/z calcd for C25H34O4Na (M11Na) 421.2355, found
1-(Tri-n-butylstannyl)-3-[bis(phenylsulfonyl)methyl]-
benzene 20. In a dry Schlenk tube (20 mL), 19 (330 mg,
730 mmol) and tetrakis(triphenylphosphine)palladium(0)
(46 mg, 40 mmol) were placed under argon. After addition
of 1,4-dioxane (5 mL), the mixture was stirred for 5 min at
room temperature. A solution of hexa-n-butylditin (1.28 g,
2.2 mmol) in 1,4-dioxane (2 mL) was added and the mixture
was stirred for 17 h at 908C. The reaction mixture was
cooled to room temperature, washed with a 20% aqueous
KF solution (5 mL), and ®ltered. The organic layer was
separated and the aqueous phase was extracted with ethyl
acetate. The combined organic extracts were dried over
Na2SO4, ®ltered, and concentrated under reduced pressure.
The residue was subjected to silica gel column chroma-
tography (60 g) using 10:1 and 5:1 mixtures of hexane
and ethyl acetate as eluents to give 20 (211.5 mg,
320 mmol, 44% yield). TLC Rf 0.48 (2:1 hexane/ethyl ace-
1
421.2355. The Rf value, H NMR, and HRMS (FAB) of
the product were identical with these of authentic 15S-TIC
methyl ester [12C]-8.
1
3-[Bis(phenylthio)methyl]bromobenzene 18. In a round-
bottomed ¯ask (500 mL), a solution of benzenethiol (7.55 g,
83.2 mmol) in CHCl3 (50 mL) was placed at room tempera-
ture followed by successive addition of solutions of
3-bromobenzaldehyde 17 (5.91 g, 32.0 mmol) in CHCl3
(50 mL) and chlorotrimethylsilane (9.4 g, 86.5 mmol) in
CHCl3 (10 mL). The resulting mixture was stirred for 12 h
at room temperature. The reaction mixture was poured into
a saturated NaHCO3 aqueous solution (100 mL). The
organic layer was separated and the aqueous phase was
extracted with CHCl3. The combined organic extracts
were washed with brine, dried over Na2SO4, ®ltered, and
concentrated under reduced pressure. The residue was
subjected to silica gel column chromatography (200 g)
using hexane, followed by 10:1, 7:1, and 5:1 mixtures of
hexane and ethyl acetate as eluents to give 18 (12.27 mg,
31.6 mmol, 99% yield). TLC Rf 0.38 (10:1 hexane/ethyl
acetate); IR (neat, cm21) 1583, 1474, 1070; 1H NMR
tate); IR (neat, cm21) 1449, 1336, 1163, 1079; H NMR
(CDCl3, 500 MHz) d 0.89 (t, 9, Jˆ7.3 Hz, 3 CH3), 9.0±
1.0 (m, 6, 3 CH2), 1.2±1.7 (m, 12, 6 CH2), 5.39 (s, 1,
benzylic CH), 7.0±7.8 (m, 14, aromatic); 13C NMR
(CDCl3, 125 MHz) d 9.6, 13.6, 27.3, 28.9, 88.8, 125.2,
128.0, 128.7, 129.7, 134.3, 138.1, 138.4, 142.9; HRMS
(FAB, NBA/NaI), m/z calcd for C31H42O4S2SnNa
(M11Na) 685.1448, found 685.1447.
Methyl 5-[(1S,5S,6R,7R)-6-(2-formylvinyl)-7-tetrahydro-
pyran-2-yloxybicyclo[3.3.0]oct-2-ene-3yl]pentanoate 22.
In a round-bottomed ¯ask (30 mL), a solution of 21
(203.8 mg, 0.58 mmol) in benzene (7.0 mL) was placed at
room temperature. After addition of (formylmethylene)tri-
phenylphosphorane (206.9 mg, 0.68 mmol), the reaction
mixture was heated to re¯ux for 36 h. The mixture was
cooled to room temperature and concentrated under reduced
pressure. The residue was subjected to silica gel column

8272
M. Suzuki et al. / Tetrahedron 56 (2000) 8263±8273
chromatography (100 g) using a 10:1 mixture of hexane and
ethyl acetate as an eluent to give 22 (144.5 mg, 0.38 mmol,
66% yield). TLC Rf 0.49 (2:1 hexane/ethyl acetate); IR
for 5 min at room temperature. Then solutions of carbonate
23 (16.5 mg, 37.8 mmol) in THF (1.5 mL) and disulfone 20
(28 mg, 42 mmol) in THF (1.5 mL) were successively
added. The resulting mixture was stirred for 26 h at 608C.
The reaction mixture was ®ltered and concentrated under
reduced pressure, and the residue was subjected to silica gel
column chromatography (3.0 g) using a 12:1 mixture of
hexane and ethyl acetate as an eluent to give 24 (37.8 mg,
37.0 mmol, 98% yield). TLC Rf 0.58 (2:1 hexane/ethyl
acetate); IR (neat, cm21) 1739, 1448, 1143, 1077; 1H
NMR (CDCl3, 500 MHz) d 0.89 (t, 9, Jˆ7.3 Hz, 3 CH3),
0.9±1.1 (m, 6, 3 CH2), 1.1±1.9 (m, 25, 12 CH2 and CH),
1.9±2.4 (m, 7, 3 CH2 and CH), 2.9±3.1 (br, 1, allylic CH in
ring), 3.3±4.0 (m, 5, CH2O, CHO, and allylic CH2 in chain),
3.64 (s, 3, OCH3), 4.5±4.7 (m, 1, CHO), 5.24 (m, 1, vinylic
in ring), 5.3±5.7 (m, 2, vinylic in chain), 7.2±7.9 (m, 14,
aromatic); 13C NMR (CDCl3, 125 MHz) d 9.6, 9.7, 13.67,
13.69, 14.2, 19.57, 19.64, 24.7, 25.5, 25.6, 27.1, 27.19,
27.20, 27.3, 27.4, 27.6, 28.97, 29.02, 29.1, 30.5, 30.7,
31.0, 31.2, 33.9, 36.2, 39.0, 39.90, 39.95, 43.6, 43.7, 45.5,
45.6, 51.4, 55.2, 55.7, 60.4, 62.3, 62.4, 78.8, 83.1, 93.7,
93.8, 96.3, 99.5, 122.4, 122.6, 127.35, 127.44, 127.84,
127.87, 127.93, 128.0, 128.2, 128.7, 129.7, 131.75,
131.76, 131.78, 131.9, 134.12, 134.14, 134.2, 134.3,
136.89, 136.93, 137.0, 137.8, 141.1, 141.3, 141.8, 141.9,
174.1; HRMS (FAB, NBA/NaI), m/z calcd for
1
(neat, cm21) 1733, 1691; H NMR (CDCl3, 600 MHz) d
1.4±1.8 (m, 13, 6 CH2 and CH), 1.9±2.6 (m, 7, 3 CH2 and
CH), 2.95±3.15 (br, 1, allylic CH in ring), 3.4±4.1 (m, 3,
CH2O and CHO), 3.67 (s, 3, OCH3), 4.55±4.7 (m, 1, CHO),
5.30 (s, 1, vinylic in ring), 6.21 (dt, 1, Jˆ7.9 and 15.8 Hz,
vinylic in chain), 6.86 (dt, 1, Jˆ7.4 and 15.8 Hz, vinylic in
chain), 9.53 and 9.54 (each d, 1, Jˆ7.5 Hz, C(O)H); 13C
NMR (CDCl3, 150 MHz) d 19.3, 19.5, 24.7, 25.4, 25.5,
27.2, 30.6, 30.7, 30.9, 34.0, 36.8, 39.2, 39.7, 39.8, 43.7,
45.9, 46.0, 51.6, 53.4, 56.2, 62.2, 62.6, 79.4, 82.8, 96.7,
99.5, 128.1, 128.2, 133.2, 133.3, 141.2, 141.3, 159.7,
160.1, 174.2, 194.0, 194.2; HRMS (FAB, NBA/NaI), m/z
calcd for C22H32O5Na (M11Na) 399.2148, found 399.2162.
Methyl 5-[(1S,5S,6R,7R)-6-(3-methoxycarbonyloxy-1-
propenyl)-7-tetrahydropyran-2-yloxybicyclo[3.3.0]oct-
2-ene-3yl]pentanoate 23. In a round-bottomed ¯ask
(10 mL), a solution of 22 (15.2 mg, 40.4 mmol) in methanol
(2.0 mL) was placed at 08C. After addition of NaBH4 (2 mg,
53 mmol), the mixture was stirred for 10 min at 08C. The
reaction mixture was poured into a saturated NH4Cl aqueous
solution (2 mL). Ethyl acetate (2 mL) was added and the
organic layer was separated and the aqueous phase was
extracted with ethyl acetate. The combined organic extracts
were washed with brine, dried over MgSO4, ®ltered, and
concentrated under reduced pressure. The crude product
was dissolved in CH2Cl2 (2.0 mL) at 08C and then 4-
(dimethylamino)pyridine (10 mg, 82 mmol) and methyl
chloroformate (5 mL, 65 mmol) were added. The mixture
was stirred for 8 h at room temperature. The reaction
mixture was poured into a saturated NH4Cl aqueous solution
(2 mL). Ethyl acetate (2 mL) was added and the organic
layer was separated and the aqueous phase was extracted
with ethyl acetate. The combined organic extracts were
washed with brine, dried over MgSO4, ®ltered, and concen-
trated under reduced pressure. The residue was subjected to
silica gel column chromatography (2 g) using a 5:1 mixture
of hexane and ethyl acetate as an eluent to give 23 (16.0 mg,
36.7 mmol, 91% yield). TLC Rf 0.47 (2:1 hexane/ethyl
acetate); IR (neat, cm21) 1746; 1H NMR (CDCl3,
270 MHz) d 1.4±1.8 (m, 13, 6 CH2 and CH), 1.9±2.5 (m,
7, 3 CH2 and CH), 2.9±3.05 (br, 1, allylic CH in ring), 3.4±
3.9 (m, 3, CH2O and CHO), 3.67 (s, 3, OCH3), 3.77 and 3.78
(s each, 3, OCH3), 4.5±4.7 (m, 1, CHO), 5.26 (s, 1, vinylic in
ring), 5.6±5.9 (m, 2, vinylic in chain); 13C NMR (CDCl3,
150 MHz) d 20.0, 20.1, 24.8, 25.5, 25.6, 27.3, 30.6, 30.7,
30.9, 34.0, 36.4, 38.8, 39.7, 39.8, 43.5, 43.6, 45.5, 45.7,
51.5, 53.4, 54.7, 54.8, 54.9, 55.8, 61.5, 62.6, 68.6, 68.7,
78.9, 82.8, 95.9, 99.6, 124.2, 124.3, 128.2, 128.3, 138.3,
138.4, 141.2, 141.4, 155.7, 174.2; HRMS (FAB, NBA/
NaI), m/z calcd for C24H36O7Na (M11Na) 459.2359,
found 459.2353.
C53H74O8S2120SnNa
1045.3729.
(M11Na)
1045.3755,
found
15-Deoxy-16-[3-(tri-n-butylstannyl)phenyl]-17,18,19,20-
tetranorisocarbacyclin methyl ester 10. In a round-
bottomed ¯ask (10 mL), a solution of 24 (7.5 mg,
7.3 mmol) in dry methanol (0.5 mL) was placed at room
temperature. After addition of activated Mg (14 mg,
576 mmol), the mixture was stirred for 2 h at room tempera-
ture. A saturated NH4Cl aqueous solution (1 mL) and ether
(2 mL) were added to the reaction mixture. The organic
layer was separated and the aqueous phase was extracted
with ether. The combined organic extracts were dried over
MgSO4, ®ltered, and concentrated under reduced pressure.
The crude product (4.8 mg) was dissolved in methanol
(0.5 mL) at room temperature. After addition of pyridinium
p-toluenesulfonate (5 mg, 19 mmol), the reaction mixture
was stirred for 4 h at room temperature. After addition of
a distilled water (0.5 mL) and ether (1 mL), the organic
layer was separated and the aqueous phase was extracted
with ether. The combined organic extracts were dried over
MgSO4, ®ltered, and concentrated under reduced pressure.
Silica gel column chromatography (0.5 g) using a 12:1
mixture of hexane and ethyl acetate as an eluent gave 10
(3.3 mg, 5.0 mmol, 69% yield). TLC Rf 0.54 (2:1 hexane/
1
ethyl acetate); IR (neat, cm21) 2925, 1742, 1459; H NMR
(CDCl3, 500 MHz) d 0.89 (t, 9, Jˆ7.3 Hz, 3 CH3), 1.0±1.1
(m, 6, 3 CH2), 1.2±2.1 (m, 22, 10 CH2, CH, and OH), 2.2±
2.5 (m, 7, 3 CH2 and CH), 2.6±2.8 (m, 2, benzylic CH2),
2.9±3.0 (m, 1, allylic CH in ring), 3.6±3.7 (m, 1, CHO),
3.67 (s, 3, OCH3), 5.265 (dd, 1, Jˆ8.7 and 15.2 Hz, vinylic
in chain), 5.272 (s, 1, vinylic in ring), 5.56 (dt, 1, Jˆ6.9 and
15.2 Hz, vinylic in chain), 7.0±7.1 (d, 1, Jˆ7.3 Hz,
aromatic), 7.2±7.4 (dd, 3, Jˆ6.8 and 7.3 Hz, aromatic);
13C NMR (CDCl3, 125 MHz) d 9.5, 13.7, 24.7, 27.2, 27.4,
29.1, 30.6, 33.9, 34.6, 36.0, 39.3, 39.7, 44.3, 45.6, 51.5,
58.6, 77.1, 127.7, 128.26, 128.29, 132.0, 132.1, 133.9,
16-[Bis(phenylsulfonyl)]-15-deoxy-11-O-tetrahydropynan-
2-yl-16-[3-(tri-n-butylstannyl)phenyl]-17,18,19,20-tetra-
norisocarbacyclin methyl ester 24. In a dry Schlenk tube
(10 mL), tris(dibenzylideneacetone)dipalladium(0)-chloro-
form adduct (3.1 mg, 3 mmol) and 1,2-bis(diphenylphos-
phino)ethane (3.6 mg, 9 mmol) were placed under argon.
After addition of THF (1.5 mL), the mixture was stirred

M. Suzuki et al. / Tetrahedron 56 (2000) 8263±8273
8273
Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: 1996; Vol.
5, pp 1±53.
136.5, 141.2, 141.4, 141.9, 174.1; HRMS (FAB, NBA/NaI),
m/z calcd for C36H58O3120SnNa (M11Na) 681.3314, found
681.3307.
8. (a) Fowler, J. S.; Wolf, A. P.; Barrio, J. R.; Mazziotta, J. C.;
Phelps, M. E. In Positron Emission Tomography and Auto-
radiography; Phelps, M. E., Mazziotta, J. C., Schelbert, H. R.,
Eds.; Raven Press: New York, 1986; Chapters 9±11. (b) Fowler,
J. S., Wolf, A. P. Acc. Chem. Res. 1997, 30, 181±188. (c)
Acknowledgements
This work was supported in part by a grant-in-aid (No.
11358011, 11694143, and 07CE2004) from the Ministry
of Education, Science, Sports and Culture of Japan.
Ê
È
Langstrom, B.; Dannals, R. F. In Principles of Nuclear Medicine,
2nd ed.; Wagner, H. N., Szabo, Z., Buchanan. J. W., Eds.; W. B.
Saunders: Philadelphia, 1995; Section 1, Chapter 11. (d) Brennan,
M. B. Chem. Eng. News 1996, 74 (Feb. 19), pp 26±33 (e)
Ê
È
Langstrom, B.; Kihlberg, T.; Bergstrom, M.; Antoni, G.; Bjork-
man, M.; Forngren, B. H.; Forngren, T.; Hartvig, P.; Markides, K.;
È
È
References
È
Yngve, U.; Ogren, M. Acta Chem. Scand. 1999, 53, 651±669.
Ê
È
1. Suzuki, M.; Noyori, R.; Langstrom, B.; Watanabe, Y. Bull.
Chem. Soc. Jpn 2000, 73, 1053±1070.
2. (a) Suzuki, M.; Kato, K.; Noyori, R.; Watanabe, Yu.; Takechi,
9. The methyl ester [11C]-6 was assumed to penetrate the blood±
brain-barrier (BBB) and then to be hydrolyzed to be the corre-
sponding acid form [11C]-5 which binds to the receptor in the
brain. See references 1 and 4.
Ê
È
H.; Matsumura, K.; Langstrom, B.; Watanabe, Y. Angew. Chem.
Int. Ed. Engl. 1996, 35, 334±336. (b) Suzuki, M.; Kato, K.;
Watanabe, Yu.; Satoh, T.; Matsumura, K.; Watanabe, Y.; Noyori,
R. Chem. Commun. 1999, 307±308. (c) Takechi, H.; Matsumura,
K.; Watanabe, Yu.; Kato, K.; Noyori, R.; Suzuki, M.; Watanabe,
Y. J. Biol. Chem. 1996, 271, 5901±5906. (d) Satoh, T.; Ishikawa,
Y.; Kataoka, Y.; Cui, Y.; Yanase, H.; Kato, K.; Watanabe, Yu.;
Nakadate, K.; Matsumura, K.; Hatanaka, H.; Kataoka, K.; Noyori,
R.; Suzuki, M.; Watanabe, Y. Eur. J. Neurosci. 1999, 11, 3115±
3124. (e) Cui, Y.; Kataoka, Y.; Satoh, T.; Yamagata, A.; Shira-
kawa, N.; Watanabe, Yu.; Suzuki, M.; Yanase, H.; Kataoka, K.;
Watanabe, Y. Biochem. Biophys. Res. Commun. 1999, 265, 301±
304.
Ê
10. (a) Langstrom, B.; Antoni, G.; Gullberg, P.; Halldin, C.;
È
Ê
È
Malmborg, P.; Nagren, K.; Rimland, A.; Svard, H. J. Nucl. Med.
1987, 28, 1037±1040. (b) Ferrieri, R. A.; Wolf, A. P. Radiochim.
Acta 1983, 34, 69±83.
11. The methylation with stannyl precursors, 7 and 10, under the
conditions used in entry 5 in Table 1 (one-pot operation) gave 15R-
TIC methyl ester [12C]-6 and 15-deoxy-TIC methyl ester [12C]-11
in 82 and 92% yield, respectively.
12. Details will be reported separately.
13. The investigation for healthy volunteers and patients is in
progress. Recently, the principal author (M. S.) chosen as a ®rst
volunteer succeeded in imaging the IP2 receptor in his brain.
14. (a) Kosugi, M.; Ohya, T.; Migita, T. Bull. Chem. Soc. Jpn
1983, 56, 3855±3856. (b) Kosugi, M.; Shimizu, K.; Ohtani, A.;
Migita T. Chem. Lett. 1981, 829±830.
3. Watanabe, Yu.; Matsumura, K.; Takechi, H.; Kato, K.; Morii,
È
Ê
H.; Bjorkman, M.; Langstrom, B.; Noyori, R.; Suzuki, M.;
È
Watanabe, Y. J. Neurochem. 1999, 72, 2583±2592.
È
4. Watanabe, Y.; Suzuki, M.; Bjorkman, M.; Matsumura, K.;
Watanabe, Yu.; Kato, K.; Doi, H.; Onoe, H.; Sihver, S.; Andersson,
15. (a) Suzuki, M.; Koyano, H.; Noyori, R. Tetrahedron 1992, 48,
2635±2658. (b) Sodeoka, M.; Ogawa, Y.; Mase, T.; Shibasaki, M.
Chem. Pharm. Bull. 1989, 37, 586±598. (c) Hemmerle, H.; Gais,
H.-J. Angew. Chem. Int. Ed. Engl. 1989, 28, 349±351. (d) Manabe,
K.; Tanaka, T.; Kurozumi, S.; Kato, Y. J. Labelled Compds. Radio-
pharm. 1991, 29, 1107±1119.
È
Y.; Kobayashi, K.; Inoue, O.; Hazato, A.; Lu, L.; Bergstrom, M.;
È
Noyori, R.; Langstrom, B. NeuroImage 1997, 5 (4), A1.
Ê
È
5. Bjorkman, M.; Andersson, Y.; Doi, H.; Kato, K.; Suzuki, M.;
Noyori, R.; Watanabe, Y.; Langstrom, B. Acta Chem. Scand. 1998,
Ê
È
52, 635±640.
16. (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226±2227. (b)
Â
Luche, J.-L.; Rodriguez-Hahn, L.; Crabbe, P. J. Chem. Soc., Chem.
Commun. 1978, 601±602.
È
Ê
È
6. Suzuki, M.; Doi, H.; Bjorkman, M.; Andersson, Y.; Langstrom,
B.; Watanabe, Y.; Noyori, R. Chem. Eur. J. 1997, 3, 2039±2042.
7. For the Stille reaction, see: (a) Stille, J. K. Angew. Chem. Int.
Ed. Engl. 1986, 25, 508±524. (b) Stille, J. K.; Groh, B. L. J. Am.
Chem. Soc. 1987, 109, 813±817. (c) Farina, V.; Krishnamurthy,
V.; Scott, W. J. Org. React. 1997, 50, 1±652. (d) Motchell, T. N.
Synthesis 1992, 803±815. (e) Farina, V. Pure Appl. Chem. 1996,
68, 73±78. (f) Farina, V.; Roth, G. P. In Advances in Metal-
17. Trippett, S.; Walker, D. M. J. Chem. Soc. 1961, 1266±1272.
18. (a) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140±145.
(b) Tsuji, J. Tetrahedron 1986, 42, 4361±4401. (c) Tsuji, J.;
Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K.
J. Org. Chem. 1985, 50, 1523±1529.