Discovery of a 1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity

Article abstract of DOI:10.1021/jm050392q

Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo biological activity of this interesting compound is also rep

Full text of DOI:10.1021/jm050392q

J. Med. Chem. 2005, 48, 5639-5643
5639
Letters
of the downstream substrates Shc, IRS-1, and IRS-2.
Signaling through these molecules results in activation
of the RAS/Raf/MAPK kinase pathway primarily re-
sponsible for mitogenesis and the antiapoptotic PI-3
kinase/Akt pathway.2,3 The ability of IGF-1R signaling
to affect these two major pathways in tumorigenesis has
contributed to the wide interest in finding agents to
block IGF-1R signaling. From a clinical perspective, epi-
demiological studies have correlated elevated IGF-I
levels with increased risk of developing colon, breast,
prostate, and lung tumors,4-8 highlighting the impor-
tance of IGF-1R signaling.
A major challenge in developing small-molecule an-
tagonists of IGF-1R is achieving selectivity over the
closely related insulin receptor (IR), which regulates
glucose homeostasis and the biosynthesis of glycogen
and fat. IGF-1R and IR share an 84% sequence identity
in the tyrosine kinase domain but are identical in the
ATP-binding cleft and the residues that contact the
peptide substrate in the substrate binding site. Se-
quence differences between IGF-1R and IR occur for the
most part on the surface of the enzymes, but a subtle
difference has been observed in the hinge region
(Thr1053/Arg1054 in IGF-1R vs Ala1080/His1081 in
IR).9 Because of the high homology of the ATP binding
site and the substrate binding site, a great deal of
interest has been focused on the development of mono-
clonal antibodies10 that selectively inhibit the binding
of IGF-I/IGF-II to the ligand binding domain of the
receptor. Recently, small-molecule pyrrolopyrimidine11
based antagonists of IGF-1R have been disclosed. These
compounds, while lacking in vitro kinase selectivity
between IGF-1R and IR, are reported to demonstrate
selectivity in a cellular context. In addition to pyrrolo-
pyrimidine inhibitors, selected tryphostin analogues12
and picropodophyllin13 have also been reported to have
selective IGF-1R inhibitory activity.
Despite the selectivity challenges and encouraged by
the growing clinical importance of IGF-1R signaling in
tumorigenesis, a research program was initiated to
identify small-molecule inhibitors of IGF-1R kinase.
The initial screening effort identified benzimidazole
1 as an ATP-competitive inhibitor of the IGF-1R kinase
(IC50 ) 3.5 µM). Cocrystallization of 1 with a truncated
IGF-1R containing the kinase domain confirmed that
the inhibitor bound in the ATP binding site. A key
feature of the binding is the hydrogen bond donor/
acceptor/donor triad formed between 1 and Met123 and
Glu121. Guided by the crystallographic information
(Figure 1), the benzimidazole methyl group and the
pyridone ring were explored as potential handles to
improve the potency of this chemotype against IGF-1R.
Examination of the binding interactions in the com-
plex of 1 with IGF-1R indicates that substitution of the
methyl group or the pyridone ring of 1 would allow
access to the open ribose binding pocket. Attempts to
Discovery of a
1H-Benzoimidazol-2-yl)-1H-pyridin-2-one
(BMS-536924) Inhibitor of Insulin-like
Growth Factor I Receptor Kinase with in
Vivo Antitumor Activity
Mark Wittman,*,† Joan Carboni,‡ Ricardo Attar,‡
Balu Balasubramanian,† Praveen Balimane,×
Patrick Brassil,# Francis Beaulieu,|
Chiehying Chang, Wendy Clarke,# Janet Dell,‡
Jeffrey Eummer,† David Frennesson,†
Marco Gottardis,‡ Ann Greer,‡ Steven Hansel,#
Warren Hurlburt,‡ Bruce Jacobson,
Subramaniam Krishnananthan,[ Francis Y. Lee,‡
Aixin Li,‡ Tai-An Lin,‡ Peiying Liu,† Carl Ouellet,|
Xiaopeng Sang,† Mark G. Saulnier,† Karen Stoffan,†
Yax Sun,∞ Upender Velaparthi,† Henry Wong,[
Zheng Yang,× Kurt Zimmermann,†
Mary Zoeckler,# and Dolatrai Vyas†
Discovery Chemistry, Department of Metabolism and
Pharmacokinetics, Department of Computer Aided Drug
Design, and Department of Chemical Synthesis,
Bristol-Myers Squibb Co, 5 Research Parkway,
Wallingford, Connecticut 06492, Discovery Chemistry,
Bristol-Myers Squibb Co, Candiac, Quebec, Canada, and
Department of Oncology Drug Discovery, Department of
Metabolism and Pharmacokinetics, Department of
Macromolecular Structure, Bristol-Myers Squibb Co, Route
206 and Province Line Road, Princeton, New Jersey 08540
Received April 25, 2005
Abstract: Compound 3 (BMS-536924), a novel small-molecule
inhibitor of the insulin-like growth factor receptor kinase with
equal potency against the insulin receptor is described. The
in vitro and in vivo biological activity of this interesting
compound is also reported.
Considerable attention has been focused on under-
standing the role of insulin-like growth factor I receptor
(IGF-1R) signaling in stimulating mitogenesis, trans-
formation to the oncogenic phenotype, and the anti-
apoptotic effects observed in malignant cells.1 Signaling
through IGF-1R is initiated upon the binding of the
IGF-I ligand to the receptor leading to receptor dimer-
ization, autophosphorylation, and subsequent activation
* To whom correspondence should be addressed. Phone: 203-677-
6318. Fax: 203-677-7702. E-mail: mark.wittman@bms.com.
† Discover Chemistry, Bristol-Myers Squibb Co., CT.
‡ Department of Oncology Drug Discovery, Bristol-Myers Squibb Co.,
NJ.
# Department of Metabolism and Pharmacokinetics, Bristol-Myers
Squibb Co., CT.
| Discovery Chemistry, Bristol-Myers Squibb Co., Canada.
Department of Macromolecular Structure, Bristol-Myers Squibb
Co., NJ.
[ Department of Chemical Synthesis, Bristol-Myers Squibb Co., CT.
× Department of Metabolism and Pharmacokinetics, Bristol-Myers
Squibb Co., NJ.
∞ Department of Computer Aided Drug Design, Bristol-Myers
Squibb Co., CT.
10.1021/jm050392q CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/06/2005

5640 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 18
Letters
Table 2. Kinase Selectivity and Cellular Activity of 3
IC50 a (nM)
IGF-1R
IR
FAK
100
73
150
Lck
341
CDK2/cyclic Eb
Akt1b
>1000
>5000
>5000
∼5000
1600
17100
182
MAPK1b
MAPK2b
EGF
Her2
Mek
Met
4870
>5000
1400
PDGFRb
VEGFR2
IGF-1R Sal16
RD1(rhabdomyosarcoma)
MDA PCa-2b (prostate)
Colo205 (colon)
Geo (colon)
MCF-7 (breast)
110
202
194
212
320
460
Figure 1. A 1.7 Å resolution X-ray structure of 1 with IGF-
1R.
a IC50 values were determined with ATP concentration at 1/2Km
for each kinase. b Values were determined from % inhibition at 1
or 5 µM.
Table 1. In Vitro Profile for Compounds 2 and 3
and saturated and unsaturated heterocycles were pre-
pared and profiled for kinase and cell potency, CYP
inhibition, and oral exposure. The morpholine group
represents the optimal balance between P450 inhibition,
in vitro potency, and oral exposure.15 Introduction of the
morpholine ring coupled with resolution of the hydroxyl
group enantiomers provided (S)-3 (BMS-536924). The
difference in potency between the enantiomers was
about 8-fold ((S)-3, 100 nM; (R)-3, 830nM).
IC50 (µm)
2
3
The in vitro kinase selectivity and cellular activity for
3 is presented in Table 2. Cross-reactivity is observed
for the insulin receptor with modest activity noted for
Mek, Fak, and Lck with very little activity for Akt1,
MAPK1/2.
IGF-1R
0.180
<0.018
<0.018
0.026
0.100
CYP1A2
34a
CYP2C9
CYP2C19
CYP2D6
CYP3A4-BFC
CYP3A4-BzRes
1.2a
2.0a
b
>40a
<0.018
<0.018
0.5a
5.3
The cellular activity of 3 was investigated using the
IGR-1R Sal cell line. This cell line is derived from
salivary tumors that develop in transgenic mice that
overexpress an IGF-1R/CD8 construct under the MMTV
promoter.16 Passage of the salivary tumor in nude mice
provided an IGF-1R driven in vivo model. The CD-8
fusion renders this cell line with a constitutively acti-
vated form of the IGF-1R kinase. Compound 3 ef-
fectively inhibits proliferation of this cell line in vitro
and disrupts Akt and MAPK phosphorylation. Com-
pound 3 blocks cellular proliferation in prostate, breast,
and colon tumor cell lines (Table 2) for which there is
ample evidence of the involvement of IGF-1R signaling
in vitro, in vivo, and clinically.4-7 Potency against a
rhabdomyosarcoma line (RD1) is noteworthy because
signaling of IGF-II through the IGF-1R in rhabdomyo-
sarcoma has been shown to be a significant factor
driving proliferation and metastasis in this tumor
type.17 The inhibition of Akt phosphorylation strongly
correlates with the inhibition of cell growth in vitro and
activity in vivo. In contrast, inhibition of MAPK phos-
phorylation did not correlate with cellular potency in
vitro or activity in vivo, suggesting that the antiprolif-
erative activity of 3 is consistent with inhibition of IGF-
1R primarily through the antiapoptotic Akt pathway.18
With in vitro activity consistent with IGF-1R inhibi-
a IC50 values represent an average of 10 determinations. b A
value could not be determined because of UV interference.
substitute the methyl group did not improve kinase
potency, so attention was redirected toward the pyri-
done ring. The description of 2-methoxy-3-formyl-4-
iodopyridine by Fang et al.14 suggested that a 4-iodo-
pyridone would provide a useful intermediate for ex-
ploring SAR at the 4-position. Using a 1,4 addition/
elimination reaction, a structurally diverse set of 4-ami-
no analogues were prepared. Potency improvements
were realized for C-4 primary amines with a one or two
carbon tether to an aromatic ring system. Additionally,
incorporation of a hydroxyl group in the tether improved
the in vitro kinase and cell potency. Further refinement
with various substituted 2-amino-1-phenylethanols led
to the identification of racemate 2 with an IC50 of 180
nM for IGF-1R.
The cytochrome P450 inhibition (Cyp) profile of 2 is
shown in Table 1. While Cyp inhibition is anticipated
for a compound with a pendent imidazole ring, the
potency exhibited across all the isozymes is surprising.
Replacement of the imidazole ring with various imid-
azole isosteres was examined. Amidines, imidazolines,

Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 18 5641
Table 3. Pharmacokinetics Parameters for 3 in Multiple
Speciesa
mouse
rat
iv/po dose (mg kg-1
Fpo (%)
)
4/20
50
3.8
37.8
1.9
4/50
>100
69
5.8
0.8
Cmax,po (µM)
CLtot (mL min-1 kg-1
)
Vss (L kg-1
)
dog
monkey
iv/po dose (mg kg-1
Fpo (%)
)
2/5
70
4.1
4.1
1.3
2/5
32
1.3
16.5
1.4
Cmax,po (µM)
CLtot (mL min-1 kg-1
)
Vss (L kg-1
)
a Administered as a solution in PEG400/water (80:20 v/v).
Figure 2. Efficacy of 3 in Colo205 (human colon carcinoma).
schedule (100-300 mpk) or a twice a day schedule (50,
100 mpk) demonstrated antitumor activity in this tumor
model.
With in vivo activity demonstrated for 3, the potential
disruption of glucose homeostasis by 3 arising from
inhibition of the IR could be evaluated in an in vivo
context. An oral glucose tolerance test (OGTT) was
performed following 21 days of dosing in the Colo205
efficacy experiment (Figure 3). The active doses of 50
and 100 mpk (b.i.d.) did not cause a significant elevation
in glucose levels prior to glucose challenge. However,
after glucose challenge a significant elevation in glucose
levels is observed at the 100 mpk dose. While there is
no IGF-1R/IR selectivity in the in vitro kinase assay,
there is a 2-fold window between antitumor efficacy and
glucose elevation observed in vivo. Insulin levels 2 h
after glucose challenge did show a dose-dependent
increase over vehicle control. While it would appear that
the hyperglycemia and hyperinsulinemia observed are
a direct result of IR inhibition, the role of Akt inhibition
cannot be dismissed because Akt-2 knockout animals
show similar effects on glucose and insulin levels.19
The pharmacokinetic parameters of 3, administered
orally in poly(ethylene glycol) 400 and water (80:20 v/v),
were determined in mouse, rat, dog, and monkey (Table
3). Good bioavailability is evident in all species. Sig-
nificant nonlinear pharmacokinetics is observed in
rodents at increasing po dose (greater than dose pro-
Figure 3. OGTT results following 21 days of dosing. Final
dose of 3 was given on day 21 of the Colo205 efficacy
experiment, and glucose levels (ng/mL) were measured for 2
h (240, 120, and 0 min). A glucose bolus was given at t ) 0,
and glucose levels (mg/dL) were measured every 30 min.
tion and favorable oral exposure, the in vivo activity of
3 could be investigated. Beginning with the constitu-
tively activated IGR-1R Sal tumor model described
previously, strong in vivo activity could be demonstrated
following oral administration of 100-300 mpk once a
day for 14 days.16 Efficacy is also observed in the
nonengineered Colo205 human colon carcinoma model
(Figure 2). Oral administration of 3 on a once a day
Scheme 1a
a (a) Morpholine, 2.5% Pd2(dba)3, 5% 2-[(t-C4H9)2P]biphenyl, NaOt-Bu, THF, reflux (61%); (b) Pd(OH)2C, MeOH, 60 psi of H2; 6, MeOH
(63%); (c) 4 N HCl, dioxane (quantitative); (d) 9, Et3N, CH3CN, 85 °C (75%).

5642 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 18
Letters
(5) (a) Hankinson, S. E.; Willett, W. C.; Colditz, G. A.; Hunter, D.
J.; Michaud, D. S.; Deroo, B.; Rosner, B.; Speizer, F. E.; Pollak,
M. Circulating concentrations of insulin-like growth factor-I and
risk of breast cancer. Lancet 1998, 351, 1393-1396. (b) Martin,
J. L. In Insulin-Like Growth Factors; LeRoith, D., Zumkeller,
W., Baxter, R. C., Eds.; Landes Bioscience, Georgetown, TX,
2003; pp 367-384.
(6) Chan, J. M.; Stampfer, M. J.; Giovannucci, E.; Gann, P. H.; Ma,
J.; Wilkinson, P.; Hennekens, C. H.; Pollak, M. Plasma insulin-
like growth factor-I and prostate cancer risk: a prospective
study. Science (Washington, D.C.), 1998, 279, 563-566.
(7) Wolk, A.; Mantzoros, C. S.; Andersson, S. O.; Bergstrom, R.;
Signorello, L. B.; Lagiou, P.; Adami, H. O.; Trichopoulos, D.
Insulin-like growth factor 1 and prostate cancer risk: a popula-
tion-based, case-control study. J. Natl. Cancer Inst. 1998, 90,
911-915.
portional increases in AUC). Greater than 100% bio-
availability at higher po doses suggests that 3 can
saturate clearance (elimination) pathways. The total
body clearance is moderate in mouse and monkey and
low in rat and dog with moderate to high tissue
distribution in all species. Compound 3 was adminis-
tered to bile duct cannulated rats (10 mpk, iv, in
PEG400 and water 80:20 by volume). Less than 5% of
the parent drug is eliminated in bile and urine, with
the major metabolites being associated with oxidation
and cleavage of the morpholine ring. Compound 3 is
highly protein bound (>99% in mouse and human
plasma).
Compound 3 is prepared starting from the commer-
cially available nitroaniline 4 (Scheme 1). Palladium-
catalyzed amination of 4 with morpholine20 provides
nitroaniline 5. Reduction to the diamine followed di-
rectly by addition of aldehyde 614 gives the desired
benzimidazole 7 without the need for the addition of
oxidant. There was no obvious benefit in yield when
oxidants such as iodine are added. Cleavage of the
methoxy group of 7 occurs smoothly under acidic condi-
tions to provide the 4-iodopyridone 8 along with varying
amounts of the 4-chloropyridone 8′. The 4-chloropyri-
dones and 4-iodopyridones participate in the addition/
elimination reaction with various amines including the
chiral amino alcohol 9. Amino alcohol 9 is prepared from
the known R-chloroketone21 using a chiral oxazaboro-
lidine22 catalyzed reduction followed by stirring in 7 M
ammonia/methanol solution. The resulting hydrochlo-
ride can then be crystallized to high enantiomeric
purity. Compound 3 is then converted to the mono-HCl
salt for biological and pharmacokinetics evaluation.
(8) Yu, H.; Spitz, M. R.; Mistry, J.; Gu, J.; Hong, W. K.; Wu, X.
Plasma levels of insulin-like growth factor-I and lung cancer
risk: a case-control analysis. J. Natl. Cancer Inst. 1999, 91, 151-
156.
(9) Favelyukis, S.; Till, J. H.; Hubbard, S. R.; Miller, W. T. Nat.
Struct. Biol. 2001, 8, 1058-1063.
(10) Burtrum, D.; Zhu, Z.; Lu, D.; Anderson, D. M.; Prewett, M.;
Pereira, D. S.; Bassi, R.; Abdullah, R.; Hooper, A. T.; Koo, H.;
Jimenez, X.; Johnson, D.; Apblett, R.; Kussie, P.; Bohlen, P.;
Witte, L.; Hicklin, D. J.; Ludwig, D. L. A fully human monoclonal
antibody to the insulin-like growth factor I receptor blocks
ligand-dependent signaling and inhibits human tumor growth
in vivo. Cancer Res. 2003, 63, 8912-8921.
(11) (a) Garcia-Echeverria, C.; Pearson, M. A.; Marti, A.; Meyer, T.;
Mestan, J.; Zimmermann, J.; Gao, J.; Brueggen, J.; Capraro, H.
G.; Cozens, R.; Evans, D. B.; Fabbro, D.; Furet, P.; Porta, D. G.;
Liebetanz, J.; Martiny-Baron, G.; Ruetz, S.; Hofmann, F. In vivo
antitumor activity of NVP-AEW541sA novel, potent, and selec-
tive inhibitor of the IGF-1R kinase. Cancer Cell 2004, 5, 231-
239. (b) Mitsiades, C. S.; Mitsiades, N. S.; McMullan, C. J.;
Poulaki, V.; Shringarpure, R.; Akiyama, M.; Hideshima, T.;
Chauhan, D.; Joseph, M.; Libermann, T. A.; Garcia-Echeverria,
C.; Pearson, M. A.; Hofmann, F.; Anderson, K. C.; Kung, A. L.
Inhibition of the insulin-like growth factor receptor-1 tyrosine
kinase activity as a therapeutic strategy for multiple myeloma,
other hematologic malignancies, and solid tumors. Cancer Cell
2004, 5, 221-230.
(12) Blum, G.; Gazit, A.; Levitzki, A. Development of new insulin-
like growth factor-1 receptor kinase inhibitors using catechol
mimics. J. Biol. Chem. 2003, 278, 40442-40454.
(13) Girnita, A.; Girnita, L.; del Prete, F.; Bartolazzi, A.; Larsson,
O.; Axelson, M. Cyclolignans as inhibitors of the insulin-like
growth factor-1 receptor and malignant cell growth. Cancer Res.
2004, 64, 236-242.
(14) Fang, F. G.; Xie, S.; Lowery, M. W. Catalytic enantioselective
synthesis of 20(S)-camptothecin: A practical application of the
sharpless asymmetric dihydroxylation reaction. J. Org. Chem.,
1994, 59, 6142-6143.
The discovery of BMS-536924 (3) represents a novel
class of IGF-1R inhibitor with cellular and in vivo
activity. This compound represents a useful tool for
further understanding of the biological effects of IGF-
1R inhibition.
Acknowledgment. The authors thank David R.
Langley for generating Figure 1, the Lead Profiling
Department for generating the CYP inhibition data, and
the analytical departments for the analytical data
presented herein.
(15) Oral exposure was determined using a coarse pharmacokinetics
screen. Screening was accomplished by dosing three mice per
group with 20 mg/kg in 80:20 PEG400/water (v/v). Serum
concentrations were determined at 30 min, 1 h, and 4 h.
(16) Carboni, J. M.; Lee, A. V.; Hadsell, D. L., Rowley, B. R.; Lee, F.
Y.; Bol, D. K.; Camuso, A. E.; Gottardis, M.; Greer, A. F.; Ho, C.
P.; Hurlburt, W.; Li, A.; Saulnier, M.; Velaparthi, U.; Wang, C.;
Wen, M.-L.; Westhouse, R. A.; Wittman, M.; Zimmermann, K.;
Rupnow, B. A., Wong, T. W. Tumor development by transgenic
expression of a constitutively active insulin-like growth factor-1
receptor. Can. Res. 2005, 65, 3781-3787.
Supporting Information Available: Experimental de-
tails and analytical data for 3 and 5-9. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) (a) Kalebic, T.; Tsokos, M.; Helman, L. J. In vivo treatment with
antibody against IGF-I receptor suppresses growth of human
rhabdomyosarcoma and down-regulates p34cdc2. Cancer Res.
1994, 54, 5531-5534. (b) Navid, F.; Helman, L. J. In Insulin-
Like Growth Factors; LeRoith, D., Zumkeller, W., Baxter, R. C.,
Eds.; Landes Bioscience, Georgetown, TX, 2003; pp 390-
398.
(18) Tai-An, L. A more complete discussion will be presented in a
manuscript to be submitted. Compound 3 does not have a direct
effect on MAPK or Akt (see Table 2). In some cells lines where
proliferation could be inhibited at <1 µM, no evidence of MAPK
inhibition was observed, suggesting that MEK inhibition is not
a significant contributor to the activity observed in vitro or in
vivo.
(19) Garofalo, R. S.; Orena, S. J.; Rafidi, K.; Torchia, A. J.; Stock, J.
L.; Hildebrandt, A. L.; Coskran, T.; Black, S. C.; Brees, D. J.;
Wicks, J. R.; McNeish, J. D.; Coleman, K. G. Severe diabetes,
age-dependent loss of adipose tissue, and mild growth deficiency
in mice lacking Akt2/PKBΒ. J. Clin. Invest. 2003, 112, 197-
208.
References
(1) Grothey, A.; Voigt, W.; Schober, C.; Muller, T.; Dempke, W.;
Schmoll, H. J. The role of insulin-like growth factor I and its
receptor in cell growth, transformation, apoptosis, and chemo-
resistance in solid tumors. J. Cancer Res. Clin. Oncol. 1999, 125,
166-173.
(2) Vicentini, L. M.; Zhou, M.; Daly, R.; Myers, M. J., Jr.; Backer,
J. M.; Ullrich, A.; White, M. F.; Schlessinger, J.; Skolnik, E. Y.;
Lee, C. H.; Batzer, A. The SH2/SH3 domain-containing protein
GRB2 interacts with tyrosine-phosphorylated IRS-1 and Shc:
implications for insulin control of ras signaling. EMBO J. 1993,
12, 1929-1936.
(3) Vanhaesebroeck, B.; Alessi, D. R. The PI3K-PDK1 connection:
more than just a road to PKB. Biochem. J. 2000, 346, 561-576.
(4) Ma, J.; Pollak, M. N.; Giovannucci, E.; Chan, J. M.; Tao, Y.;
Hennekens, C. H.; Stampfer, M. J. Prospective study of colorectal
cancer risk in men and plasma levels of insulin-like growth factor
(IGF)-I and IGF-binding protein-3. J. Natl. Cancer Inst. 1999,
91, 620-625.

Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 18 5643
(20) Marcoux, J.-F.; Wagaw, S.; Buchwald, S. L. Palladium-catalyzed
amination of aryl bromide: Use of phosphinoether ligands for
the efficient coupling of acyclic secondary amines. J. Org. Chem.
1997, 62, 1568-1569.
(21) Devocelle, M.; Mortreux, A.; Agbossou, F.; Dormoy, J.-R. Alter-
native synthesis of the chiral atypical â-adrenergic phenyl-
ethanolaminotetraline agonist SR58611A using enantioselective
hydrogenation. Tetrahedron Lett. 1999, 40, 4551-4554. A modi-
fied procedure was used in which methanol was added to greatly
enhance the yield of the desired R-chloroketone.
(22) Corey, E. J.; Shibata, S.; Bakshi, R. K. An efficient and
catalytically enantioselective route to (S)-(-)-phenyloxirane. J.
Org. Chem. 1988, 53, 2861-2863.
JM050392Q