Synthesis of a14C-labeled FPTase inhibitor via a Pd-catalyzed cyanation with Zn(14CN)2 and via bromo[ 14C]acetic acid

Article abstract of DOI:10.1002/jlcr.1545

¹⁴C-Labeled farnesyl-protein transferase inhibitor 1a was required for drug metabolism studies. The first approach was to synthesize ¹⁴C-labeled 1b using Zn(¹⁴CN)₂ in a Pd-catalyzed cyanation. A second approach was to prepare labeled 1c with the 14C-label in the piperazine ring. All metabolites from 1b were non-radioactive whereas the same metabolites from 1c were all radioactive and quantifiable. Copyright

Full text of DOI:10.1002/jlcr.1545

Research Article
Received 25 April 2008,
Revised 13 August 2008,
Accepted 19 August 2008
Published online 7 October 2008 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1545
Synthesis of a 14C-labeled FPTase inhibitor via
a Pd-catalyzed cyanation with Zn(14CN)2 and
via bromo[14C]acetic acid
Ã
Jonathan Z. Ho, Charles S. Elmore, and Matthew P. Braun
14C-Labeled farnesyl-protein transferase inhibitor 1a was required for drug metabolism studies. The first approach was to
synthesize 14C-labeled 1b using Zn(14CN)2 in a Pd-catalyzed cyanation. A second approach was to prepare labeled 1c with
the 14C-label in the piperazine ring. All metabolites from 1b were non-radioactive whereas the same metabolites from 1c
were all radioactive and quantifiable.
Keywords: 14C-labeled ; cyanation ; Zn(14CN)2; bromo[14C]acetic acid; FPTase
of the protein but are not required for activity.6 Therefore,
inhibition of FPTase represents a potential therapeutic target for
anticancer efforts.7
Introduction
Ras is a guanosine triphosphate (GTP) binding protein that
cycles between the inactive guanosine diphosphate (GDP)
binding conformation and the active GTP binding conformation.
The protein exists primarily in the GDP binding conformation,
but phosphorylation by receptor tyrosine kinases (e.g. the
receptors of vascular endothelial and epidermal growth factors)
leads to the GTP binding conformation. This form transfers
growth signals from the receptor to the mitogen-activated
protein kinase cascade, which puts Ras at the heart of the
signaling pathway leading to cellular growth.1 Ras mutations
that result in a preference for the GTP binding form lead to
unregulated cell growth and are observed in approximately
20–30% of human cancers.2
FPTase is a heterodimeric, GTP-binding protein with subunits
of 48 and 46 kDa. It selectively farnesylates Ras proteins with the
amino acid sequence of CAAX at the carboxy terminus where C
is cysteine, A is an aliphatic amino acid, and X is usually
methionine or serine. Farnesylation occurs at the thiol of the
cysteine and facilitates association of the peptide and the
cellular membrane. This places it in close proximity to the
tyrosine kinases of the cellular growth factor receptors.6,7
Compound 1a (Figure 1) was developed as a potent inhibitor
of FPTase for treatment of cancer. For its preclinical metabolism
3
study a radio-labeled tracer of 1a was needed. Two H-labeled
tracers, with tritium label at different locations, were made
Ras NH HN Val-Ile-Met-CO2H
FPTase
Ras NH HN Val-Ile-Met-CO2H
Endoprotease
O
S
Farnesyl
O
HOPP
FPP
SH
Ras NH OMe
Ras NH OH
O
Methyltransferase
O
S
Farnesyl
S
Farnesyl
Farnesyl =
Scheme 1. Post-translational modifications of RAS required to give maximal enzymatic activity.
Ras proteins must undergo a series of post-translational
Department of Process Research, Merck Research Laboratories, 126 E. Lincoln
modifications to become active (Scheme 1). The first modifica- Avenue, PO Box 2000, RY80R-104, Rahway, New Jersey 07065, USA
tion – addition of a 15 carbon isoprenoid unit, farnesol, to Ras –
*Correspondence to: Jonathan Z. Ho, Department of Process Research, Merck
is catalyzed by farnesyl-protein transferase (FPTase).3 Further
modifications, such as hydrolysis of the three C-terminal amino
Research Laboratories, 126 E. Lincoln Avenue, PO Box 2000, RY80R-104, Rahway,
NJ 07065, USA.
acids4 and esterification of the C-terminus,5 increase the activity E-mail: jonathan_ho@merck.com
J. Label Compd. Radiopharm 2008, 51 399–403
Copyright r 2008 John Wiley & Sons, Ltd.

J. Z. Ho et al.
Cl
Cl
Cl
O
O
O
*
N
N
N
N
N
N
N
N
N
N
N
N
*
CN
CN
CN
1a
1b
1c
* denotes 14C label
Figure 1A new FPTase inhibitor 1a, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile.
initially but they all suffered with 2–3% of tritium loss during the Zn(14CN)2 to be an attractive reagent for the preparation of the
microsone covalent binding (CV) studies. Consequently, a tracer compound containing benzo[14C]nitrile subunits for several
labeled with 14C was highly desired for required metabolic reasons, including its commercial availability, low cost, good
studies.8 The details of preparation of 3H-labeled tracers and yields and tolerance of unprotected function groups. This
related CV results are subjected to a separated publication.
strategy was adopted to label 1b with 14C since there would
be only one radiochemical step with no protected functional
groups.
Results and discussion
The preparation of unlabeled 4-((5-((4-(3-chlorophenyl)-3-
oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile
(1a) was carried out by a Pd-catalyzed cyanation reaction of
Zn(CN)2 with 1-(4-bromobenzyl)-5-(chloromethyl)-1H-imidazole
(2) (Scheme 2). The palladium catalyzed cyanation of aryl
bromides with Zn(CN)2 has been reported, and the reaction
The classical 14C-labeled cyanation procedure utilizes Cu14CN as
the source of 14C-labeled cyanide.9a The cyanation reaction with
CuCN is known as the Rosenmund von Braun reaction and is
usually carried out at high temperatures (150–2501C) for long
reaction times (24 h or more).10 The development of a milder
N
N
a
Cl
Cl
N
N
2
3
Br
CN
Cl
Cl
O
O
c
b
N
N
NH
NH
4a
4a
Cl
Cl
O
O
d
N
N
N
N
N
N
N
N
Br
1a: R = CN
5
1b: R = 14CN
R
Scheme 2. Reaction conditions: a) Zn(CN)2, Pd(PPh3)4, DMF, 70 1C, 96%, b) iPrNEt, MeCN, rt, 73% for 1a, c) iPrNEt, MeCN, rt, 69%, d) Zn(14CN)2, Pd(PPh3)4, DMF, 70 1C,
chemical yield 88% and radiochemical yield 44% for 1b.
and general route to access aryl cyanides in the presence of temperature was in the range of 120–1501C.11b We found that
other sensitive functional groups would be highly desirable. In bromide 2 can be transformed to its cyanide 3 under a much
recent years, several transition-metal-mediated processes to milder (701C) condition. Reaction of 3 with 1-(3-chlorophenyl)-
transform an aryl halide to its cyanide have been developed piperazin-2-one (4a) is a known procedure9b and it provided the
with significant success; many of these use palladium or nickel product 1a in good overall yield. For the synthesis of 14C-labeled
complexes as catalysts together with inexpensive cyanide salts 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imida-
such as Zn(CN)2 NaCN or KCN.11 The aryl halides include iodide, zol-1-yl)methyl)-benzonitrile (1b), however, we adopted
a
bromide and even chloride.12 Current methodology involving different reaction sequence in which it consisted of only one
transition metal mediated cyanation reaction has been widely radiochemical step (the last step) (Scheme 2). Treatment of 2
used in both organic and medicinal chemistry.13 We found with 1-(3-chlorophenyl)piperazin-2-one (4a) gave bromide 5.
www.jlcr.org
Copyright r 2008 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2008, 51 399–403

J. Z. Ho et al.
Cl
Cl
O
O
N
N
R
N
R
N
NH
Cl
NH
O
M1 R=H
M2 R= O-sulfate
M3 R=OH
M4 R=H
M5 R=O-glucuronide
M6 R-OH
N
N
N
N
Cl
Cl
1b
14CN
O
O
N
O
N
NH
NH
M7
M8
Scheme 3. Metabolism of 1b results in non-radioactive metabolites.
Subsequent Pd-catalyzed cyanation of 5 with Zn(14CN)2 afforded Mitsunobu reaction15 and subsequent cyclization afforded the
the desired 14C-labeled tracer 1b. In this reaction, two key intermediate 4b with a 14C label located at the carbonyl
equivalents of Zn(14CN)2 were used. The chemical yield was carbon. The same chemistry used to prepare 1a from 4a in
88% based on the limited starting material bromide 5, and the Scheme 2 was followed to prepare 14C-labeled 1c from 14C-
radiochemical yield was 44% based on the excess Zn(14CN)2. labeled 4b. After preparative HPLC purification, a total of 2.1 mCi
After final purification with preparative HPLC, total of 4.7 mCi of of 1c was obtained in 64% yield at 97.6% radiochemical purity.
1b (99.4% radiochemical purity) was obtained as a free base. To
In conclusion, we reported two radiochemical synthesis of a
the best of our knowledge, this is the first example of palladium- 14C-labeled FPTase inhibitor 1b. The first synthesis used
catalyzed cyanation of an aryl bromide with 14C-labeled a Pd-catalyzed coupling of aryl bromide 5 and Zn(14CN)2.
Zn(14CN)2, although there are reports on cyanation of an aryl A second synthesis with bromo[1-14C]acetic acid provided
iodide with Zn(14CN)2 (or K14CN) in the literature.9c–d
labeled 1c, which was suitable for quantification of the
Metabolism of the tracer 1b resulted in many non-radioactive metabolites related to this program. The metabolite profile of
metabolites (Scheme 3),14 mainly arising from oxidative FPTase inhibitor 1 will be addressed in a separate publication.
cleavage of the molecule between the imidazole and piper-
azinone rings. To quantify these metabolites, we need to Experimental part
synthesize another 14C-labeled tracer where the 14C label should
be located in either the piperazinone ring or chlorophenyl
General
group. Based on the availability of radiochemical starting
materials and the evaluation of the synthetic strategies, we
Na14CN was obtained from NEN, Zn(14CN)2 and Bromo[1-14C]a-
decided to put the 14C label in piperazinone ring via the 14C-
cetic acid were obtained from American Radiolabeled
labeled intermediate 4b (Scheme 4).
Chemicals. Tetrakistriphenylphosphinepalladium (Pd(PPh3)4)
was obtained from Aldrich. Anhydrous solvents were obtained
Our second synthesis began with the conversion of commer-
cially available bromo[1-14C]acid 6 into the corresponding
bromo[1-14C]acetyl chloride (7) (Scheme 4). After coupling 7 with
3-chloroaniline, the intermediate 8 was immediately reacted with
ethanolamine to afford the aminoalcohol 9. An intramolecular
˚
from Aldrich and were dried over 4 A molecular sieves for at
least 24 h prior to use. 1H NMR spectra were recorded on a
Varian U-400 spectrometer in CD3CN, which was referenced to
1.93 ppm. Analytical HPLC was performed using a Shimadzu
Cl
Cl
O
*
O
O
*
O
*
d
c
b
a
Br
Br
Br
N
H
HO
N
Cl
*
H
NH
8
7
6
N
N
HO
9
Cl
Cl
Cl
O
*
O
*
3
N
N
CN
N
N
N
e
NH
4b
1c
* denotes 14C label
CN
Scheme 4. Reaction conditions: (a) Oxalyl chloride, CH2Cl2-DMF, 60%; (b) 3-Chloroaniline, KHCO3, iPrOAc-H2O; (c) Ethanolamine, iPrOAc, 99% over 2 steps; (d) PBu3, EtOAc,
Diisopropyl azodicarboxylate (DIAD), 65%; (e) Hunig’s base, MeCN, Preparative HPLC, 64%.
J. Label Compd. Radiopharm 2008, 51 399–403
Copyright r 2008 John Wiley & Sons, Ltd.
www.jlcr.org

J. Z. Ho et al.
HPLC system with LC-10ATVP pumps, a SPD-10AVP UV detector, (48 mg) and 14C labeled 1b (4.7 mCi) were dissolved in benzene
a CTO-10ASVP column oven heated to 301C, a SCL-10A (10 mL) to form a clear solution, to which a solution of HCl in
controller and a Packard RadiomaticTM 150TR flow monitor. EtOH (1 mL, 7% w/w) was added. After removal of solvent, the
The radioactive products were identified by HPLC comparison solid was re-crystallized from EtOAc (4.5 mL) and EtOH (0.5 mL)
with unlabeled reference material using either method A to give 1b (74 mg, 0.19 mmol, 3.72 mCi) as a white solid. The
(30–100% MeCN-0.1% aq. trifluoroacetic acid over 30 min, specific activity was determined to be 25.1 mCi/mmol by
ODS-AM) or method B (50% MeOH-0.1% aq. NEt3 over 45 min, gravimetric determination. HPLC analysis showed a radio-
Zorbax RX C8). All HPLC analyses were concluded with a 10 min chemical purity of 99.4% (Method B). 1H NMR: d 7.67 (d, 2H,
wash of 100% organic solvent.
J = 8.3 Hz), 7.63 (s, 1H), 7.37 (t, 1H, J = 8.1), 7.29 (t, 1H, J = 2.0 Hz),
7.26 (d, 1H, 8.1 Hz), 7.24 (d, 2H, J = 8.4 Hz), 7.15 (d, 1H, J = 8.1),
6.93 (s, 1H), 5.34 (s, 2H), 3.41 (s, 2H), 3.32 (t, 2H, J = 5.4), 3.03 (s,
2H), 2.61 (t, 2H, J = 5.5 Hz).
Zinc [14C]cyanide (Zn(14CN)2)
Although this reagent is a commercially available one, it can be
easily made as follows. Aqueous solution of MgCl2 (150 mL,
0.36 g/mL 0.58 mmol) was added to a solution of Na14CN (87 mg,
N-(3-chlorophenyl)-2-[(2-hydroxyethyl)amino][1-14C]acetamide (9)
1.7 mmol, 69 mCi, 40.6 mCi/mmol) in deionized water (1 mL). A solution of oxalyl chloride (59 mg, 0.47 mmol) in DMF (10 mL)
After stirring for 5 min, a small amount of white precipitate was was added to a suspension of bromo[1-14C]acetic acid (21 mCi,
formed and filtered. The filtrate was added to a solution of ZnCl2 0.39 mmol, 54.3 mCi/mmol) in CH2Cl2 (1 mL). The resulting
(251 mg, 1.84 mmol) in a mixed solvent of H2O (0.5 mL) and suspension was stirred at rt for 16 h to provide bromo[1-14C]a-
EtOH (0.5 mL). White precipitate started to form after stirring for cetyl chloride, and it was used immediately without further
0.5 h. Additional H2O (5 mL) was added to this suspension, and purification.
the mixture was stirred at room temperature for another 0.5 h.
A biphasic mixture of K2CO3 (66 mg, 0.66 mmol) in water
Solid was collected by vacuum filtration, washed with EtOH (1 mL) and 3-chloroaniline (60 mg, 0.47 mmol) in iPrOAc
(1 mL) then Et2O (2 mL), and dried at ambient temperature (3 mL) was stirred at 01C as above mentioned [14C]bromoacetyl
under a high vacuum (less than 1 mm of Hg) for 16 h to give chloride (21 mCi) in CH2Cl2 (1 mL) was added. The progress
Zn(14CN)2 (75 mg, 75%) as a white solid.
of the reaction was followed by HPLC and was judged
complete after 15 min. The aqueous layer was removed and
ethanolamine (95 mg, 1.56 mmol) in iPrOAc (0.3 mL) was
added. The reaction mixture was stirred at 601C for 3 h, then
water (1 mL) was added at 601C. The layers were separated
and the organic layer was dried (Na2SO4), filtered and
4-(1-[(4-bromophenyl)methyl]imidazol-5-ylmethyl)-1-(3-chlorophe-
nyl)-piperazin-2-one (5)
Hunig’s base (0.83 mL, 4.76 mmol) was added dropwise over
30 min to a suspension of piperazinone 4a (441 mg, 1.64 mmol)
and chloride 2 (421 mg, 1.54 mmol) in MeCN (2 mL) at 01C. The
resulting solution was warmed to rt and stirred overnight. The
solution was concentrated to afford a yellow oil, which was
purified by flash column chromatography on silica gel with 2%
MeOH in CH2Cl2 as an eluant. Product containing fractions were
combined, and solvent was removed under vacuum to give 5
(347 mg, 69%) as a white solid. The radiochemical purity was
1
concentrated to give 9 as a solid (91 mg, 21 mCi). H NMR:d7.45
(s, 1H), 7.41 (t, 1H, J = 8.0 Hz), 7.38 (d, 1H, J = 8.9 Hz) 7.28
(d, 1H, J = 7.9 Hz) 3.99 (s, 2H), 3.94 (t, 2H, J = 5.5 Hz), 3.66 (t, 2H,
5.5 Hz), 3.55 (br s, 2H).
1-(3-chlorophenyl)-[2-14C]-piperazin-2-one (4b)
A solution of ethanolamine 9 (5 mCi), Bu3P (109 mg) and
diisopropyl azodicarboxylate (DIAD, 109 mg) in EtOAc (0.5 mL)
was stirred at 01C. The progress of the reaction was monitored
by HPLC (method A), which indicated that this reaction was
completed in 0.5 h. MeOH (2 mL) was added and the reaction
mixture concentrated to near dryness. The residue was
purified by flash chromatography on silica gel (flash elute
40S column, 6% MeOH in CH2Cl2 with 0.1% of triethyl amine) to
give desired product 4b (3.3 mCi, 65%). 1H NMR:d7.43 (s, 1H),
7.43 (t, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.9 Hz) 7.29 (d, 1H,
J = 7.9 Hz) 3.99 (s, 2H), 3.94 (t, 2H, J = 5.5 Hz), 3.66 (t, 2H, 5.5 Hz),
1.61 (br s, 1H).
1
99.4% determined by HPLC (method A). H NMR: d 7.61 (s, 1H),
7.48 (d, 2H, J = 8.4 Hz), 7.37 (t, 1H, J = 7.9), 7.31 (t, 1H, J = 1.9 Hz),
7.27 (d, 1H J = 8.0 Hz), 7.18 (d, 1H, J = 8.0 Hz), 7.05 (d, 2H,
J = 8.4 Hz), 6.91 (s, 1H), 5.23 (s, 2H), 3.42 (s, 2H), 3.34 (t, 2H,
J = 5.2 Hz), 3.06 (s, 2H), 2.62 (t, 2H, J = 5.6 Hz).
4-[(5-[4-(3-chlorophenyl)-3-oxopiperazinyl]methylimidazolyl)-
methyl]-benzenecarbo-[14C]-nitrile hydrochloride (1b)
A
thoroughly degassed suspension of Zn(14CN)2 (26 mg,
0.21 mmol, 11 mCi, 110 mCi/mmol), bromide (129 mg,
5
0.21 mmol), and Pd(PPh3)4 (20 mg, 0.017 mmol) in DMF
(0.5 mL) was heated at 701C for 20 h. The reaction progress
was monitored by HPLC (method A). After being cooled to rt,
solvent was removed under vacuum and the residue was
dissolved in MeCN (2 mL) to give crude 1b (7.4 mCi) with 95%
radiochemical purity (method B). The sample was purified by
preparative HPLC (ODS-AM column, 22.1 Â 250 mm, 20 mL/min,
isocratic, 31% MeCN-69% H2O with 0.1% TFA) and the product
containing fractions were combined. MeCN was removed under
vacuum. After its pH was adjusted to 10 with saturated aqueous
Na2CO3, the solution was extracted with benzene (10 mL Â 3).
The combined organic layers were concentrated to provide 1b
(4.7 mCi) with 99.5% radiochemical purity. Unlabeled 1a14
4-[(5-[4-(3-chlorophenyl)-[3-14C]-3-oxopiperazinyl]methylimidazo-
lyl)-methyl]-benzenecarbonitrile hydrochloride (1c)
A solution of 4b (3.3 mCi), chloroimidazole 3 (18 mg, 0.7 mmol)
and diisopropylethyl amine (17 mg) in MeCN (1 mL) was stirred
at rt for 4 days. Solvent was removed under vacuum and the
residue was dissolved in MeCN-H2O-TFA (2, 2 and 0.1 mL,
respectively). The mixture was purified by preparative
HPLC (MeCN:H2O:TFA = 30:70:0.1; Zorbax RX C8 column
22.1 Â 250 mm, 20 mL/min). The product containing fractions
were combined, and aqueous NaHCO3 (2 mL) was used to adjust
the pH to 6.50. MeCN was removed under vacuum and the
www.jlcr.org
Copyright r 2008 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2008, 51 399–403

J. Z. Ho et al.
aqueous solution was extracted with EtOAc (50 mL Â 3) to give
1c (2.1 mCi, 64%). EtOAc was removed, and EtOH (10 mL) was
added. Final purity analysis showed the compound to have
[6] D. M. Leonard, J. Med. Chem. 1997, 40, 2971–2990.
[7] A. Oliff, Biochim. Biophys. Acta 1999, 1423(3), c19–c30.
[8] (a) R. Singh, I-W. Chen, L. Jin, M. V. Silva, B. H. Arison, J. H. Lin, B. K.
Wong, Drug Metab. Disp. 2001, 29, 1578–1587. (b) K. E. McCarthy,
Curr. Pharm. Des. 2000, 6, 1057–1083.
1
97.6% radiochemical purity (Method B). H NMR: d 7.67 (d, 2H,
J = 8.3 Hz), 7.63 (s, 1H), 7.37 (t, 1H, J = 8.1), 7.29 (t, 1H, J = 2.0 Hz),
7.26 (d, 1H, J = 8.1 Hz), 7.24 (d, 2H, J = 8.4 Hz), 7.15 (d, 1H, J = 8.1),
6.93 (s, 1H), 5.34 (s, 2H), 3.41 (s, 2H), 3.32 (t, 2H, J = 5.4), 3.03 (s,
2H), 2.61 (t, 2H, J = 5.5 Hz).
[9] (a) H. Matloubi, A. Shafiee, N. Saemian, G. Shirvani, F. J. Daha, J.
Label Compd. Radiopharm. 2004, 47, 31–36. (b) P. E. Maligres, M.S.
Waters, S. A. Weissman, J. C. McWilliams, S. Lewis, J. Cowen, R. A.
Reamer, R. P. Volante, R. J. Reider, D. Askin, J. Heterocycl. Chem.
2003, 40(3), 229–241. (c) K. M. Cable, G. N. Wells, D. R. Sutherland,
J. Label Compd. Radiopharm. 2000, 43, 29–45. (d) A. J. Allentoff, B.
Markus, T. Duelfer, A. Wu, L. Jones, G. Ciszewska, T. Ray, J. Label
Compd. Radiopharm. 2000, 43, 1075–1085.
Acknowledgement
[10] (a) K. W. Rothemund, E. Struck, Berichte der Deutschen Chemischen
Gesellschaft 1916, 52, 1749–1750. (b) J. von Braun, G. Manz, Justus
Liebig’s Annalen der Chemie 1931, 488, 111–113. (c) D. T. Mowry,
Chem. Rev. 1948, 42, 189–283. (d) G. P. Ellis, T. M. Romney-
Alexander, Chem. Rev. 1987, 87, 779–794.
[11] (a) M. Sundermeier, A. Zapf, M. Beller, Angew. Chem. Int. Ed. 2003,
42, 1661–1664. (b) P. E. Maligres, M. S. Waters, F. Fleitz, D. Askin,
Tetrahedron Lett. 1999, 40, 8193–8195.
J. Z. H. dedicates this paper to his Ph.D. advisor, Professor
Robert M. Coates, Ph.D., Department of Chemistry, University
of Illinois at Urbana-Champaign, Urbana, IL 61801, USA,
on the occasion of his 70th birthday. The authors thank Mr.
Steven Staskiewicz for analytical support, and Dr Romi Singh
and Dr Lixia Jin for performing the metabolism studies reported
herein. We thank Dr David Schenk for proof reading of the
manuscript.
[12] K. M. Marcantonio, L. F. Frey, Y. Liu, Y. Chen, J. Strine, B. Phenix, D.
J. Wallace, C. Chen, Org. Lett. 2004, 6, 3723–3725.
[13] (a) N. H. Khan, R. I. Kureshy, S. H. R. Abdi, S. Agrawal, R. V. Jasra,
Coord. Chem. Rev. 2008, 252, 593–623. (b) M. Sundermeier, A. Zapf,
M. Beller, Eur. J. Inorg. Chem. 2003, 19, 3513–3526. (c) A. Murray III,
D. L. Williams, Organic Synthesis With Isotopes, Interscience
Publishers Inc., New York, 1958, pp. 38–39. (d) R. Adams, I. Levine,
J. Am. Chem. Soc. 1923, 45, 2373–2377.
[14] (a) C. J. Dinsmore, C. B. Zartman, W. F. Baginsky, T. J. O’Neill, K. S.
Koblan, I-W. Chen, D. A. McLoughlin, T. V. Olah, J. R. Huff, Org. Lett.
2000, 2, 3473–3476. (b) H. D. Burns, W. S. Eng, R. E. Gibson, World
Patent 1999, WO 99:00654. (c) J. P. Davide, R. B. Lobell, World
Patent 2000, WO 00:70083.
References
[1] D. R. Lowry, B. M. Willumsen, Ann. Rev. Biochem. 1993, 62, 851–891.
[2] G. Bollag, F. McCormick, Ann. Rev. Cell Biol. 1991, 7, 601–632.
[3] P. J. Casey, P. A. Solski, C. J. Der, J. E. Buss, Proc. Nat. Acad. Sci. USA
1989, 86, 8323–8327.
[4] M. N. Ashby, D. S. King, J. Rine, Proc. Nat. Acad. Sci. USA 1992, 89,
4613–4617.
[15] S. Weissman, S. Lewis, D. Askin, R. P. Volante, P. J. Reider,
Tetrahedron Lett. 1998, 39, 7459–7462.
[5] S. Clarke, J. P. Vogel, R. J. Deschenes, J. Stock, Proc. Nat. Acad. Sci.
USA 1988, 85, 4643–4647.
J. Label Compd. Radiopharm 2008, 51 399–403
Copyright r 2008 John Wiley & Sons, Ltd.
www.jlcr.org