Heterotricyclic himbacine analogs as potent, orally active thrombin receptor (protease activated receptor-1) antagonists

Article abstract of DOI:10.1021/jm070704k

Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several p

Full text of DOI:10.1021/jm070704k

J. Med. Chem. 2007, 50, 5147-5160
5147
Heterotricyclic Himbacine Analogs as Potent, Orally Active Thrombin Receptor (Protease
Activated Receptor-1) Antagonists
Mariappan V. Chelliah,*,† Samuel Chackalamannil,† Yan Xia,† Keith Eagen,† Martin C. Clasby,† Xiaobang Gao,†
William Greenlee,† Ho-Sam Ahn,‡ Jacqueline Agans-Fantuzzi,‡ George Boykow,‡ Yunsheng Hsieh,§ Matthew Bryant,§
Jairam Palamanda,§ Tze-Ming Chan,| David Hesk, and Madhu Chintala‡
Central NerVous System and CardioVascular Chemical Research, CardioVascular and Metabolic Disease Research, Drug Metabolism and
Pharmacokinetics Research, Department of Analytical Spectroscopy, and Radiochemistry, Schering-Plough Research Institute,
2015 Galloping Hill Road, Kenilworth, New Jersey 07033
ReceiVed June 18, 2007
Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesized
a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has
resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin
receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo
model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark
compound in this series, with a Ki of 4.3 nM, is presented.
Introduction
there exists an unmet clinical need for novel, orally active
antiplatelet agents.
Platelet activation plays an important role in arterial
thrombosis.1-3 When the rupture of a vulnerable atherosclerotic
plaque occurs, platelets are recruited to the site of injury where
they form an initial haemostatic plug by binding to von
Willebrand factor and collagen. Further activation of platelets
by collagen and thrombin in the local milieu causes platelet
shape changes and the release of platelet activating granular
contents, which in turn amplify the platelet activation process.
Activated platelets express GpIIb/IIIa receptors on their surfaces
which bind to fibrinogen causing platelets to aggregate. Ag-
gregated platelets are trapped by fibrin meshwork, produced
by thrombin-mediated cleavage of fibrinogen, to form a rapidly
growing thrombus that further traps red blood cells and other
plasma particles, leading to an occlusive clot that can result in
unstable angina and myocardial infarction.
Besides its central role in hemostasis and wound healing,
thrombin activates platelets and other cell types via proteolytic
activation of specific cell-surface receptors known as protease
activated receptors (PARs).7-12 PARs are activated by a unique
“tethered ligand mechanism” in which a proteolytic enzyme such
as thrombin cleaves the extracellular domain of the receptor
and the newly unmasked amino terminus binds to the proximally
located transmembrane loop of the GPCR, eliciting intracellular
signaling.13-16 Four PARs are known, PAR-1, PAR-2, PAR-3,
and PAR-4. PAR-1, PAR-3, and PAR-4 are activated by
thrombin, and PAR-2 is activated by trypsin. PAR-1, also known
as the thrombin receptor, is the major thrombin-activated
receptor on human and monkey platelets. PAR-4 is a second
thrombin receptor on human and monkey platelets, but it is
activated only at high thrombin concentration, as in the case of
a severe injury. PAR-3 and PAR-4 are the major protease
activated receptors on rodent platelets. Because thrombin is the
most potent activator of human platelets, a thrombin receptor
antagonist (TRA) is expected to show potent antiplatelet effects.
Antiplatelet drugs constitute an integral part of antithrombotic
therapy.4,5 Platelets are activated by a variety of agonists such
as thrombin, ADP,a thromboxane A2, epinephrine, collagen, and
so on. Among these, thrombin is the most potent activator of
platelets. The most widely used antiplatelet agents are ADP
antagonists such as clopidogrel, thromboxane A2 biosynthetic
inhibitors, such as aspirin, and GpIIb/IIIa antagonists, which
inhibit platelet aggregation irrespective of the mode of activation
of the platelets. Among these three classes of antiplatelet agents,
ADP antagonists and aspirin have a relatively modest level of
potency. However, several of them have the advantage of being
orally active. The GpIIb/IIIa antagonists are potent antiplatelet
agents; however, the currently used GpIIb/IIIa antagonists are
all IV formulations. Efforts to achieve orally active GpIIb/IIIa
antagonists have uniformly failed in clinical trials.6 Therefore,
We have reported potent, orally active thrombin receptor
(PAR-1) antagonists 1 and 2 based on the structure of the natural
product himbacine.17,18 Compared with previously known
peptide-mimetic19-21 and nonpeptide22-24 antagonists, these
compounds are high affinity thrombin receptor antagonists (1,
Ki ) 2.7 nM; 2, Ki ) 8.7 nM) with excellent oral efficacy in
an ex vivo platelet aggregation model in cynomolgus monkeys.
Although the enzyme induction issues surrounding the earlier
* To whom corresondence should be addressed. Tel.: 908-740-7261.
Fax: 908-740-7164. E-mail: mariappan.chelliah@spcorp.com.
† Central Nervous System and Cardiovascular Chemical Research.
‡ Cardiovascular and Metabolic Disease Research.
§ Drug Metabolism and Pharmacokinetics Research.
| Department of Analytical Spectroscopy.
Radiochemistry.
a Abbreviations: ADP, adenosine diphosphate; GPCR, G-protein-coupled
receptor; PAR, protease activated receptor; TRAP, thrombin receptor
activating peptide.
10.1021/jm070704k CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/14/2007

5148 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Chelliah et al.
Scheme 1a
a Reagents and conditions: (a) (EtO)2P(O)CH2CO2Me, NaHMDS, THF, 58%; (b) KOH, THF-MeOH-H2O, 97%; (c) 7, DCC, DMAP, 41%; (d) toluene,
200 °C, 6 h; (e) DBU, rt, 69% from 9; (f) BBr3, CH2Cl2, 89%; (g) 40psi H2, PtO2, MeOH-AcOH, 79%; (h) (COCl)2, cat. DMF, CH2Cl2; (i) Bu3SnH,
Pd(PPh3)4, toluene, 80% from 13; (j) BuLi, THF, then 14, 91%; (k) NaBO3·4H2O, MeSO3H, AcOH.
Scheme 2a
a Reagents and conditions: (a) (EtO)2P(O)CH2CO2Et, NaH, THF; (b) KOH, THF-MeOH-H2O (90%, 2 steps); (c) (COCl)2, cat. DMF, then 21, DMAP,
Et3N (78%); (d) H2, Lindlar catalyst, quinoline; (e) m-xylene, 185 °C, 6 h; (f) DBU, rt (56%, 3 steps); (g) 1 atm H2, Pd-C, EtOAc; (h) 50 psi H2, PtO2,
MeOH (96%, 2 steps); (i) (COCl)2, cat. DMF, CH2Cl2; (j) Bu3SnH, Pd(PPh3)4, toluene (83%-91%, 2 steps); (k) 26, BuLi, THF, then 25a,b; (l) 32, LHMDS,
Ti(Oi-Pr)4 then 25b; (m) ArB(OH)2, Pd(PPh3)4, K2CO3; (n) 28, TMSI, CH2Cl2; (o) acid chlorides, chloroformates, isocyanates, and sulfonyl chlorides, Et3N;
(p) BuLi, toluene then DMF; (q) NaBH4 (51%, 2 steps); (r) MsCl, Et3N, CH2Cl2; (s) NaH, HP(O)(OEt)2, THF (97%, 2 steps).

Himbacine Analogs as Thrombin Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21 5149
Scheme 3a
a Reagents and conditions: (a) n-BuLi, EtOCOCl, THF, -78 °C-rt (99%); (b) LHMDS, 2-[N,N-bis(trifluoromethylsulfonyl)-amino]-5-chloropyridine,
THF, -78 °C-rt (61%); (c) 35, Pd(OAc)2, 2-(di-t-butylphosphino)biphenyl, KF, THF, 55 °C (89%); (d) NaOH, H2O, MeOH, THF (93.5%); (e) DCC, ppy,
8, CH2Cl2 (66%); (f) m-xylene 150 °C; (g) DBU, THF (46%, 2 steps); (h) Pd(C), H2, EtOAc; (i) PtO2, H2 (50 psi), MeOH (98%, 2 steps); (j) (COCl)2, DMF
(1 drop), CH2Cl2; (k) Pd(Ph3P)4, Bu3SnH, PhMe, 0 °C-rt (60%, 2 steps); (l) 32, LHMDS, Ti(Oi-Pr)4, THF, 0 °C-rt (75%); (m) Pd(Ph3P)4, K2CO3, ArB(OH)2,
PhMe/EtOH/H2O (65%).
Table 1. Binding Data for 16, 17, 18a,b, 27a-g, 28a, 43a-e
cmpd
X
Y
Ar
IC50 (nM) ( SEMa
rat AUCb
16
17
S
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
NCO2Et
NCO2Et
NCO2Et
NCO2Et
NCO2Et
(m-CF3)-phenyl
(m-CF3)-phenyl
(m-CF3)-phenyl
(m-CF3)-phenyl
(m-CF3)-phenyl
(m-F)-phenyl
22 ( 6.5
200 ( 0
SO2
SO
SO
O
O
O
O
O
O
O
NCO2Et
CH2
CH2
CH2
CH2
CH2
18a
18b
27a
27b
27c
27d
27e
27f
27g
28a
43a
43b
43c
43d
43e
80 ( 20
375 ( 125
17 ( 1.5
26 ( 2.1
25 ( 6.6
26 ( 6.5
19 ( 1.0
13 ( 3.0
21 ( 0.5
11 ( 0
224 ( 73.5
153 ( 16.5
600 ( 101
295 ( 81.5
inactive
545
850
1050
1190
(o-F)-phenyl
(o,m-difluoro)-phenyl
(m-Cl)-phneyl
(o-Cl)-phneyl
(o,m-dichloro)-phenyl
(m-CF3)-phenyl
(m-F)-phenyl
(o-F)-phenyl
(o-Me)-phenyl
(m-CN)-phenyl
m-pyridyl
a n ) 2 or more. b AUC from 0 to 6 h in ng‚hr/mL, following a 10 mg/kg oral dose (0.4% methylcellulose).
compound 1 were effectively addressed by the discovery of the
second generation compound 2, the latter compound showed a
less than optimal clearance profile.25 Compound 2 also generated
a considerable amount of 7,8-dihydroxy metabolites such as 3.
This prompted us to identify a replacement candidate for 2 with
an improved metabolic profile. In this pursuit, we decided to
incorporate heteroatoms into the C-ring of the tricyclic motif
to prepare analogs represented by structure 4. In addition to
potentially altering the metabolic pattern of the C-ring, this
approach would increase the overall polarity of these com-
pounds.
Synthesis
The synthesis of tetrahydrothiopyranyl derivatives represented
by structures 16-18b is shown in Scheme 1. The synthesis
started with the known26 enal 5, which was subjected to the

5150 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Chelliah et al.
Figure 1. Ex vivo platelet aggregation inhibition in cynomolgus monkey, following a single oral dose (1 mg/kg in 20% PEG-HPBCD) of 27b and
27c.
Horner-Wadsworth-Emmons reaction using methyl dieth-
ylphosphonoacetate to give the ester 6, which was hydrolyzed
to the dienoic acid 7. The Diels-Alder precursor 9 was obtained
by coupling the dienoic acid 7 and alcohol 8, which was
prepared from optically active (R)-3-butyn-2-ol,27 as described
before.18 Intramolecular Diels-Alder reaction of 9 at 200 °C
yielded the exo-adduct 10 as the major product. Based on our
previous work, the facial selectivity of this reaction is attributed
to the 1,3-allylic strain induced by the C3-methyl group of the
dienophile.28 The trans-lactone 10 was epimerized in situ with
DBU to provide the cis-lactone 11. Debenzylation under Lewis
acid conditions followed by hydrogenation over platinum oxide
gave the tricyclic acid 13. Conversion of acid 13 to aldehyde
14 was achieved by the reduction of the corresponding acid
chloride with Bu3SnH under palladium catalysis.29 Finally,
coupling of the aldehyde with the known18 phosphonate 15 gave
the desired target 16. When 16 was oxidized with sodium
perborate, it gave a mixture consisting of sulfone 17 and the
sulfoxides 18a and 18b, which were separated by silica gel
chromatography.
The synthesis of tetrahydropyranyl and the decahydroiso-
quinoline derivatives is outlined in Scheme 2. Enals 19a and
19b were converted to the corresponding dienoic acids 20a and
20b and esterified with the alcohol 2118 to give alkynes 22a
and 22b, respectively. Lindlar reduction followed by thermal
cyclization and base-catalyzed epimerization gave 23a and 23b,
which were subsequently subjected to debenzylation and double
bond reduction to give the corresponding acids 24a and 24b.
Conversion of the acids to the corresponding acid chlorides,
followed by reduction with tributyltin hydride, gave aldehydes
25a and 25b. The aldehydes were subjected to the Horner-
Wadsworth-Emmons reaction using the phosphonate 26 to give
tetrahydropyranyl derivative 27 and the decahydroisoquinoline
derivative 28, respectively. Alternatively, the aldehyde 25b can
be coupled with the bromo-substituted phosphonate 32 to give
29, which can be subsequently coupled with aryl boronic acids
under Suzuki coupling conditions to give 28. Phosphonates,
represented by 26, with appropriately substituted aryl groups,
were prepared using procedures similar to the preparation of
15 described previously.18 Phosphonate 32 was prepared from
2,5-dibromopyridine, which was subjected to selective lithiation
at the 2-position followed by quenching with dimethyl forma-
mide.30 The resultant aldehyde was reduced with sodium
borohydride to give the alcohol 31. The alcohol 31 was
converted to the phosphonate 32 via its mesylate. To study the
effect of substitution on the nitrogen of the decahydroisoquino-
Scheme 4
line analogs (30), the ethyl carbamate group of 28 was cleaved
using iodotrimethylsilane, and the resultant amine was subse-
quently derivatized with acid chlorides, chloroformates, isocy-
anates, and sulfonyl chlorides to prepare the corresponding
amides, carbamates, ureas, and sulfonamides, respectively.
The synthesis of isomeric decahydroquinoline derivatives
represented by 43 (Scheme 3) started with δ-valerolactam, which
was protected as ethylcarbamate 33 and then converted to the
vinyl triflate 34. Initially we attempted to form dienoic ester
36 via a Heck reaction of 34; this was met with limited success,
generally resulting in low chemical yields. However, we found
that coupling of the vinyl boronic ester 35 with 34 using
potassium fluoride31 as base led to good yields of the desired
product in a reproducible manner. Coupling of an analogous
vinyl tin reagent was moderately successful, but required more
time-consuming purifications and was consequently less repro-
ducible. Hydrolysis of 36 led to the dienoic acid 37, which was
subsequently converted to the target compounds represented by
43 using the route described in Scheme 3.
Results and Discussion
The in vitro binding assays were carried out on human platelet
membrane-derived PAR-1 receptors using a tritiated high affinity
thrombin receptor activating peptide ([3H]haTRAP]) as de-
scribed previously.32 The tetrahydrothiopyran analog 16 (Table
1) showed good binding affinity (IC50 ) 21.5 nM), which is
comparable to the corresponding carbocyclic analog 1 (IC50
)
11 nM). Because 16 is likely to undergo in vivo oxidation by
liver P450 enzymes to sulfoxides and sulfone, we also evaluated
these potential metabolites in the binding assay. Although the
incorporation of the sulfur atom in the ring is well-tolerated, as
indicated by the binding affinity of 16, the corresponding sulfone
17 and the sulfoxides 18a and 18b showed reduced binding

Himbacine Analogs as Thrombin Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21 5151
Table 2. Binding Data for 28b-d and 30a-m
cmpd
Ar
R
IC50 (nM) ( SEM (n ) 2)
10.5 ( 1.5
ex vivoa
rat AUCb
2220
28b
(m-F)-phenyl
CO2Et
CO2Et
CO2Et
100% (6 h),
70% (24 h)
55% (6 h),
55% (24 h)
67% (6 h),
29% (24 h)
28c
28d
(o-F)-phenyl
o-pyridyl
8.0 ( 1.0
3780
33.5 ( 14.0
30a
30b
30c
30d
30e
30f
(m-CF3)-phenyl
(m-CF3)-phenyl
(m-CF3)-phenyl
(m-CF3)-phenyl
(m-CF3)-phenyl
(m-F)-phenyl
H
Me
COMe
COi-Pr
COCypr
COCypr
600 ( 300
762 ( 336
550 ( 50
113 ( 8.0
37.5 ( 7.5
15.5 ( 4.5
100% (6 h),
72% (24 h)
45% (6 h),
39% (24 h)
4370
6010
30g
(o-F)-phenyl
COCypr
8.0 ( 2.0
30h
30i
(m-F)-phenyl
(m-F)-phenyl
CONH2
CONHEt
1101 ( 351
18.5 ( 6.5
47% (6 h),
34% (24 h)
54% (6 h),
50% (24 h)
2050
5350
30j
(m-F)-phenyl
SO2Me
15.0 ( 5.0
30k
30l
30m
(m-F)-phenyl
(m-CF3)-phenyl
(m-F)-phenyl
SO2Pr
CO2Bn
CO2C2H4OMe
101 ( 52.0
25 ( 4.0
16.5 ( 2.5
88
a Reduction in haTRAP induced platelet aggregation in c. monkey following a 3 mg/kg oral dose (20% PEG-HPBCD). b AUC from 0 to 6 h in ng‚hr/mL
and at 10 mg/kg oral dose (0.4% methylcellulose).
affinity. As a result, this series was not pursued further. The
incorporation of oxygen also was well-tolerated, as indicated
by the in vitro binding potencies for compound 27a-g (Table
1). Both ortho- and meta-substituted biaryl analogs showed good
potency. The chloro and fluoro substitutions at the ortho- and
the meta-positions (27a-c; 27e,f) as well as the 2,3-dichloro
and 2,3-difluoro substitutions (27d, 27g) were well-tolerated.
The in vitro affinity of this series is comparable to that of the
carbocyclic analog 1.17 The incorporation of a nonbasic nitrogen
at the 7-position is well-tolerated, as indicated by the excellent
potency of the ethylcarbamate analog 28a. Moving the ethyl-
carbamate-derived nitrogen from the 7-position to the 8-position
resulted in analogs 43a-e with marked reduction in in vitro
binding affinity.
We also evaluated selected compounds in a rat pharmaco-
kinetic model at 10 mg/kg oral dose and the plasma levels were
assayed for a 6 h period (Table 1). The plasma levels (AUCs)
Figure 2. Ex vivo platelet aggregation inhibition in cynomolgus
monkey following a single oral dose (1 and 3 mg/kg in 20% PEG-
were moderate and ranged from 545 to 1190 ng.hr/mL. The in
vivo efficacy of the tetrahydropyranyl analogs 27b and 27c were
HPBCD) of 28b.
evaluated in the ex vivo platelet aggregation inhibition assay
in cynomolgus monkeys, as reported previously.21 Cynomolgus
monkeys were orally dosed with 27b and 27c and blood samples
were drawn at 1 h intervals up to 6 h then at 24 h, while being
chaired consciously. Subsequently, haTRAP was added to the
samples as an agonist for the thrombin receptor activation to
induce the platelet aggregation. The inhibition of the agonist
induced platelet aggregation by the dosed analogs was assayed
in a whole blood aggregometer. Both 27b and 27c showed
complete inhibition of haTRAP-induced platelet aggregation at
1 mg/kg oral dose up to 6 h (Figure 1). At 24 h, 27c produced
about 55% inhibition, while 27b showed about 80% inhibition
in the platelet aggregation. The detailed pharmacokinetic profile
of compound 27c was also evaluated in the c. monkey at 1 mg/
kg i.v. dose and 1.5 mg/kg oral dose, which showed very good
oral bioavailability (AUC0-24 h ) 3700 ng‚hr/mL; Cmax ) 610
ng/mL; Tmax ) 1.7 h; half-life ) 8.6 h; and F ) 71%).
Although both 27b and 27c showed excellent efficacy in the
ex vivo platelet aggregation inhibition assay, analysis of the
plasma samples for both compounds indicated a considerable
amount of (M + 16) metabolites.33 To identify the structure of
the metabolites of 27c, this compound was incubated with liver
microsomes, and the metabolites were assayed using LC/NMR

5152 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Chelliah et al.
and MS/MS techniques. The metabolites were found to be a
mixture of C8-R and -â lactols 44 and 45 (Scheme 4).34 Due to
the reactive nature of the lactol metabolites and their consider-
able presence in the monkey plasma, this series was not further
pursued.
Experimental Section
General Comments. Flash chromatographic purification was
performed using Universal Scientific or Selecto Scientific flash
silica gel (particle size 32-63 µm). 1H NMR spectra were
determined on a Gemini 400 MHz instrument using either tetram-
ethylsilane or residual solvent peaks as internal standards. Optical
rotations were either determined on a Perkin-Elmer 243B polarim-
eter or by Quantitative Technologies, Inc., 291 Route 22 East, Salem
Ind. Park, Bldg. 5, Whitehouse, NJ 08888-0470. Elemental analyses
were determined by the Physical-Analytical Department of Scher-
ing-Plough Research Institute using either CEC 240-HA, CEC CE-
440, or Fisons EA 1108 CHNS elemental analyzers. Elementals
analyses were also performed by Quantitative Technologies, Inc.
Unless specified, NMR spectra were determined using the free form
of the compounds, and optical rotation and elemental analyses were
carried out on the hydrochloride salts. Mass spectra were obtained
on VG-ZAB-SE, Extrel-401, HP-MS Engine, JEOL HX-110, Sciex
API 100, or Sciex API 150 mass spectrometers.
Because the decahydroisoquinoline analog 28a showed good
in vitro potency, a variety of substitutions at the nitrogen as
well as the biaryl portion of 28a were carried out. The in vitro
binding values for these analogs are given in Table 2. Similar
to 28a, the ethylcarbamate analogs 28b-d showed very good
potency. Compared to 1, the unsubstituted amine 30a and its
N-methyl derivative 30b showed substantial reduction in binding
affinity. The isopropyl amide 30d showed slightly better affinity
than the acetamide 30c, but the corresponding cyclopropyl
amides 30e-g showed potency comparable to 1. The N-ethyl-
substituted urea derivative 30i showed good affinity, although
the unsubstituted urea 30h showed reduced affinity. Methane-
sulfonamide analog 30j showed better affinity than the pro-
panesulfonamide analog 30k. Both the methoxyethylcarbamate
30m and the bulkier benzylcarbamate derivative 30l were well-
tolerated.
3-(5,6-Dihydro-2H-thiopyran-3-yl)-2-propenoic Acid, Methyl
Ester (6). To a suspension of 60% NaH (6.3 g, 158 mmol, 1.3
equiv) in THF (200 mL) at 0 °C was added methyl diethylphospho-
noacetate (29 mL, 158 mmol, 1.3 equiv), and the mixture was stirred
at 0 °C for 30 min. The solution was then transferred to a solution
of 325 (15.6 g, 122 mmol) in THF (100 mL) and stirred at 0 °C for
1 h. The reaction was quenched by the addition of aq NH4Cl (500
mL), and the THF was evaporated. The aqueous phase was extracted
with Et2O (3 × 200 mL), and the combined organic layer was
washed with H2O and brine (200 mL each). The solution was dried
over MgSO4 and concentrated, and the resultant residue was
chromatographed with 5% EtOAc-hexane to provide 13.0 g (58%)
Several analogs with promising in vitro binding affinities
were evaluated in the c. monkey ex vivo platelet aggregation
inhibition and the rat pharmacokinetic assay. Both of the cyclo-
propyl amide derivatives, 30f and 30h, showed good rat plasma
levels following oral dose. Although analog 30g exhibited plate-
let aggregation inhibition only up to ∼6 h, 30f showed efficacy
up to 24 h at a 3 mg/kg oral dose. The urea analog 30i and the
sulfonamide 30j exhibited only moderate levels of efficacy de-
spite excellent rat plasma levels, as indicated in Table 2. Carba-
mate 28b showed excellent efficacy at a 3 mg/kg dose, showing
∼70% inhibition of platelet aggregation at the 24 h time point,
whereas 28c showed ∼55% inhibition of the platelet aggregation
at the 24 h time point. Both of these analogs also showed good
plasma levels in the rat pharmacokinetic model. In further dose-
down experiments, carbamate 28b showed efficacy even at a
lower dose of 1 mg/kg oral dose, as indicated in Figure 2.
1
of oil. H NMR (400 MHz, CDCl3) 7.26 (d, J ) 15.9 Hz, 1H),
6.26 (t, J ) 4.4 Hz, 1H), 5.78 (dd, J ) 15.9, 0.6 Hz, 1H), 3.75 (s,
3H), 3.25-3.23 (m, 2H), 2.71 (t, J ) 5.8 Hz, 2H), 2.57-2.53 (m,
2H).
3-(5,6-Dihydro-2H-thiopyran-3-yl)-2-propenoic Acid (7). To
a solution of 6 (13.0 g, 70.6 mmol) in THF and MeOH (50 mL
each) was added a solution of KOH (11.9 g, 212 mmol, 3.0 equiv)
in H2O (50 mL). The mixture was stirred at rt for 1 h, diluted with
H2O (100 mL), and acidified with 1 N HCl. The aqueous phase
was extracted with EtOAc (3 × 200 mL), and the combined organic
layer was washed with H2O and brine (300 mL each). The solution
was dried over MgSO4, filtered, and evaporated to give 11.66 g
(97%) of a pale yellow solid. 1H NMR (400 MHz, CDCl3) 7.34 (d,
J ) 15.6 Hz, 1H), 6.32 (t, J ) 4.4 Hz, 1H), 5.78 (d, J ) 15.6 Hz,
1H), 3.26 (d, J ) 1.6 Hz, 2H), 2.72 (t, J ) 5.8 Hz, 2H), 2.59-2.55
(m, 2H).
(2Z,4R)-4-[[(2E)-3-(5,6-Dihydro-2H-thiopyran-3-yl)-1-oxo-2-
propenyl]oxy]-2-pentenoic Acid, Phenylmethyl Ester (9). To a
solution of 7 (2.45 g, 14.39 mmol) in CH2Cl2 (60 mL) at 0 °C was
added DCC (3.27 g, 15.85 mmol, 1.1 equiv) followed by DMAP
(352 mg, 2.88 mmol, 0.2 equiv), and the mixture was stirred at
0 °C for 30 min. To this was added a solution of 3.27 g (15.85
mmol, 1.1 equiv) of 8 in 10 mL of CH2Cl2, and the mixture was
stirred at 0 °C for 5 h and at rt for 1 h. The solution was diluted
with 350 mL of Et2O and washed with 2 × 200 mL of aq citric
acid, 200 mL of aq NaHCO3, and 200 mL of brine. The solution
was dried over MgSO4, filtered, and concentrated, and the resultant
residue was chromatographed with 6% EtOAc-hexane to provide
2.1 g (41%) of 7 as resin. 1H NMR (400 MHz, CDCl3) 7.38-7.32
(m, 5H), 7.45 (d, J ) 16.0 Hz, 1H), 6.38-6.34 (m, 1H), 6.26 (t, J
) 4.6 Hz, 1H), 6.21 (d, J ) 11.6 Hz, 1H), 6.19 (d, J ) 11.2 Hz,
1H), 5.85 (dd, J ) 11.6, 1.2 Hz, 1H), 5.76 (d, J ) 16.0 Hz, 1H),
5.18 (d, J ) 1.2 Hz, 2H), 3.24 (d, J ) 2.0 Hz, 2H), 2.71 (t, 2H, J
) 5.6 Hz, 2H), 2.56-2.52 (m, 2H), 1.41 (d, J ) 6.4 Hz, 3H).
Due to the excellent efficacy profile exhibited by 28b, this
compound was subjected to a more detailed study. In the
radioligand binding assay, 28b showed a Ki of 4.5 nM against
PAR-1. In cynomolgus monkeys, 28b showed an oral bioavail-
ability of 62% at a dose of 3 mg/kg. The Cmax following the
oral dose was 0.990 µM, and the half-life was 6.2 h following
intravenous administration. The compound is absorbed rapidly,
as indicated by a short Tmax (0.7 h) with 85% absorption. More
importantly, unlike compounds 1 and 27c, no major presence
of (M + 16) metabolites was observed. The compound was
clean in an 8-day P450 enzyme induction model in the mouse
at the tested doses ranging up to 100 mg/kg and no increase in
mouse liver weights, liver-to-body weight ratio, or spectral
CYP450 were observed. In a mass balance study using tritiated
28b,35 complete recovery or radioactivity within the targeted
10 days after intravenous administration of the compound was
achieved.
In summary, our current studies exploring heterotricyclic
himbacine analogs have led to the identification of potent
thrombin receptor antagonists, as exemplified by 28b, which is
a potent thrombin receptor antagonist with a Ki of 4.5 nM and
robust inhibition of agonist-induced ex vivo platelet aggregation
in a cynomolgus monkey model. Compound 28b was selective
over other GPCRs, showed excellent oral bioavailability in rat
and monkey models, and showed a clean profile in a mouse
enzyme induction model and a cynomolgus monkey clearance
model.
(1R,3aR,8aS,9S,9aR)-1,3a,5,7,8,8a,9,9a-Octahydro-1-methyl-
3-oxo-3H-thiopyrano[3,4-f]isobenzofuran-9-carboxylic Acid, Phen-
ylmethyl Ester (11). A solution of 9 (2.1 g, 5.85 mmol) in m-xylene
(50 mL) was heated at 200 °C for 6 h in a sealed tube. The solution
was cooled to rt and stirred with DBU (178 µL, 1.19 mmol, 0.2
equiv) for 1 h, concentrated, and chromatographed with 15%

Himbacine Analogs as Thrombin Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21 5153
EtOAc-hexane to provide 1.44 g (69%) of the desired exo-product.
1H NMR (400 MHz, CDCl3) 7.39-7.35 (m, 5H), 5.46 (br s, 1H),
5.16 (ABq, J ) 21.6, 12.0 Hz, 2H), 4.42 (dq, J ) 9.2, 6.0 Hz,
1H), 3.36-3.33 (m 2H), 3.08 (dd, J ) 14.4, 2.4 Hz, 1H), 2.85
(ddd, J ) 13.9, 12.4, 2.5 Hz, 1H), 2.72-2.57 (m, 4H), 2.27-2.21
(m, 1H), 1.47-1.25 (m, 1H), 1.12 (d, J ) 6.4 Hz, 3H).
13C NMR (100 MHz, CDCl3) 171.14, 153.72, 147.85, 138.16,
135.93, 134.88, 133.53, 131.00, 129.94, 129.48, 124.58, 124.55,
123.49, 123.45, 121.69, 48.62, 45.34, 41.85, 41.35, 40.47, 34.16,
33.08, 31.33, 28.89, 22.16; HRMS calcd for C26H27F3NO2S,
474.1715; found, 474.1721.
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-1-methyl-9-[(1E)-2-[5-[3-
(trifluoromethyl)phenyl]-2-pyridinyl]ethenyl]-3H-thiopyrano-
[3,4-f]isobenzofuran-3-one-6,6-dioxide (17) and (1R,3aR,4aS,-
8aS,9S,9aS)-Decahydro-1-methyl-9-[(1E)-2-[5-[3-(trifluoro-
methyl)phenyl]-2-pyridinyl]ethenyl]-3H-thiopyrano[3,4-f]isoben-
zofuran-3-one-6-oxide (18a, 18b). To a solution of 16 (70 mg,
0.15 mmol) in AcOH (2 mL) was added CH3SO3H (50 µL, 5 equiv)
and NaBO3‚4H2O (30 mg, 0.19 mmol, 1.3 equiv), and the mixture
was stirred overnight at rt. The acetic acid was evaporated, and
the resultant residue was taken up in an aq NaHCO3-Na2SO3 mix-
ture (25 mL) and extracted with CH2Cl2 (3 × 15 mL). The com-
bined organic layer was washed with brine (20 mL), dried over
MgSO4, filtered, concentrated, and purified by preparative thin layer
chromatography using 4% MeOH in dichloromethane to pro-
vide 36 mg of 17, 11 mg of 18a (isomer 1), and 4 mg of 18b
(isomer 2).
(1R,3aR,8aS,9S,9aS)-1,3a,5,7,8,8a,9,9a-Octahydro-1-methyl-
3-oxo-3H-thiopyrano[3,4-f]isobenzofuran-9-carboxylic Acid (12).
To a solution of 11 (750 mg, 2.09 mmol) in CH2Cl2 (10 mL) at
-78 °C was added BBr3 in CH2Cl2 (4.2 mL of 1 M solution). The
solution was stirred at -78 °C for 30 min and at 0 °C for 30 min
and then poured into aq K2CO3 (100 mL). The aqueous phase was
washed with Et2O (2 × 50 mL), and the organic layer was back-
extracted with aq K2CO3 (50 mL). The combined aqueous phase
was acidified with 1 N HCl and extracted with EtOAc (3 × 50
mL). The EtOAc layer was washed with brine (50 mL), dried over
MgSO4, filtered, and evaporated to provide 500 mg (89%) of acid.
1H NMR (400 MHz, CDCl3) 5.50 (br s, 1H), 4.47 (dq, J ) 9.6, 6.0
Hz, 1H), 3.43-3.39 (m, 1H), 3.36 (d, J ) 15.6 Hz, 1H), 3.10 (dd,
J ) 14.0, 2.4 Hz, 1H), 2.91-2.84 (m, 1H), 2.82-2.77 (m, 1H),
2.70 (dd, J ) 10.6, 4.2 Hz, 1H), 2.69-2.63 (m, 1H), 2.57-2.52
(m, 1H), 2.34-2.29 (m, 1H), 1.53-1.42 (m, 1H), 1.34 (d, J ) 6.0
Hz, 3H).
(1R,3aR,4aS,8aS,9S,9aR)-Decahydro-1-methyl-3-oxo-3H-thi-
opyrano[3,4-f]isobenzofuran-9-carboxylic Acid (13). To a solu-
tion of 12 (500 mg, 1.86 mmol) in MeOH (30 mL) was added
acetic acid (3 mL) and PtO2 (250 mg), and the suspension was
shaken under 40 psi H2 in a Parr vessel for 1.5 days. The catalyst
was filtered off with a celite pad, the solution was concentrated,
and the resultant residue was dissolved in an AcOH-MeOH-CH2-
Cl2 mixture (0.5:2:97.5 v/v/v/) and filtered through a short SiO2
column to provide 400 mg (79%) of the reduced product as a resin
that solidified on standing. 1H NMR (400 MHz, CDCl3) 4.68 (dq,
J ) 9.4, 5.9 Hz, 1H), 2.76-2.69 (m, 2H), 2.60-2.55 (m, 3H), 2.49
(d, J ) 11.6 Hz, 1H), 2.10 (br s, 1H), 1.93 (ddd, J ) 13.5, 6.0, 2.7
Hz, 1H), 1.60-1.48 (m, 2H), 1.45-1.19 (m, 3H), 1.33 (d, J ) 5.6
Hz, 3H).
1
Sulfone 17: H NMR (400 MHz, CDCl3) 8.80 (d, J ) 2.2 Hz,
1H), 7.88 (dd, J ) 2.6, 8.5 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J ) 8.1
Hz, 1H), 7.67 (d, J ) 8.1 Hz, 1H), 7.62 (t, J ) 7.7, 1H), 6.68 (d,
J ) 8.1 Hz, 1H), 6.68-6.58 (m, 2H), 4.77-4.70 (m, 1H), 3.10-
3.03 (2H), 2.96 (dt, J ) 3.4, 13.7 Hz, 1H), 2.82-2.74 (m, 2H),
2.56-2.43 (m, 2H), 2.32-2.26 (m, 1H), 2.12-1.99 (m, 2H), 1.83-
1.72 (m, 1H), 1.46 (d, J ) 5.9 Hz, 3H), 1.45-1.34 (m, 2H); HRMS
calcd for C26H27F3NO4S, 506.1613; found, 506.1612 (MH+).
1
Sulfoxide 18a (Isomer 1): H NMR (400 MHz, CDCl3) 8.79
(d, J ) 2.2 Hz, 1H), 8.80 (d, J ) 2.2, 8.1 Hz, 1H), 7.81 (s, 1H),
7.76 (d, J ) 8.1 Hz, 1H), 7.67 (d, J ) 7.3 Hz, 1H), 7.61 (t, J ) 7.7
Hz, 1H), 7.28 (d, J ) 8.1 Hz, 1H), 6.68-6.58 (m, 2H), 4.79-4.72
(m, 1H), 3.05-2.97 (m, 2H), 2.84-2.77 (m, 1H), 2.62-2.56 (m,
1H), 2.48-2.19 (m, 4H), 2.10-2.00 (m, 1H), 1.95-1.89 (m, 2H),
1.46 (d, J ) 5.9 Hz, 3H), 1.50-1.34 (m, 2H); HRMS calcd for
C26H27F3NO3S, 490.1664; found, 490.1661 (MH+).
1
Sulfoxide 18b (Isomer 2): H NMR (400 MHz, CDCl3) 8.80
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-1-methyl-3-oxo-3H-thi-
opyrano[3,4-f]isobenzofuran-9-carboxaldehyde (14). To a solu-
tion of 13 (97 mg, 0.36 mmol) in CH2Cl2 (4 mL) was added oxalyl
chloride (94 µL) followed by 1 drop of DMF. The solution was
stirred for 1 h at rt and concentrated to provide the crude acid
chloride, which was dissolved in toluene (3 mL) and cooled to
0 °C. Pd(PPh3)4 (42 mg, 0.04 mmol, 0.1 equiv) was added, followed
by Bu3SnH (94 µL). The mixture was stirred at 0 °C for 3 h,
concentrated, and chromatographed with 25% EtOAc-hexane to
provide 73 mg (80%) of the title compound as white solid. 1H NMR
(400 MHz, CDCl3) 9.75 (d, J ) 2.8 Hz, 1H), 4.62 (dq, J ) 9.7,
6.0 Hz, 1H), 2.8-2.70 (m, 2H), 2.65-2.55 (m, 3H), 2.50 (d, J )
7.2 Hz), 2.10 (ddd, J ) 13.2, 6.4, 3.0 Hz, 1H), 1.94 (ddd, J )
13.6, 6.0, 3.0, 1H), 1.69 (dq, J ) 10.9 Hz, 3.00 Hz, 1H), 1.58-
1.48 (m, 1H), 1.42-1.20 (m, 3H), 1.33(d, J ) 6.4 Hz, 3H).
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-1-methyl-9-[(1E)-2-[5-[3-
(trifluoromethyl)phenyl]-2-pyridinyl]ethenyl]-3H-thiopyrano-
[3,4-f]isobenzofuran-3-one (16). To a solution of 15 (156 mg, 0.42
mmol, 2.0 equiv) in THF (1 mL) at 0 °C was added a 2.5 M solution
of BuLi in hexanes (170 µL, 0.42 mmol, 2.0 equiv), and the mixture
was stirred for 30 min. To this was added a solution of 14 (53 mg,
0.21 mmol) in THF (1.5 mL), and the mixture was stirred at 0 °C
for 1 h. The reaction was quenched by the addition of aq NH4Cl
(20 mL), the THF was evaporated, and the aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layer
was washed with aq NaHCO3 (15 mL) and brine (15 mL), dried
over MgSO4, filtered, concentrated, and chromatographed with 40%
(d, J ) 2.4 Hz, 1H), 7.87 (dd, J ) 8.0, 2.0 Hz, 1H), 7.81 (s, 1H),
7.76 (d, J ) 7.6 Hz, 1H), 7.67 (d, J ) 7.6 Hz, 1H), 7.61 (t, J ) 7.8
Hz, 1H), 7.27 (d, J ) 9.6 Hz, 1H), 6.67-6.55 (m, 2H), 4.78-4.71
(m, 1H), 3.44-3.40 (m, 1H), 3.35 (dt, J ) 12.1, 2.8 Hz, 1H), 2.78-
2.71 (m, 1H), 2.64-2.57 (m, 1H), 2.52-2.36 (m, 3H), 2.26-2.21
(m, 1H), 2.04 (ddd, J ) 13.5, 6.5, 2.7 Hz, 1H), 1.45 (d, J ) 6.0
Hz, 3H), 1.60-1.25 (m, 6H).
Enal 19a36 was converted to aldehyde 25a using procedures used
for the preparation of 25b described below.
3-(5,6-Dihydro-2H-pyran-3-yl)-2-propenoic Acid (20a). 1H
NMR (400 MHz, CDCl3) 7.28 (d, J ) 16.1 Hz, 1H), 6.34 (t, J )
4.2 Hz, 1H), 5.62 (d, J ) 16.1 Hz, 1H), 4.31 (d, J ) 2.2 Hz, 2H),
3.80 (t, J ) 5.5 Hz, 2H), 2.37-2.35 (m, 2H); MS 155.1 (MH+).
(2Z,4R)-4-[[(2E)-3-(5,6-Dihydro-2H-pyran-3-yl)-1-oxo-2-pro-
penyl]oxy]-2-pentenoic Acid, Phenylmethyl Ester (22a). 1H NMR
(400 MHz, CDCl3) 7.38-7.35 (m, 5H), 7.23 (d, J ) 16.6 Hz, 1H),
6.32 (t, J ) 4.2 Hz, 1H), 5.64-5.59 (m, 1H), 5.60 (d, J ) 16.4
Hz, 1H), 5.19 (s, 2H), 4.29 (d, J ) 2 Hz, 1H), 3.78 (t, J ) 5.3 Hz,
1H), 2.37-2.34 (m, 2H), 1.56 (d, J ) 7.2 Hz, 3H); MS 341.2
(MH+).
(1R,3aR,8aS,9S,9aR)-1,3a,5,7,8,8a,9,9a-Octahydro-1-methyl-
3-oxo-3H-pyrano[3,4-f]isobenzofuran-9-carboxylic Acid, Phe-
1
nylmethyl Ester (23a). H NMR (400 MHz, CDCl3) 7.40-7.26
(m, 5H), 5.49 (s, 1H), 5.16 (ABq, J ) 12.4 Hz, 2H), 4.50-4.43
(m, 1H), 4.17 (d, J ) 12.8 Hz, 1H), 3.99 (dd, J ) 4.4, 11.6 Hz,
1H), 3.95-3.91 (m, 1H), 3.58 (dt, J ) 2.4, 12.2 Hz, 1H), 3.40-
3.36 (m, 1H), 2.78-2.73 (m, 2H), 2.62 (dd, J ) 11.2, 4.0 Hz, 1H),
1.91-1.87 (m, 1H), 1.37-1.26 (m, 1H), 1.13 (d, J ) 5.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) 174.17, 172.40, 137.39, 134.71,
128.60, 128.57, 128.52, 114.76, 76.40, 71.44, 67.57, 67.13, 44.59,
43.90, 43.77, 32.66, 31.89, 20.07; HRMS 343.1548 (MH+).
(1R,3aR,4aS,8aS,9S,9aR)-Decahydro-1-methyl-3-oxo-3H-pyr-
ano[3,4-f]isobenzofuran-9-carboxylic Acid (24a). 1H NMR (400
1
EtOAc-hexane to provide 90 mg (91%) of resin. H NMR (400
MHz, CDCl3) 8.78 (d, J ) 2.2 Hz, 1H), 7.85 (dd, J ) 2.2, 8.1 Hz,
1H), 7.80 (s, 1H), 7.75 (d, J ) 7.3 Hz, 1H), 7.65 (d, J ) 8.1 Hz,
1H), 7.59 (t, J ) 7.7 Hz, 1H), 7.27 (d, J ) 8.1 Hz, 1H), 6.62-6.53
(m, 2H), 4.78-4.71 (m, 1H), 2.77-2.63 (m, 2H), 2.56-2.34 (m,
5H), 2.17-2.13 (m, 1H), 1.94 (ddd, J ) 3.3, 6.3, 13.7 Hz, 1H),
1.57-1.48 (m, 1H), 1.43 (d, J ) 5.9 Hz, 1H), 1.33-1.22 (m, 3H);

5154 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Chelliah et al.
MHz, CDCl3) 4.73-4.66 (m, 1H), 4.01 (dd, J ) 3.7, 11.7 Hz, 1H),
3.87 (dd, J ) 4.0, 11.4 Hz, 1H), 3.48 (dt, J ) 2.0, 11.9 Hz, 1H),
3.09 (t, J ) 11.0 Hz, 1H), 2.76-2.70 (m, 1H), 2.63-2.52 (m, 2H),
1.81 (ddd, J ) 2.0, 6.0, 13.4 Hz, 1H), 1.77-1.73 (m, 1H), 1.65
(dq, J ) 3.1, 11.1 Hz, 1H), 1.33 (d, J ) 5.9 Hz, 3H), 1.47-1.24
(m, 2H), 1.08 (q, J ) 13.0 Hz, 1H); MS 255.1 (MH+).
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-1-methyl-3-oxo-3H-pyr-
ano[3,4-f]isobenzofuran-9-carboxaldehyde (25a). 1H NMR (400
MHz, CDCl3) 9.79 (d, J ) 2.2 Hz, 1H), 4.64-4.57 (m, 1H), 3.99
(dd, J ) 4.4, 11.7 Hz, 1H), 3.87 (dd, J ) 4.0, 11.4 Hz, 1H), 3.48
(dt, J ) 2.2, 12.3 Hz, 1H), 3.12 (t, J ) 11.0 Hz, 1H), 2.78-2.60
(m, 3H), 1.85-1.73 (m, 3H), 1.47-1.38 (m, 1H), 1.34 (d, J ) 5.9
Hz, 3H), 1.29-1.22 (m, 1H), 1.10 (q, J ) 12.9 Hz, 1H).
124.54, 124.51, 121.21, 116.24, 116.02, 76.65, 71.99, 68.42, 48.20,
44.78, 41.42, 39.59, 38.81, 31.18, 26.33, 22.18; [R]20D ) +23.9 (c
10.6 mg/mL, MeOH); HRMS calcd for C25H26FNO3 (MH+),
408.1975; found, 408.1989; Anal. (C25H26FNO3‚HCl‚0.5H2O) C,
H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(2,3-Difluorophenyl)-2-
pyridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]-
1
benzopyran-3-one (27d). H NMR (400 MHz, CDCl3) 8.71 (s,
1H), 7.83 (d, J ) 8.1 Hz, 1H), 7.27 (d, J ) 8.8 Hz, 1H), 7.23-
7.14 (m, 3H), 6.65-6.54 (m, 2H), 4.79-4.72 (m, 1H), 3.98 (dd, J
) 4.1, 11.4 Hz, 1H), 3.86 (dd, J ) 3.3, 11.4 Hz, 1H), 3.40 (t, J )
12.1 Hz, 1H), 3.06 (t, J ) 10.6 Hz, 1H), 2.77-2.70 (m, 1H), 2.48-
2.37 (m, 2H), 1.83 (dd, J ) 6.3, 11.4 Hz, 1H), 1.67 (d, J ) 12.5
Hz, 1H),1.44 (d, J ) 5.9 Hz, 3H), 1.48-1.38 (m, 2H), 1.28-1.01
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-1-methyl-9-[(e)-2-[5-[3-
(trifluoromethyl)phenyl]-2-pyridinyl]ethenyl]-3H-furo[3,4-g][2]-
benzopyran-3-one (27a). To a solution of [5-(3-trifluoromethyl-
phenyl)-pyridin-2-ylmethyl]-phosphonic acid diethyl ester (200 mg,
0.536 mmol) in 2 mL of THF at 0 °C was added a 2.5 M solution
of BuLi in hexanes (0.21 mL, 0.537 mmol), and this mixture was
stirred for 10 min. To this was added Ti(Oi-Pr)4 (0.16 mL, 0.538
mmol) followed by a solution of aldehyde 25a in 1 mL of THF
(68 mg, 0.285 mmol). The mixture was stirred for 2 h, poured into
20 mL of aq sodium potassium tartrate, and extracted with
dichloromethane (3 × 15 mL). The combined organic layer was
washed with brine, dried over MgSO4, filtered, concentrated, and
chromatographed using 50% ethyl acetate in hexanes to provide
(m, 2H); [R]20 ) +12.2 (c 8 mg/mL, MeOH); HRMS calcd for
D
C25H26F2NO3 (MH+), 426.1881; found, 426.1881; Anal. (C25H25F2-
NO3‚HCl‚0.4H2O) C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(3-Chlorophenyl)-2-py-
ridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]benzopyran-
1
3-one (27e). H NMR (400 MHz, CDCl3) 8.75 (d, J ) 1.5 Hz,
1H), 7.81 (dd, J ) 2.2, 8.1 Hz, 1H), 7.55-7.54 (m, 1H), 7.47-
7.35 (m, 3H), 7.25 (d, J ) 8.1 Hz, 1H), 6.63-6.52 (m, 2H), 4.80-
4.72 (m, 1H), 3.99 (dd, J ) 3.7, 11.7, 1H), 3.87 (dd, J ) 3.7, 11.0
Hz, 1H), 3.40 (dt, J ) 2.0, 11.9 Hz, 1H), 3.06 (t, J ) 10.9 Hz,
1H), 2.77-2.71 (m, 1H), 2.47-2.36 (m, 2H), 1.84 (ddd, J ) 2.2,
6.6, 13.2 Hz, 1H), 1.68 (d, J ) 12.5 Hz, 1H), 1.44 (d, J ) 5.9 Hz,
3H), 1.48-1.38 (m, 2H), 1.28-1.07 (m, 2H); 13C NMR (100
MHz, CDCl3) 177.27, 153.51, 139.09, 135.06, 134.83, 133.62,
131.10, 130.20, 127.94, 126.79, 124.83, 121.63, 72.04, 68.45, 48.26,
1
105 mg of product. H NMR (400 MHz, CDCl3) 8.78 (d, J ) 2.2
Hz, 1H), 7.86 (dd J ) 8.1, 2.2 Hz, 1H), 7.80 (s, 1H), 7.75 (d, J )
8.1 Hz, 1H), 7.65-7.57 (m, 2H,), 7.28 (d, J ) 8.1 Hz, 1H), 6.64-
6.55 (m, 2H), 4.79-4.72 (m, 1H), 3.98 (dd, J ) 3.7, 11.7 Hz, 1H),
3.86 (dd, J ) 3.3, 11.4 Hz, 1H), 3.40 (dt, J ) 2.0, 12.1 Hz, 1H),
3.06 (t, J ) 11.0 Hz, 1H), 2.77-2.70 (m, 1H), 1.83 (dq, J ) 1.9,
7.0 Hz, 1H), 1.67 (d, J ) 11.7 Hz, 1H), 1.44 (d, J ) 5.9 Hz, 3H),
1.48-1.39 (m, 2H), 1.28-1.07 (m, 2H); 13C NMR (100 MHz,
CDCl3) 177.20, 153.75, 147.89, 147.80, 138.16, 135.25, 134.88,
133.53, 131.07, 129.94, 129.47, 124.57, 123.48, 121.63, 76.63,
72.02, 68.43, 48.29, 44.87, 41.50, 39.64, 38.87, 31.24, 26.37, 22.17;
[R]20D ) +25.7 (c 10 mg/mL, MeOH); HRMS calcd for C26H27F3-
NO3 (MH+), 458.1943; found, 458.1941; Anal. (C26H26F3NO3‚HCl‚
0.6H2O) C, H, N.
44.87, 41.47, 39.65, 38.86, 31.23, 26.38, 22.20; [R]20 ) -8.2 (c
D
1.7 mg/mL, MeOH); HRMS calcd for C25H27ClNO3 (MH+),
424.1679; found, 424.1686; Anal. (C25H26ClNO3‚HCl‚0.8H2O) C,
H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(2-Chlorophenyl)-2-py-
ridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]benzopyran-
1
3-one (27f). H NMR (400 MHz, CDCl3) 8.63 (d, J ) 2.2 Hz,
1H), 7.70 (dd, J ) 2.9, 8.1 Hz, 1H), 7.52-7.49 (m, 1H), 7.37-
7.31 (m, 3H), 7.26 (d, J ) 7.3 Hz, 1H), 6.64-6.55 (m, 2H), 4.81-
4.74 (m, 1H), 4.00 (dd, J ) 3.7, 11.7 Hz, 1H), 3.88 (dd, J ) 3.7,
11.0 Hz, 1H), 3.41 (dt, J ) 2.0, 12.1 Hz, 1H), 3.07 (d, J ) 10.7
Hz, 1H), 2.78-2.72 (m, 1H), 2.47-2.38 (m, 2H), 1.85 (ddd, J )
2.2, 6.6, 13.4 Hz, 1H), 1.70 (d, J ) 13.2 Hz, 1H), 1.47 (d, J ) 5.9
Hz, 3H), 1.49-1.39 (m, 2H), 1.30-1.08 (m, 2H); 13C NMR (100
MHz, CDCl3) 177.24, 153.22, 149.67, 137.31, 136.49, 134.82,
133.43, 132.48, 131.37, 130.93, 130.02, 129.20, 127.01, 120.79,
76.67, 72.04, 68.45, 48.27, 44.88, 41.48, 39.65, 38.90, 31.24, 26.40,
The following compounds were prepared using a procedure
similar to the preparation of 27a using appropriate phosphonate
reagents.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(3-Fluorophenyl)-2-py-
ridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]benzopyran-
1
3-one (27b). H NMR (400 MHz, CDCl3) 8.75 (d, J ) 1.5 Hz,
22.25; [R]20 ) +16.9 (c 6 mg/mL, MeOH); HRMS calcd for
1H), 7.80 (dd, J ) 2.9, 8.1 Hz, 1H), 7.45-7.39 (m, 1H), 7.34 (d,
J ) 7.3 Hz, 1H), 7.09-7.05 (m, 1H), 6.61-6.51 (m, 2H), 4.78-
4.71 (m, 1H), 3.97 (dd, J ) 3.6, 11. 7 Hz, 1H), 3.85 (dd, J ) 3.3,
11.4 Hz, 1H), 3.39 (t, J ) 11.7 Hz, 1H), 3.05 (t, J ) 10.6 Hz, 1H),
2.76-2.69 (m, 1H), 2.45-2.36 (m, 1H), 1.84-1.79 (m, 1H), 1.66
(d, J ) 13.2 Hz, 1H), 1.43 (d, J ) 5.9 Hz, 3H), 1.47-1.37 (m,
2H), 1.27-1.06 (m, 2H); 13C NMR (100 MHz, CDCl3) 177.21,
164.17, 161.72, 153.56, 147.87, 147.76, 139.53, 139.46, 134.93,
134.72, 133.68, 131.17, 130.52, 130.44, 122.33, 122.30, 121.54,
114.85, 114.65, 113.70, 113.48, 71.99, 68.42, 48.24, 44.84, 41.42,
39.63, 38.86, 31.21, 26.35, 22.18, 22.13; [R]20D ) +25.9 (c 8 mg/
mL, MeOH); HRMS calcd for C25H26FNO3 (MH+), 408.1975;
found, 408.1982; Anal. (C25H26FNO3‚HCl‚0.5H2O) C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(2-Fluorophenyl)-2-py-
ridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]benzopyran-
D
C25H27ClNO3 (MH+), 424.1679; found, 424.1684; Anal. (C25H26-
ClNO3‚HCl‚0.7H2O) C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(2,3-Dichlorophenyl)-2-
pyridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]-
1
benzopyran-3-one (27g). H NMR (400 MHz, CDCl3) 8.60 (d, J
) 2.2 Hz, 1H), 7.74 (dd, J ) 2.2, 8.1 Hz, 1H), 7.53 (dd, J ) 1.9,
7.7 Hz, 1H), 7.31-7.22 (m, 3H), 6.67-6.56 (m, 1H), 4.81-4.74
(m, 1H), 4.00 (dd, J ) 4.1, 11.4 Hz, 1H), 3.88 (dd, J ) 3.7, 11.7
Hz, 1H), 3.40 (dt, J ) 2.2, 11.7 Hz, 1H), 3.07 (t, J ) 10.7 Hz,
1H), 2.78-2.72 (m, 1H), 2.49-2.38 (m, 2H), 1.84 (ddd, J ) 2.2,
6.6, 13.6 Hz, 1H), 1.70 (d, J ) 13.2 Hz, 1H), 1.47 (d, J ) 5.9 Hz,
3H), 1.44-1.37 (m, 2H), 1.30-1.05 (m, 2H); 13C NMR (100 MHz,
CDCl3) 177.24, 153.58, 149.48, 138.80, 137.25, 135.22, 133.80,
133.34, 131.25, 131.13, 130.08, 129.09, 127.35, 120.85, 76.65,
72.06, 68.46, 48.28, 44.91, 41.50, 39.66, 38.90, 31.25, 26.40, 22.26;
[R]20D ) +15.5 (c 5 mg/mL, MeOH); HRMS calcd for C25H26Cl2-
NO3, 458.1290; found, 458.1299; Anal. (C25H25Cl2NO3‚HCl‚
1.5H2O) C, H, N.
3-Formyl-5,6-dihydro-1(2H)-pyridinecarboxylic Acid, Ethyl
Ester (19b). To a solution of 5,6-dihydro-2H-pyridine-1,3-dicar-
boxylic acid 1-ethyl ester 3-methyl ester37 (35.4 g, 166 mmol) in
CH2Cl2 (600 mL) at -78 °C was slowly added a solution of 1 M
DIBAL (365 mL, 365 mmol, 2.2 equiv) in CH2Cl2, and the mixture
was stirred for 1.5 h. The reaction was quenched by the addition
1
3-one (27c). H NMR (400 MHz, CDCl3) 8.74 (s, 1H), 7.85 (d, J
) 8.1, Hz, 1H), 7.44 (dt, J ) 1.7, 7.7 Hz, 1H), 7.41-7.35 (m,
1H), 7.28-7.17 (m, 4H), 6.64-6.55 (m, 2H), 4.80-4.74 (m, 1H),
4.00 (dd, J ) 3.7, 11.7 Hz, 1H), 3.88 (dd, J ) 4.1, 11.4 Hz, 1H),
3.41 (dt, J ) 2.0, 12.1 Hz, 1H), 3.07 (t, J ) 10.7 Hz, 1H), 2.78-
2.72 (m, 1H), 2.40-2.38 (m, 2H), 1.85 (ddd, J ) 2.6, 6.3, 13.2
Hz, 1H), 1.70 (d, J ) 13. 2 Hz, 1H), 1.46 (d, J ) 5.9 Hz, 3H),
1.49-1.36 (m, 2H), 1.29-1.08 (m, 2H); 13C NMR (100 MHz,
CDCl3) 177.26, 160.75, 158.29, 153.16, 149.14, 136.70, 136.67,
134.82, 131.24, 129.98, 129.95, 129.74, 129.67, 125.18, 125.05,

Himbacine Analogs as Thrombin Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21 5155
of 1 L of satd aq Rochelle’s salt, and the organic layer was
separated. The aqueous layer was extracted with 2 × 250 mL of
CH2Cl2, and the combined organic layer was washed with 500 mL
of brine, dried over MgSO4, filtered, and concentrated, and the
resultant crude was chromatographed with 40% EtOAc-hexane
to provide 17 g (55%) of alcohol as an oil.
g, 10 wt %) in 150 mL of THF was stirred under a H2 balloon for
2.5 h. Another batch of 10 g of 22b was similarly reduced with
Lindlar catalyst. The two batches were combined, filtered through
a celite pad, and evaporated, and the residue was redissolved in
600 mL of EtOAc. It was washed with 3 × 200 mL of 1 N HCl
and 200 mL of brine, dried over MgSO4, filtered, and evaporated
to give 20 g of resin, which was used immediately for the Diels-
Alder reaction.
A solution of the above product (20 g) in 500 mL of toluene in
a sealed glass vessel was heated at 185 °C for 6 h using an oil
bath. The solution was cooled to rt, treated with DBU (1.8 mL, 12
mmol, 0.2 equiv) for 1 h, concentrated, and chromatographed with
25% EtOAc-hexane to provide 11.3 g (56%) of the cyclized exo-
product 23b. 1H NMR (400 MHz, CDCl3) 7.39-7.35 (m, 5H), 5.56
(s, 1H), 5.17 (dd, J ) 18.4, 12.0 Hz, 2H), 4.53 (br, 1H), 4.47 (dq,
J ) 9.8, 6.0 Hz, 1H), 4.17 (br, 1H), 4.12 (q, J ) 7.1 Hz, 2H), 3.42
(d, J ) 14.8 Hz, 1H), 3.38-3.34 (m, 1H), 2.93 (t, J ) 12.0 Hz,
1H), 2.77-2.72 (m, 1H), 2.65-2.63 (m, 1H), 2.58 (dd, J ) 10.8,
4.0 Hz, 1H), 1.93-1.89 (m, 1H), 1.25 (t, J ) 7.2 Hz, 3H), 1.14 (d,
J ) 5.6 Hz, 3H); HRMS calcd for C23H28NO6 (MH+), 414.1917;
found, 414.1923.
To a solution of above alcohol (17.0 g, 92 mmol) in 150 mL of
CH2Cl2 at rt was added NaHCO3 (15.4 g, 183 mmol, 2 equiv) and
Dess-Martin reagent (46.7 g, 110 mmol, 1.2 equiv), and the
suspension was stirred for 45 min. To this was added 300 mL of
Et2O, and a solution of Na2S2O3‚5H2O (70 g, 282 mmol, 2 equiv)
and NaHCO3 (15.4 g, 183 mmol, 2 equiv) in 600 mL of H2O. The
mixture was stirred vigorously until the two layers became clear.
The organic layer was separated and the aqueous layer was extracted
with 2 × 150 mL of Et2O. The combined organic layer was washed
with 300 mL each of aq Na2S2O3/NaHCO3 and brine, dried over
1
MgSO4, filtered, and evaporated to give 15.3 g (91%) of oil. H
NMR (400 MHz, CDCl3) 9.43 (s, 1H), 6.93 (s, 1H), 4.15 (q, J )
7. 1 Hz, 2H), 4.14 (s, 2H), 3.58 (t, J ) 5.7 Hz, 2H), 2.46 (bs, 2H),
1.25 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) 191.40,
155.41, 147.85, 138.68, 61.62, 40.96, 39.71, 26.23, 14.78; HRMS
calcd for C9H13NO3 (MH+), 184.0974; found, 184.0966.
3-[(1E)-2-Carboxyethenyl]-5,6-dihydro-1(2H)-pyridinecar-
boxylic Acid, 1-Ethyl Ester (20b). To a suspension of 60% NaH
(4.35 g, 109 mmol, 1.3 equiv) in THF (300 mL) at 0 °C was added
dropwise triethyl phosphonoacetate (20 mL, 109 mmol, 1.3 equiv),
and the mixture was stirred at 0 °C for 30 min. To this was added
a solution of 19b (15.3 g, 83.5 mmol), and the mixture was stirred
for 30 min at 0 °C. The reaction was quenched by the addition of
600 mL of aq NH4Cl, the THF was evaporated, and the aqueous
slurry was extracted with 3 × 200 mL of Et2O. The combined
organic layer was washed with 200 mL of brine, dried over MgSO4,
filtered, concentrated, and chromatographed with 15% EtOAc-
hexane to provide 19.9 g (94%) of the ester as oil.
(1R,3aR,4aS,8aR,9S,9aR)-Decahydro-1-methyl-3-oxo-furo[3,4-
g]isoquinoline-6,9(3H)-dicarboxylic Acid, 6-Ethyl Ester (24 b).
A suspension of 23b (11.2 g, 27 mmol) and 10% Pd-C (1.2 g, 10
wt %) in 200 mL of EtOAc was stirred under a H2 balloon until
the debenzylation was complete. It was filtered through a celite
pad, concentrated, and redissolved in 200 mL of CH3OH. To this
was added 900 mg of PtO2, and the suspension was shaken under
50 atm of H2 in a Parr vessel. The mixture was filtered through a
celite pad and concentrated to provide 8.5 g (96%) of 24b. 1H NMR
(400 MHz, CDCl3) 4.72-4.65 (m, 1H), 4.22-4.09 (m, 2H), 4.12
(q, J ) 6.8 Hz, 2H), 2.78 (br, 1H), 2.74-2.68 (m, 1H), 2.59 (dt, J
) 10.1, 6.5 Hz, 1H), 2.51-2.46 (m, 1H), 2.43 (br, 1H), 1.94-
1.90 (m, 1H), 1.82 (d, J ) 10.4 Hz, 1H), 1.64-1.53 (m, 1H), 1.33
(d, J ) 5.9 Hz, H), 1.24 (t, J ) 7.1 Hz, 3H), 1.39-1.03 (m, 3H);
13C NMR (100 MHz, CDCl3) 176.33, 155.25, 76.22, 61.76, 48.86,
46.18, 44.16, 43.99, 41.20, 37.56, 37.45, 30.00, 27.66, 20.20, 14.74;
To a solution of the above ester (19.9 g, 79 mmol) in 100 mL
each of CH3OH, THF and H2O was added KOH (13.3 g, 237 mmol,
3 equiv), and the mixture was stirred at rt for 2 h. The mixture was
diluted with 200 mL of H2O, acidified with 1 N HCl to ∼pH 2,
and extracted with 3 × 200 mL of EtOAc. The combined organic
layer was washed with 200 mL each of H2O and brine, dried over
MgSO4, filtered, and evaporated to give 17.0 g (96%) of 20b as a
[R]25 ) -11.5 (c 13 mg/mL, MeOH); HRMS calcd for C16H24-
D
NO6 (MH+), 326.1604; found, 326.1600.
(1R,3aR,4aS,8aR,9S,9aS)-9-Formyldecahydro-1-methyl-3-oxo-
furo[3,4-g]isoquinoline-6(3H)-carboxylic Acid, Ethyl Ester (25b).
To a solution of 24b (415 mg, 1.28 mmol) in 10 mL of CH2Cl2 at
rt was added oxalyl chloride (225 µL, 2.58 mmol, 2 equiv), followed
by 1 drop of DMF. The solution was stirred at rt for 1 h, at which
time there was no evolution of gas. It was concentrated and
evaporated with anhydrous toluene to give the acid chloride. The
acid chloride was dissolved in 6 mL of anhydrous toluene and
cooled to 0 °C, and Pd(PPh3)4 (74 mg, 0.064 mmol, 5 mol %) was
added, followed by Bu3SnH (520 µL, 1.93 mmol, 1.5 equiv). The
mixture was stirred at 0 °C for 3 h, concentrated, and chromato-
graphed with 50% EtOAc-hexane to provide 360 mg (91%) of
1
pale yellow solid. H NMR (400 MHz, CDCl3) 7.33 (d, J ) 16.0
Hz, 1H), 6.33 (s, 1H), 5.80 (d, J ) 16.0 Hz, 1H), 4.18 (q, J ) 7.1
Hz, 2H), 4.12 (br, 2H), 3.57 (t, J ) 5.8 Hz, 2H), 2.36 (br, 2H),
1.29 (t, J ) 7.2 Hz, 3H); HRMS calcd for C11H16NO4 (MH+),
226.1079; found, 226.1083.
3,6-Dihydro-5-[(1E)-3-[[(1R)-1-methyl-4-oxo-4-(phenylmethoxy)-
2-butynyl]oxy]-3-oxo-1-propenyl]-1(2H)-pyridinecarboxylic Acid,
Ethyl Ester (22b). To a solution of 20b (17.0 g, 76 mmol) in 400
mL of CH2Cl2 at rt was added oxalyl chloride (13.2 mL, 151 mmol,
2 equiv) and DMF (120 µL, 1.6 mmol, 2 mol %). The mixture
was stirred for 1 h, concentrated, and evaporated with 100 mL of
anhydrous toluene to provide the acid chloride. To a solution of
this acid chloride in 200 mL of CH2Cl2 at 0 °C was added DMAP
(925 mg, 7.6 mmol, 0.1 equiv), 21 (15.4 g, 75 mmol, 1.0 equiv) in
15 mL of CH2Cl2, followed by Et3N (12.7 mL, 91 mmol, 1.2 equiv).
The mixture was stirred for 1.5 h at 0 °C, then diluted with 600
mL of Et2O. The solution was washed successively with 200 mL
of H2O, 2 × 200 mL 1 N HCl, 200 mL of aq NaHCO3, and 200
mL of brine. It was dried over anhydrous MgSO4, filtered,
concentrated, and chromatographed with 20% EtOAc-hexane to
1
25b as a resin. H NMR (400 MHz, CDCl3) 9.78 (d, J ) 2.2 Hz,
1H), 4.62-4.55 (m, 1H), 4.16 (br, 2H), 4.11 (q, J ) 7.1 Hz, 2H),
2.79 (br, 1H), 2.75-2.65 (m, 2H), 2.58 (ddd, J ) 11.0, 5.1, 2.2.
Hz, 1H), 2. 46 (br, 1H), 1.96-1.91 (m, 1H), 1.87-1.83 (m, 1H),
1.67 (dq, J ) 3.1, 11.1 Hz, 1H), 1.32 (d, J ) 5.9 Hz, 3H), 1.24 (t,
J ) 7.3 Hz, 3H), 1.42-1.21 (m, 2H), 1.04 (dq, J ) 4.0, 12.3 Hz,
1H); MS (ESI) m/z 310.1 (MH+).
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-1-methyl-3-oxo-9-[(1E)-
2-[5-[3-(trifluoromethyl)phenyl]-2-pyridinyl]ethenyl]-furo[3,4-
g]isoquinoline-6(3H)-carboxylic Acid Ethyl Ester (28a). To a
solution of [5-(3-trifluoromethyl-phenyl)-pyridin-2-ylmethyl]-phos-
phonic acid diethyl ester (110 mg, 0.295 mmol, 2.0 equiv) in 1
mL of THF at 0 °C was added 2.5 M solution of BuLi in hexanes
(0.11 mL, 0.295 mmol, 2.0 equiv) and stirred for 15 min. To this
was added a solution of aldehyde 25b in 1.5 mL of THF (45 mg,
0.145 mmol). The mixture was stirred for 1 h, diluted with 30 mL
of water, and extracted with dichloromethane (3 × 15 mL). The
combined organic layer was washed with brine, dried over MgSO4,
filtered, concentrated, and chromatographed using 50% ethyl acetate
in hexanes to provide 68 mg of (28a). 1H NMR (400 MHz, CDCl3)
1
provide 20 g (78%) of resin. H NMR (400 MHz, CDCl3) 7.38-
7.35 (m, 5H), 7.28 (d, J ) 16.0 Hz, 1H), 6.31 (s, 1H), 5.77 (d, J
) 16.0 Hz, 1H), 5.62 (q, J ) 6.8 Hz, 1H), 5.19 (s, 2H), 4.17 (q, J
) 7.2 Hz, 2H), 4.08 (br, 2H), 3.56 (br, 2H), 2.34 (br, 2H), 1.57 (d,
J ) 6.8 Hz, 3H), 1.28 (t, J ) 7. 2 Hz); HRMS calcd for C23H26-
NO6 (MH+), 412.1760; found, 412.1764.
(1R,3aR,8aS,9S,9aR)-1,3a,5,7,8,8a,9,9a-Octahydro-1-methyl-
3-oxo-furo[3,4-g]isoquinoline-6,9(3H)-dicarboxylic Acid, 6-Ethyl
9-(Phenylmethyl) Ester (23b). A suspension 22b (10 g, 29 mmol),
quinoline (700 µL, 5.9 mmol, 0.2 equiv), and Lindlar catalyst (1.0

5156 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Chelliah et al.
8.78 (d, J ) 2.2 Hz, 1H), 7.84 (dd, J ) 2.2, 8.1 Hz, 1H), 7.80 (s,
1H), 7.75 (d, J ) 7.3 Hz, 1H), 7.66-7.58 (m, 2H), 7.27 (dd, J )
8.8 Hz, 1H), 6.65-6.53 (m, 2H), 4.79-4.72 (m, 1H), 4.18 (br,
2H), 4.11 (q, 7.1 Hz, 2H), 2.76-2.70 (m, 2H), 2.44-2.36 (m, 3H),
1.96 (dd, J ) 6.2, 12.1 Hz, 1H), 1.77 (d, J ) 13.2 Hz, 1H), 1.43
(d, J ) 5.9 Hz, 3H), 1.24 (t, J ) 7.0 Hz, 3H), 1.34-1.15 (m, 3H),
1.10-1.00 (m, 1H); 13C NMR (100 MHz, CDCl3) 177.17, 155.10,
153.70, 147.85, 138.17, 135.30, 134.89, 133.59, 131.05, 129.96,
129.49, 124.60, 123.51, 123.48, 121.73, 76.64, 61.39, 49.08, 48.44,
44.94, 44.30, 41.57, 40.36, 38.35, 30.69, 28.15, 22.17, 14.79; HRMS
calcd for C29H32F3N2O4 (MH+), 529.2314; found, 529.2313.
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-1-methyl-3-oxo-9-[(1E)-
2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]-furo[3,4-g]isoquino-
line-6(3H)-carboxylic Acid Ethyl Ester (28b). To a solution of
[5-(3-fluorophenyl)-pyridin-2-ylmethyl]-phosphonic acid diethyl
ester (660 mg, 2.04 mmol, 1.5 equiv) in 10 mL of THF at 0 °C
was added 2.5 M solution of BuLi in hexanes (0.82 mL, 2.04 mmol,
1.5 equiv) and stirred for 15 min. To this was added Ti(Oi-Pr)4
(0.6 mL, 2.03 mmol, 1.5 equiv), followed by a solution of aldehyde
25b in 4 mL of THF (420 mg, 1.36 mmol). The mixture was stirred
for 1.5 h at rt, diluted with 60 mL of aqueous sodium potassium
tartrate solution, and extracted with dichloromethane (3 × 15 mL).
The combined organic layer was washed with brine, dried over
MgSO4, filtered, concentrated, and chromatographed using 50%
ethyl acetate in hexanes to provide 510 mg of (28b). 1H NMR (400
MHz, CDCl3) 8.76 (d, J ) 2.0 Hz, 1H), 7.82 (dd, J ) 2.6, 8.2 Hz,
1H), 7.43 (dt, J ) 6.1, 7.6 Hz, 1H), 7.35 (d, 1H, J ) 8.0 Hz, 1H),
7.28-7.24 (m, 2H), 7.08 (dt, J ) 2.8, 8.1 Hz, 1H), 6.64-6.52 (m,
2H), 4.78-4.71 (m, 1H), 4.17 (br, 2H), 4.11 (q, J ) 6.9 Hz, 2H),
2.75-2.69 (m, 2H), 2.43-2.36 (m, 3H), 1.95 (dd, J ) 6.2, 12.2
Hz, 1H), 1.77 (d, J ) 6.4 Hz, 1H), 1.43 (d, J ) 6.4 Hz, 3H), 1.24
(t, J ) 7.2 Hz, 3H), 1.31-1.14 (m, 3H), 1.10-1.00 (m, 1H); 13C
NMR (100 MHz, CDCl3) 177.10, 164.20, 161.76, 155.09, 153.46,
147.80, 139.43, 135.15, 134.81, 133.78, 131.05, 130.56, 130.47,
122.34, 121.66, 114.92, 114.71, 113.75, 113.53, 76.61, 61.37, 49.09,
48.45, 44.96, 44.31, 41.57, 40.37, 38.38, 30.65, 28.17, 22.19, 14.79;
6.66 (m, 3H), 4.71-4.78 (m, 1H), 4.05-4.3 (m, 4H), 2.68-2.76
(m, 2H), 2.36-2.44 (m, 3H), 1.96 (dd, J ) 5.9 Hz, 11.7 Hz, 1H),
1.78 (d, 12.4 Hz, 1H), 1.43 (d, 5.9 Hz, 3H), 2.24 (t, 7.3 Hz, 3H),
1.00-1.36 (m, 5H); HRMS calcd for C27H32N3O4 (MH+), 462.2393;
found, 462.2401.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(1E)-2-(5-Bromo-2-pyridinyl)-
ethenyl]decahydro-1-methyl-3-oxo-furo[3,4-g]isoquinoline-6(3H)-
carboxylic Acid, Ethyl Ester (29). To a solution of the phosphonate
32 (3.49 g, 11.3 mmol, 2 equiv) in THF (50 mL) at 0 °C was added
a 1 M solution of LHMDS in THF (11.3 mL, 11.3 mmol, 2 equiv).
After stirring for 10 min, Ti(Oi-Pr)4 (3.4 mL, 11.3 mmol, 2 equiv)
was added, followed by a solution of 25b (1.75 g, 5.7 mmol, 1
equiv) in THF (10 mL), and the mixture was stirred for 1 h under
N2. The reaction mixture was poured into saturated aqueous sodium
potassium tartrate solution (100 mL) and extracted with EtOAc (3
× 100 mL). The combined organic layers were washed with brine,
dried with MgSO4, filtered, and evaporated to dryness. Purification
by silica gel chromatography, eluting with 5% CH3OH-CH2Cl2,
yielded 1.80 g (70%) of the title compound as a pale yellow foam.
1H NMR (400 MHz, CDCl3) 8.59 (d, J ) 4.8 Hz, 1H), 7.76 (dd, J
) 3 Hz, 8.4 Hz, 1H), 7.06 (d, J ) 8.4 Hz, 1H), 6.56 (dd, J ) 9.6
Hz, 15.2 Hz, 1H), 6.45 (d, J ) 15.2 Hz, 1H), 4.73 (m, 1H), 4.35-
4.05 (m, 2H), 4.12 (q, J ) 6.8 Hz, 2H), 2.73-2.69 (m, 2H), 2.47-
2.35(m, 3H), 1.96 (q, 6.0 Hz, 1H), 1.74 (d, J ) 12.8 Hz, 1H), 1.41
(d, J ) 6.0 Hz, 3H), 1.35-1.18 (m, 7H), 1.10-0.98 (m, 1H).
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-1-methyl-9-[(e)-2-[5-[3-
(trifluoromethyl)phenyl]-2-pyridinyl]ethenyl]furo[3,4-g]isoquin-
olin-3(1H)-one (30a). A solution of 28a (250 mg, 0.473 mmol)
and iodotrimethylsilane (0.34 mL, 2.39 mmol, 5 equiv) in 5 mL of
dichloromethane was heated at reflux for 3 h. The reaction mixture
was cooled to rt, quenched by the addition of aq NaHCO3, and
stirred for 15 min at rt, and the mixture was extracted three times
with dichloromethane. The combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated to provide
240 mg of 30a. 1H NMR (400 MHz, CDCl3) 8.79 (d, J ) 2.2 Hz,
1H), 7.85 (dd, J ) 2.2, 8.1 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J ) 8.1
Hz, 1H), 7.67-7.59 (m, 2H), 7.29 (d, J ) 8.1 Hz, 1H), 6.65-6.55
(m, 2H), 4.80-4.73 (m, 1H), 3.12 (br, 2H), 2.77-2.71 (m, 1H),
2.65 (br, 1H), 2.48-2.36 (m, 3H), 1.91 (dd, J ) 6.2, 12.8 Hz, 1H),
1.80 (br, 2H), 1.44 (d, J ) 5.9 Hz, 3H), 1.47-1.08 (m, 4H); 13C
NMR (100 MHz, CDCl3) 177.56, 153.66, 147.78, 138.08, 134.88,
134.62, 133.55, 131.58, 131.43, 131.11, 129.92, 129.43, 124.50,
123.42, 121.77, 76.99, 49.79, 48.19, 45.55, 44.44, 41.36, 38.81,
37.08, 28.93, 28.09, 22.12; HRMS calcd for C26H28F3N2O2 (MH+),
457.2103; found, 457.2093
[R]20 ) -56.1 (c 7.6 mg/mL, MeOH); HRMS calcd for C28H32-
D
FN2O4 (MH+), 479.2346; found, 479.2348; Anal. (C28H31FN2O4‚
HCl‚1.5H2O) C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-Ethyl Decahydro-1-methyl-3-oxo-9-
[(e)-2-[5-(2-fluorophenyl)-2-pyridinyl]ethenyl]furo[3,4-g]iso-
quinoline-6(3H)-carboxylate (28c). 1H NMR (400 MHz, CDCl3)
8.73 (s, 1H), 7.84 (dt, J ) 8.1, 1.9 Hz, 1H), 7.42 (dt, J ) 1.7, 7.7
Hz, 1H), 7.39-7.34 (m, 1H), 7.27-7.15 (m, 3H), 6.64-6.53 (m,
2H), 4.77-4.71 (m, 1H), 4.20 (br, 2H), 4.11 (q, J ) 7.0 Hz, 2H),
2.75-2.69 (m, 2H), 2.42-2.37 (m, 3H), 1.95 (dd, J ) 5.9, 12.5
Hz, 1H), 1.77 (d, J ) 12.5 Hz, 1H), 1.44 (d, J ) 5.9 Hz, 3H), 1.24
(t, J ) 7.0 Hz, 3H), 1.34-1.17 (m, 3H), 1.09-1.00 (m, 1H); 13C
NMR (100 MHz, CDCl3) 177.19, 160.81, 158.34, 155.10, 153.06,
136.83, 135.10, 131.13, 130.06, 130.02, 129.99, 129.83, 129.75,
124.59, 124.55, 121.35, 116.31, 116.08, 61.38, 49.07, 48.42, 44.92,
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-6-methyl-1-methyl-9-
[(e)-2-[5-[3-(trifluoromethyl)phenyl]-2-pyridinyl]ethenyl]furo-
[3,4-g]isoquinolin-3(1H)-one (30b). A mixture of 30a (62 mg,
0.136 mmol), sodium cyanoborohydride (100 mg), and excess
paraformaldehyde in 2 mL of dichloromethane was stirred overnight
at rt and quenched with aq NH4Cl. The mixture was extracted with
dichloromethane, the organic layer was washed with brine, dried
over MgSO4, filtered, and concentrated to give residue. The residue
was purified by preparative TLC using 5% MeOH-dichlo-
romethane as eluent to provide 31 mg of 30b. 1H NMR (400 MHz,
CDCl3) 8.78 (d, J ) 2.2 Hz, 1H), 7.84 (dd, J ) 2.2, 8.1 Hz, 1H),
7.80 (s, 1H), 7.76 (d, J ) 7.3 Hz, 1H), 7.66-7.57 (m, 2H), 7.27
(d, J ) 8.1 Hz, 1H), 6.65-6.54 (m, 2H), 4.77-4.70 (m, 1H), 2.90
(d, J ) 11.7 H, 1H), 2.85 (dd, J ) 2.9, 11.7 Hz, 1H), 2.76-2.70
(m, 1H), 2.45-2.36 (m, 2H), 2.28 (s, 3H), 1.95-1.88 (m, 2H),
1.77 (dd, J ) 2.6, 12.8 Hz, H), 1.69 (t, J ) 11.0 Hz, 1H), 1.43 (d,
J ) 6.6 Hz, 3H), 1.50-1.42 (m, 1H), 1.27-1.10 (m, 3H); 13C NMR
(100 MHz, CDCl3) 177.48, 153.87, 147.98, 147.85, 138.22, 135.70,
134.86, 133.50, 131.52, 131.19, 130.82, 129.95, 129.48, 124.58,
124.54, 123.52, 123.48, 121.73, 76.72, 61.47, 56.02, 48.66, 46.19,
44.29, 41.57, 40.35, 38.35, 30.64, 28.15, 22.22, 14.79; [R]25
)
D
-58.7 (c 7.3 mg/mL, MeOH); HRMS calcd for C28H32FN2O4
(MH+), 479.2346; found, 479.2339; Anal. (C28H31FN2O4‚HCl‚
0.6H2O) C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-Ethyl 9-[(e)-2-[[2,3′-Bipyridin]-6′-yl]-
ethenyl]-decahydro-1-methyl-3-oxofuro[3,4-g]isoquinoline-6(3H)-
carboxylate (28d). To a solution of 29 (100 mg, 0.22 mmol) in
toluene (5 mL) was added Pd(OAc)2 (5 mg, 0.022 mmol, 0.1 equiv),
(S)-(-)-2,2′-bis(diphenylphoshphino)-1,1′-binaphthyl (13 mg, 0.022
mmol, 0.1 equiv), and 2-tributylstannyl pyridine (119 mg, 0.32
mmol, 1.5 equiv). The mixture was bubbled with N2 for 5 min,
then heated to 100 °C in a pressure tube. After 16 h, the mixture
was poured onto aqueous NH4Cl (15 mL) and extracted with EtOAc
(3 × 15 mL). The combined organic layers were washed with brine,
dried over MgSO4, filtered, and evaporated to dryness. Purification
by silica gel chromatography, eluting with 2% CH3OH-CH2Cl2,
followed by silica gel chromatography, eluting with 60% EtOAc-
44.97, 41.76, 39.67, 38.53, 30.85, 28.86, 22.19; [R]20 ) +3.3 (c
D
3.0 mg/mL, MeOH); HRMS calcd for C27H30F3N2O2 (MH+),
471.2259; found, 471.2255; Anal. (C27H29F3N2O2‚2HCl‚0.8H2O)
C, H, N.
1
hexane, yielded 30 mg of 28d. H NMR (400 MHz, CDCl3) 9.12
(d, J ) 2.2 Hz, 1H), 8.70 (d, J ) 6.6 Hz, 1H), 9.8.29 (dd, J ) 2.2
Hz, 8.1 Hz 1H), 7.74-7.80 (m, 3H), 7.25-7.30 (m, 3H), 6.57-
(1R,3aR,4aS,8aS,9S,9aS)-6-Acetyl-decahydro-1-methyl-9-[(e)-
2-[5-[3-(trifluoromethyl)phenyl]-2-pyridinyl]ethenyl]furo[3,4-g]-

Himbacine Analogs as Thrombin Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21 5157
isoquinolin-3(1H)-one (30c). To a solution of 30a (26 mg, 0.057
mmol) in 1 mL of dichloromethane was added acetic anhydride
(27 µL, 0.286 mmol, 5 equiv), followed by triethyl amine (24 µL,
0.172 mmol, 3 equiv). The mixture was stirred overnight at rt,
diluted with ethyl acetate, and washed with aq NaHCO3, followed
by brine. It was dried over MgSO4, filtered, and concentrated to
give 21 mg of 30c. 1H NMR (400 MHz, CDCl3) 8.79 (s, 1H), 7.86
(dt, J ) 2.2, 8.1 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J ) 7.3 Hz, 1H),
7.67-7.59 (m, 2H), 7.28 (d, J ) 9.5 Hz, 1H), 6.67-6.54 (m, 2H),
4.79-4.64 (m, 2H), 3.86-3.74 (m, 1H), 3.07-2.27 (m, 2H), 2.48-
2.37 (m, 2H), 2.23-1.96 (m, 5H), 1.89-1.73 (m, 2H), 1.46-1.02
(m, 6H); HRMS calcd for C28H30F3N2O3 (MH+), 499.2209; found,
499.2209; Anal. (C28H29F3N2O3‚HCl), H, N, C: calcd, 62.86; found,
63.64.
(1R,3aR,4aS,8aS,9S,9aS)-N-Ethyl-dodecahydro-1-methyl-3-
oxo-9-[(e)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]furo[3,4-g]-
isoquinoline-6-carboxamide (30i). H NMR (400 MHz, CDCl3)
1
8.72 (d, J ) 2.2 Hz, 1H), 7.78 (dd, J ) 2.2, 8.1 Hz, 1H), 7.92-
7.36 (m, 1H), 7.31 (d, J ) 7.3 Hz, 1H), 7.22 (d, J ) 8.1 Hz, 2H),
7.04 (dt, J ) 2.2, 8.1 Hz, 1H), 6.59-6.49 (m, 2H), 4.84 (t, J ) 5.1
Hz, 1H), 4.74-4.68 (m, 1H), 3.95 (d, J ) 9.5 Hz, 2H), 3.23-3.13
(m, 2H), 2.71-2.65 (m, 2H), 2.40-2.32 (m, 3H), 1.89 (dd, J )
5.9, 12.5 Hz, 1H), 1.73 (d, J ) 13.2 Hz, 1H), 1.38 (d, J ) 5.9 Hz,
3H), 1.29-1.26 (m, 2H), 1.07 (t, J ) 7.0 Hz, 3H), 1.19-1.02 (m,
2H); 13C NMR (100 MHz, CDCl3) 177.21, 164.02, 161.57, 157.16,
153.37, 147.71, 139.37, 139.29, 134.93, 134.67, 133.58, 130.99,
130.45, 130.37, 122.25, 121.55, 114.76, 114.55, 113.56, 113.34,
76.60, 49.23, 48.25, 44.72, 44.43, 41.45, 40.28, 38.09, 35.67, 30.45,
28.09, 22.04, 15.55; HRMS calcd for C28H33FN3O3 (MH+),
478.2506; found, 478.2515; [R]20D ) -64.4 (c 3.4 mg/mL, MeOH);
Anal. (C28H32FN3O3‚HCl‚1.5H2O), C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-1-methyl-6-(2-methyl-1-
oxopropyl)-9-[(e)-2-[5-[3-(trifluoromethyl)phenyl]-2-pyridinyl]-
1
ethenyl]furo[3,4-g]isoquinolin-3(1H)-one (30d). H NMR (400
MHz, CDCl3) 8.79 (s, 1H), 7.86 (d, J ) 8.1 Hz, 1H), 7.81 (s, 1H),
7.76 (d, J ) 7.3 Hz, 1H), 7.69-7.59 (d, J ) 8.1 Hz, 1H), 7.27 (d,
J ) 8.1 Hz, 1H), 6.67-6.55 (m, 2H), 4.78-4.67 (m, 2H), 3.99-
3.90 (m, 1H), 3.04-3.71 (m, 3H), 2.41-2.17 (m, 3H), 2.04-1.95
(m, 1H), 1.86 (t, J ) 15.4 Hz, 1H), 1.72 (br, 1H), 1.49-1.41 (m,
4H), 1.27-1.05 (m, 8H); HRMS calcd for C30H34F3N2O3 (MH+),
527.2522; found, 527.2517; Anal. (C30H33F3N2O3‚HCl‚1.5H2O) C,
H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(3-Fluorophenyl)-2-py-
ridinyl]ethenyl]-decahydro-1-methyl-6-(methylsulfonyl)furo[3,4-
g]isoquinolin-3(1H)-one (30j). 1H NMR (400 MHz, CDCl3) 8.77
(d, J ) 2.2 Hz, 1H), 7.83 (dd, J ) 2.2, 8.1 Hz, 1H), 7.14 (dt, J )
5.9, 8.1 Hz, 1H), 7.36-7.34 (m, 1H), 7.28-7.24 (m, 2H), 7.09
(dt, J ) 3.3, 8.4 Hz, 1H), 6.65-6.55 (m, 2H), 4.76-4.70 (m, 1H),
3.84 (d, J ) 11.7 Hz, 1H), 3.78 (dd, J ) 4.4, 11.4 Hz, 1H), 2.78
(s, 3H), 2.79-2.73 (m, 1H), 2.65-2.59 (m, 1H), 2.49-2.32 (m,
3H), 1.97 (ddd, J ) 2.9, 6.1, 13.5 Hz, 1H), 1.90 (d, J ) 10.3 Hz,
1H), 1.53-1.47 (m, 1H), 1.44 (d, J ) 5.9 Hz, 3H), 1.30-1.16 (m,
3H); 13C NMR (100 MHz, CDCl3) 176.92, 164.19, 161.74, 153.23,
147.75, 139.46, 139.38, 134.89, 134.54, 133.89, 131.27, 130.59,
130.51, 122.38, 122.36, 121.99, 114.98, 114.76, 113.75, 113.53,
76.60, 50.95, 48.34, 46.44, 44.62, 41.39, 39.85, 38.25, 34.92, 30.43,
28.13, 22.11; HRMS calcd for C26H30FN2O4S (MH+), 485.1910;
found, 485.1901; Anal. (C26H29FN2O4S‚HCl‚0.5H2O) C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(3-Fluorophenyl)-2-py-
ridinyl]ethenyl]-decahydro-1-methyl-6-(propylsulfonyl)furo[3,4-
g]isoquinolin-3(1H)-one (30k). 1H NMR (400 MHz, CDCl3) 8.77
(d, J ) 2.2 Hz, 1H), 7.83 (dd, J ) 2.2, 8.1 Hz, 1H), 7.44 (dt, J )
5.9, 7.7 Hz, 1H), 7.35 (d, J ) 8.1 Hz, 1H), 7.28-7.24 (m, 2H),
7.10 (dt, J ) 2.4, 8.4 Hz, 1H), 6.65-6.54 (m, 2H), 4.77-4.70 (m,
1H), 3.84 (d, J ) 12.5, 1H), 3.78 (dd, J ) 4.0, 12.1 Hz, 1H), 2.89-
2.85 (m, 2H), 2.79-2.69 (m, 3H), 2.49-2.38 (m, 3H), 1.96 (ddd,
J ) 2.9, 6.6, 13.2 Hz, 1H), 1.89-1.80 (m, 3H), 1.45 (d, J ) 5.9
Hz, 3H), 1.50-1.44 (m, 1H), 1.31-1.51 (m, 3H), 1.05 (t, J ) 7.3
Hz, 3H); HRMS calcd for C28H34FN2O4S (MH+), 513.2223; found,
513.2227; Anal. (C28H33FN2O4S‚HCl‚0.5H2O) C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-Phenylmethyl Decahydro-1-methyl-
3-oxo-9-[(e)-2-[5-[3-(trifluoromethyl)phenyl]-2-pyridinyl] ethe-
nyl]furo[3,4-g]isoquinoline-6(3H)-carboxylate (30l). 1H NMR
(400 MHz, CDCl3) 8.79 (d, J ) 2.2 Hz, 1H), 7.85 (dd, J ) 2.2,
8.1 Hz, 1H), 7.81 (s, 1H), 7.75 (d, J ) 7.3 Hz, 1H), 7.67-7.59 (m,
2H), 7.35 (br, 5H), 7.27 (d, J ) 9.5 Hz, 1H), 6.66-6.54 (m, 2H),
5.12 (s, 2H), 4.79-4.72 (m, 1H), 4.23 (br, 2H), 2.76-2.70 (m,
2H), 2.52-2.37 (m, 3H), 1.97 (br, 1H), 1.80 (d, J ) 12.5, 1H),
1.46 (d, J ) 5.9 Hz, 3H), 1.35-1.19 (m, 3H), 1.13-1.03 (m, 1H);
13C NMR (100 MHz, CDCl3) 177.04, 154.73, 153.62, 147.75,
138.09, 136.42, 135.19, 134.81, 133.47, 131.38, 131.06, 130.99,
129.90, 129.42, 128.24, 127.77, 127.61, 124.47, 123.41, 123.37,
121.66, 76.53, 67.02, 49.11, 48.32, 44.80, 44.39, 41.45, 40.20,
38.24, 28.03, 22.08; HRMS calcd for C34H34F3N2O4 (MH+),
591.2471; found, 591.2464; Anal. (C34H33F3N2O4‚HCl) H, N, C:
calcd, 65.12; found, 67.79.
(1R,3aR,4aS,8aS,9S,9aS)-6-(Cyclopropylcarbonyl)-decahydro-
1-methyl-9-[(e)-2-[5-[3-(trifluoromethyl)phenyl]-2-pyridinyl]-
1
ethenyl]furo[3,4-g]isoquinolin-3(1H)-one (30e). H NMR (400
MHz, CDCl3) 8.80 (d, J ) 2.2 Hz, 1H), 7.85 (dd, J ) 2.9, 8.1 Hz,
1H), 7.81 (s, 1H), 7.77 (d, J ) 7.3 Hz, 1H), 7.68-7.59 (m, 2H),
7.27 (d, J ) 8.1 Hz, 1H), 6.68-6.55 (m, 2H), 4.79-4.63 (m, 2H),
4.28-4.17 (m, 1H), 3.11-2.74 (m, 2H), 2.53-2.26 (m, 2H), 2.00
(dd, J ) 6.2, 11. 4 Hz, 1H), 1.93-1.73 (m, 2H), 1.46 (d, J ) 5.9
Hz, 3H), 1.5-1.09 (m, 4H), 1.01-0.96 (m, 2H), 0.76 (br, 2H);
HRMS calcd for C30H32F3N2O3 (MH+), 525.2365; found, 525.2372;
Anal. (C30H31F3N2O3‚HCl) C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-6-(Cyclopropylcarbonyl)-9-[(e)-2-[5-
(3-fluorophenyl)-2-pyridinyl]ethenyl]-decahydro-1-methylfuro-
1
[3,4-g]isoquinolin-3(1H)-one (30f). H NMR (400 MHz, CDCl3)
8.74 (s, 1H), 7.80 (d, J ) 8.1 Hz, 1H), 7.40 (dd, J ) 8.1, 13.9 Hz,
1H), 7.32 (d, J ) 8.1 Hz, 1H), 7.25 (s, 1H), 7.24 (d, J ) 8.1 Hz,
1H), 7.05 (t, J ) 8.4 Hz, 1H), 6.62-6.51 (m, 2H), 4.78-4.58 (m,
2H), 4.24-4.13 (m, 1H), 3.07-2.67 (m, 3H), 2.51-2.19 (m, 3H),
1.94 (dd, J ) 6.2, 11.4 Hz, 1H), 1.87-1.69 (m, 2H), 1.42 (d, J )
5.9 Hz, 3H), 1.46-1.07 (m, 4H), 0.98-0.82 (m, 2H), 0.72 (br,
2H); HRMS calcd for C29H32FN2O3 (MH+), 475.2397; found,
475.2406; [R]25D ) -77.4 (c 3.5 mg/mL, MeOH); Anal. (C29H31-
FN2O3‚HCl‚0.3H2O), C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-6-(Cyclopropylcarbonyl)-9-[(e)-2-[5-
(2-fluorophenyl)-2-pyridinyl]ethenyl]-decahydro-1-methylfuro-
[3,4-g]isoquinolin-3(1H)-one (30g). 1H NMR (400 MHz, CDCl3)
8.72 (s, 1H), 7.83 (d, J ) 8.1 Hz, 1H), 7.42 (t, J ) 8.7 Hz, 1H),
7.38-7.33 (m, 1H), 7.26-7.14 (m, 3H), 6.64-6.53 (m, 2H), 4.77-
4.40 (m, 2H), 4.26-4.15 (m, 1H), 3.08-2.69 (m, 2H), 2.53-2.21
(m, 3H), 1.97 (dd, J ) 6.6, 11.0 Hz, 1H), 1.44 (d, J ) 5.9 Hz,
3H), 1.47-1.09 (m, 4H), 1.06-0.84 (m, 2H), 0.73 (br, 2H); HRMS
calcd for C29H32FN2O3 (MH+), 475.2397; found, 475.2411; [R]25
D
) -145.7 (c 3.2 mg/mL, MeOH); Anal. (C29H31FN2O3‚HCl) C,
H, N.
(1R,3aR,4aS,8aS,9S,9aS)-Dodecahydro-1-methyl-3-oxo-9-[(e)-
2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]furo[3,4-g]isoquinoline-
1
6-carboxamide (30h). H NMR (400 MHz, CDCl3) 8.77 (d, J )
(1R,3aR,4aS,8aS,9S,9aS)-2-Methoxyethyl 9-[(e)-2-[5-(3-Fluo-
rophenyl)-2-pyridinyl]ethenyl]-decahydro-1-methyl-3-oxo-furo-
[3,4-g]isoquinoline-6(3H)-carboxylate (30m). To a solution of 29
(0.270 g, 0.58 mmol) in CH2Cl2 (15 mL) was added TMSI (624
µL, 4.4 mmol, 7.5 equiv), and the mixture was heated to reflux.
After 6 h, the mixture was poured onto aqueous NaHCO3 (30 mL)
and extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were washed with brine, dried with MgSO4, filtered, and
evaporated to dryness resulting in 209 mg of amine (92%). To this
product in CH2Cl2 (15 mL) at 0 °C was added Et3N (97 µL, 0.69
2.2 Hz, 1H), 7.83 (dd, J ) 2.9, 8.1 Hz, 1H), 7.45 (dt, J ) 5.9, 8.1
Hz, 1H), 7.37-7.34 (m, 1H), 7.28-7.24 (m, 2H), 7.10 (dt, J )
2.9, 8.4 Hz, 1H), 6.64-6.53 (m, 2H), 4.79-4.72 (m, 1H), 4.55 (s,
2H), 3.98 (d, J ) 13.2 Hz, 1H), 3.92 (d, J ) 13.9 Hz, 1H), 2.81
(dt, J ) 2.9, 13.2 Hz, 1H), 2.75-2.71 (m, 1H), 2.51-2.37 (m,
3H), 1.96 (dd, J ) 5.9, 11.7 Hz, 1H), 1.81 (dd, J ) 2.2, 13.2 Hz,
1H), 1.44 (d, J ) 5.9 Hz, 1H), 1.37-1.31 (m, 2H), 1.26-1.07 (m,
2H); HRMS calcd for C26H29FN3O3 (MH+), 450.2193; found,
450.2187; Anal. (C26H28FN3O3‚HCl‚1.8H2O), C, H, N.

5158 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Chelliah et al.
mmol, 1.3 equiv) and chloroformic acid 2-methoxyethyl ester (68
µL, 5.9 mmol, 1.1 equiv), and the mixture was allowed to slowly
warm to rt while stirring under N2. After 1 h, the mixture was
poured into water (30 mL) and extracted with CH2Cl2 (3 × 15
mL). The combined organic layers were washed with brine (30
mL), dried over MgSO4, filtered, and evaporated to dryness.
Purification by silica gel chromatography, eluting with 3% CH3-
OH-CH2Cl2, yielded 183 mg of the carbamate analog as a solid
in THF (125 mL), and the mixture was stirred at rt for 1 h. The
reaction was quenched by the addition of H2O (500 mL), the THF
was evaporated, and the aq layer was extracted with EtOAc (4 ×
150 mL). The combined organic layers were washed with aq K2-
CO3 (2 × 300 mL) and brine (300 mL), dried over MgSO4, filtered,
and evaporated, and the crude product was chromatographed with
1
5:95 MeOH-CH2Cl2 to give 31.7 g (97%) of oil. H NMR (400
MHz, CDCl3) 8.59 (d, J ) 2.0 Hz, 1H), 7.76 (dd, J ) 8.2, 2.1 Hz,
1H), 7.29 (dd, J ) 8.2, 2.2 Hz, 1H), 4.12-4.05 (m, 4 H), 3.36 (d,
J ) 22.0 Hz, 2H), 1.27 (t, J ) 7.0 Hz, 6H).
1
(69%). H NMR (400 MHz, CDCl3) 8.59 (d, J ) 2.4 Hz, 1H),
7.76 (dd, J ) 2.4, 8.2 Hz, 1H), 7.06 (d, J ) 8.3 Hz, 1H) 6.56 (dd,
J ) 9.6, 15.4 Hz, 1H), 6.45 (d, J ) 15.4 Hz, 1H), 4.72 (m, 1H),
4.1-4.28 (m, 4H), 3.59 (t, J ) 4.49 Hz, 2H), 3.38 (s, 3H), 2,75-
2.68 (m, 2H), 2.32-2.51 (m, 3H), 1.96 (dd, J ) 6.3, 12.8 Hz, 1H),
1.73 (d, J ) 12.5 Hz, 1H), 1.41 (d, J ) 5.95 Hz, 3H), 1.37-1.00
(m, 4H).
2-Oxopiperidine-1-carboxylic Acid Ethyl Ester (33). δ-Vale-
rolactam (6.7 g, 0.0675 mol) was dissolved in THF (250 mL) and
cooled to -78 °C. n-BuLi (28.44 mL, 1.1 equiv, 2.5 M solution in
hexanes) was added dropwise. The mixture was stirred for 30 min,
then ethyl chloroformate (6.49 mL, 1.05 equiv) was added, and
the mixture allowed to warm to rt. Water was added, and the organic
layer was extracted with EtOAc. The combined organic layers were
dried and concentrated to give 11.57 g of 1A (99%). 1H NMR (400
MHz, CDCl3) δ 4.29 (q, J ) 7.2 Hz, 2H), 3.71 (br t, J ) 5.6 Hz,
2H), 2.50 (br t, J ) 6.8 Hz, 2H), 1.83 (br s, 4H), 1.33 (t, J ) 7.2
Hz, 3H).
To 65 mg of the above product dissolved in toluene (2 mL)/
H2O (1 mL)/EtOH (0.5 mL) was added 3-fluorobenzene boronic
acid (28 mg, 1.5 equiv), K2CO3 (73 mg, 4 equiv), and tetrakis-
(triphenylphosphine)palladium (8 mg, 5 mol %). After bubbling
with nitrogen for 2-3 min, the mixture was heated to 100 °C in a
sealed tube for 4 h. The mixture was poured onto aq 1 N NaOH
and extracted with diethyl ether. The combined organic extracts
were washed with brine, dried with MgSO4, filtered, and evaporated
to dryness. Purification by flash chromatography yielded 62 mg of
30m. 1H NMR (400 MHz, CDCl3) 8.77 (d, J ) 2.2 Hz, 1H), 7.82
(dd, J ) 2.2 Hz, 8.1 Hz, 1H), 7.42-7.47 (m, 2H), 7.24-7.29 (m,
3H), 6.53-6.64 (m, 2H), 4.72-4.79 (m, 1H), 4.16-4.26 (m, 5H),
3.59 (t, J ) 4.4 Hz, 2H), 3.38 (s, 3H), 2.68-2.78 (m, 2H), 2.36-
2.44 (m, 2H), 1.98 (dd, J ) 5.9, 12.4 Hz, 1H), 1.80 (d, J ) 12.4
Hz, 1H), 1.45 (d, J ) 5.9 Hz, 3H), 1.10-1.38 (m, 4H); HRMS
calcd for C29H34FN2O5 (MH+), 509.2452; found, 509.2448; Anal.
(C29H33FN2O5‚HCl) C, H, N.
6-Trifluoromethanesulfonyloxy-3,4-dihydro-2H-pyridine-1-
carboxylic Acid Ethyl Ester (34). Compound 33 (11.15 g, 65
mmol) was dissolved in THF (250 mL), and the solution was cooled
to -78 °C. LHMDS (65 mL, 1 equiv, 1 M solution in THF) was
added dropwise, and the resulting mixture stirred for 30 min. A
solution of 2-[N,N-bis(trifluoromethylsulfonyl)-amino]-5-chloro-
pyridine in THF (73 mL) was added dropwise. The resulting mixture
was stirred for 10 min and allowed to warm to rt. Water was added,
and the organic layer was extracted with EtOAc. The combined
organic layers were dried and concentrated. Chromatography (5-
1
10% EtOAc in hexane) gave 12.0 g of 34 (61%). H NMR (400
MHz, CDCl3) δ 5.32 (t, J ) 3.6 Hz, 1H), 4.24 (q, J ) 7.2 Hz,
2H), 3.66 (m, 2H), 2.27 (m, 2H), 1.78 (m, 2H), 1.30 (J ) 7.2 Hz,
3H).
5-Bromo-2-pyridinemethanol (31). To a solution of 2,5-
dibromopyridine (10 g, 84.4 mmol) in 1 L toluene at -78 °C was
added 2.5 M solution of n-butyl lithium in hexanes (40.5 mL, 101.3
mmol, 1.2 equiv) drop by drop over a period of 15 min, stirred for
2 h, and then DMF (13.1 mL, 169.2 mmol) was added. The mixture
was stirred for 1 h at -78 °C, 30 min at 0 °C then warmed to rt
using a warm water bath. To the reaction mixture was added 100
mL of methanol, followed by NaBH4 (3.2 g, 84.6 mmol, 1 equiv),
and stirred for 30 min at rt. It was quenched by the addition of aq
NH4Cl and stirred vigorously for 10 min, and the organic layer
was separated. The aqueous layer was extracted twice with ethyl
acetate and the combined organic layers were washed with water
and brine, dried over MgSO4, filtered, concentrated, and evaporated
to dryness to give the crude product. Another batch of the same
reaction was carried out, and the crude products from both of these
batches were combined and recrystallized from ethyl acetate-
hexanes to provide 11.9 g of solid. The filtrate was concentrated
and recrystallized from ether-hexanes to provide another 4.29 g
of solid (51% combined yield). 1H NMR (400 MHz, CDCl3) 8.64
(d, J ) 2.0 Hz, 1H), 7.84 (dd, J ) 2.0, 8.4 Hz, 1H), 7.21 (d, J )
8.4 Hz, 1H), 4.74 (s, 2H).
[(5-Bromo-2-pyridinyl)methyl]-phosphonic Acid, Diethyl Es-
ter (32). To a solution of alcohol 31 (20 g, 106 mmol) and Et3N
(17.8 mL, 128 mmol, 1.2 equiv) in CH2Cl2 (300 mL) kept at ∼-30
°C was slowly added methanesulfonyl chloride (9.1 mL, 118 mmol,
1.1 equiv). The slurry was stirred for 1 h while it warmed up to 0
°C. The reaction mixture was diluted with aq NaHCO3 (500 mL),
and the organic layer was separated. The aqueous layer was
extracted with Et2O (2 × 200 mL), and the combined organic layers
were washed with aq NaHCO3 (2 × 300 mL) and brine (300 mL).
The solution was dried over MgSO4, filtered, and evaporated to
give the crude mesylate, which was used as such for the next step.
1H NMR (400 MHz, CDCl3) 8.67 (d, J ) 2.0 Hz, 1H), 7.89 (dd, J
) 8.4, 2.4 Hz, 1H), 7.33 (d, J ) 8.4 Hz, 1H), 5.28 (s, 2H), 3.10 (s,
3H).
(2E)-3-(Diethoxyboryl)-2-propenoic Acid Ethyl Ester (35).
Borane dimethylsulfide complex (5.82 mL, 1.05 equiv) was
dissolved in THF and cooled to 0 °C. (1R)-(+)-R-Pinene (22.56
mL, 2.32 equiv) was added dropwise, and the mixture was stirred
at 0 °C for 1 h and at rt for 2 h. The mixture was cooled to
-35 °C and ethyl propiolate (6.2 mL, 1 equiv) was added dropwise;
the mixture was stirred at -35 °C for 45 min and rt for 3 h.
Acetaldehyde (48 mL) was added, and the mixture was heated at
40-41 °C overnight. The volatile organic components were
carefully removed under reduced pressure to give 29 g of a mixture
of the product and R-pinene (1:2.3 by NMR). 1H NMR (400 MHz,
CDCl3) δ characteristic peaks for the product include, 6.95 (d, J )
18.0 Hz, 1H), 6.48 (d, J ) 18.0 Hz, 1H), 4.12 (q, J ) 7.2 Hz, 2H),
3.60 (q, J ) 7.2 Hz, 4H).
6-((E)-2-Ethoxycarbonylvinyl)-3,4-dihydro-2H-pyridine-1-
carboxylic Acid Ethyl Ester (36). Pd(OAc)2 (592 mg, 10%) and
2-(di-t-butylphosphino)biphenyl (1.57 g, 20%) were dissolved in
THF (100 mL). The mixture was stirred for 10 min under N2, and
then a mixture of compound 34 (8 g, 26 mmol) and compound 35
(20 g, 1.5 equiv) in THF (32 mL) was added. KF (4.6 g) was then
added, and the mixture was heated at 55 °C overnight. The mixture
was allowed to cool to rt and diluted with EtOAc. The mixture
was washed with NaHCO3 (satd), NH4Cl (satd), water, and finally
dried over MgSO4. Removal of solvents under reduced pressure
followed by column chromatography (10% EtOAc in hexane) gave
6 g (89%) of colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.21 (d,
J ) 15.6 Hz, 1H), 5.88 (d, J ) 15.6 Hz, 1H), 5.69 (t, J ) 4.0 Hz,
1H), 4.15 (m, 4H), 3.59 (m, 2H), 2.26 (m, 2H), 1.82 (m, 2H), 1.25
(m, 6H).
6-((E)-2-Carboxyvinyl)-3,4-dihydro-2H-pyridine-1-carboxy-
lic Acid Ethyl Ester (37). Compound 36 (6 g, 23.6 mmol) was
dissolved in a 1:1 mixture of MeOH and THF (66 mL). A solution
of 1 N NaOH (52 mL) was added, and the mixture was stirred for
2.5 h until no starting material remained. The mixture was acidified
to pH 1 with 2 N HCl and extracted with EtOAc. The extracts
were washed with NH4Cl (satd), dried, and concentrated under
To a suspension of 60% NaH (8.5 g, 212 mmol 2.0 equiv) in
THF (500 mL) at rt was added diethylphosphite (27.4 mL, 213
mmol, 2 equiv) drop by drop, and the mixture was stirred for 1 h.
To this cloudy solution was added a solution of the above mesylate

Himbacine Analogs as Thrombin Receptor Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21 5159
1
reduced pressure to give 5 g of 37 (93.5%). H NMR (400 MHz,
was dissolved in THF (4 mL) and cooled to 0 °C. LiHMDS (2.91
mL of a 1.0 M solution in THF, 2.91 mmol, 2 equiv) was added.
After stirring for 30 min, the mixture was allowed to warm to rt,
and Ti(OiPr)4 (0.859 g, 2.91 mmol, 2 equiv) was added. After 5
min, a solution of compound 41 (450 mg, 1.455 mmol, 1 equiv) in
THF (4 mL) was added, and after stirring for 1.5 h, a saturated
solution of potassium sodium tartrate was added, the THF was
removed under reduced pressure, and the mixture was extracted
with EtOAc. The organic layers were dried (MgSO4), concentrated,
and purified by silica gel chromatography (hexane/EtOAc 2:1) to
give 500 mg of compound 42 (75%). 1H NMR (400 MHz, CDCl3)
δ 1.25 (t, J ) 7.3 Hz, 3H), 1.39 (d, J ) 5.86 Hz, 3H), 1.55-1.65
(m, 2H), 1.67-1.88 (m, 3H), 2.29-2.35 (m, 1H), 2.41-2.50 (m,
2H), 2.83 (quintet, J ) 6.6 Hz, 1H), 3.07-3.14 (m, 1H), 3.25-
3.32 (m, 1H), 3.76-3.82 (m, 1H), 4.07-4.13 (m, 2H), 4.71-4.78
(m, 1H), 6.43 (d, J ) 15.4 Hz, 1H), 6.55 (dd, J ) 15.4, 10.2 Hz,
1H), 7.06 (d, J ) 8.8 Hz, 1H), 7.75 (dd, J ) 8.8, 2.2 Hz, 1H), 8.58
(d, J ) 2.2 HZ, 1H).
CDCl3) δ 7.30 (d, J ) 15.2 Hz, 1H), 5.87 (d, J ) 15.2 Hz, 1H),
5.73 (m, 1 H), 4.14 (m, 2H), 3.60 (m, 2H), 2.70 (m, 2H), 1.82 (m,
2H), 1.23 (m, 3H).
6-[(E)-2-((Z)-3-Benzyloxycarbonyl-1(R)-methylallyloxycarbo-
nyl)vinyl]-3,4-dihydro-2H-pyridine-1-carboxylic Acid Ethyl Es-
ter (38). Compound 37 (3.06 g, 13.6 mmol) and 4-pyrollidinopy-
ridine (201.6 mg, 10%) were dissolved in CH2Cl2 (70 mL) and
stirred at 0 °C. DCC (2.81 g, 1 equiv) was added, and after stirring
for 10 min, a solution of alcohol 8 (3.36 g, 1.2 equiv) was added.
The resulting mixture was stirred for 2 h. The mixture was filtered,
concentrated under reduced pressure, and finally purified by silica
gel chromatography (5:1 hexane/EtOAc) to give 3.7 g of 38 (66%).
1H NMR (400 MHz, CDCl3) δ 1.21 (t, J ) 7.2 Hz, 3H), 1.40 (d,
J ) 6.6 Hz, 3H), 1.78-1.88 (m, 2H), 2.23-2.3 (m, 2H), 3.58-
3.61 (m, 2H), 4.14 (q, J ) 7.2 Hz, 2H), 5.19 (br s, 3H), 5.7 (t, J
) 4 Hz, 1H), 5.82-5.9 (m, 2H), 6.2 (dd, J ) 11.7, 7.3 Hz, 1H),
6.29-6.38 (m, 1H), 7.32-7.4 (m, 5H).
(4aS,5S,5aS,6R,8aR)-6-Methyl-8-oxo-3,4,4a,5,5a,6,8,8a-oc-
tahydro-2H-furo[3,4-g]quinoline-1,5-dicarboxylic Acid 5-Benzyl
Ester 1-Ethyl Ester (39). Compound 38 (3.7 g, 8.96 mmol) was
dissolved in m-xylene (400 mL), the mixture was degassed and
heated in a sealed tube at 150 °C for 45 min. The solvent was
removed under reduced pressure. The residue was filtered through
a silica gel pad (eluting with hexane/EtOAc 4:1). After concentration
under reduced pressure, the residue (1.7 g) was taken up in THF
(30 mL), and DBU (0.615 mL, 4.11 mmol) was added, After stirring
for 1 h, NH4Cl(satd) was added, and the mixture was extracted with
EtOAc. The extracts were dried (MgSO4) and concentrated under
Ethyl (4aS,5S,5aS,6R,8aR,9aS)-5-[(E)-2-[5-(3-Fluorophenyl)-
2-pyridinyl]ethenyl]-decahydro-6-methyl-8-oxofuro[3,4-g]quino-
line-1(2H)-carboxylate (43a). Compound 42 (90 mg, 0.194 mmol)
was dissolved in PhMe/EtOH/H2O (0.3 mL, 0.03 mL, 0.1 mL),
K2CO3 (80.4 mg, 3 equiv), Pd(Ph3P)4 (22 mg, 10 mol %), and
3-fluorobenzeneboronic acid (33 mg, 1.2 equiv) were added. The
mixture was heated at 100 °C for 3 h. The mixture was extracted
with Et2O, and the extracts were dried (MgSO4) and concentrated
in vacuo. Purification by silica gel chromatography (hexane/EtOAc
1
2:1) gave 60 mg of 43a (65%). H NMR (400 MHz, CDCl3) δ
1.00-1.09 (m, 1H), 1.27 (t, J ) 7.3 Hz, 3H), 1.44 (d, J ) 5.86
Hz, 3H), 1.56-1.89 (m, 5H), 2.33-2.39 (m, 1H), 2.43-2.54 (m,
2H), 2.86 (quintet, J ) 6.6 Hz, 1H), 3.08-3.16 (m, 1H), 3.32 (td,
J ) 11, 2.9 Hz, 1H), 3.78-3.84 (m, 1H), 4.15 (q, J ) 7.3 Hz, 2H),
4.75-4.82 (m, 1H), 6.52-6.63 (m, 2H), 7.09 (td, J ) 8.0, 2.2 Hz,
1H), 7.25-7.29 (m, 2H), 7.35 (d, J ) 8.0 Hz, 1H), 7.41-7.47 (m,
1H), 7.82 (dd, J ) 8.0, 2.2 Hz, 1H), 8.77 (d, J ) 2.2 Hz, 1H), MS
(CI) m/z 479 (MH+, 100%); HRMS calcd for C28H31FN2O4 (MH+),
479.2346; found, 479.2350; Anal. (C28H31FN2O4‚HCl‚1.5H2O) C,
H, N.
1
reduced pressure to give 1.7 g of 39 (46%). H NMR (400 MHz,
CDCl3) δ 1.15 (d, J ) 5.86 Hz, 3H), 1.18 (t, J ) 7.3 Hz, 3H),
1.57-1.73 (m, 3H), 2.02-2.07 (m, 1H), 2.55 (m, 1H), 2.63-2.82
(m, 3H), 3.39-3.43 (m, 1H), 4.04 (q, J ) 7.3 Hz, 2H), 4.31 (br d,
J ) 12.5 Hz, 1H), 4.55-4.62 (m, 1H), 5.17 (m, 2H), 5.48 (s, 1H),
7.34-7.39 (m, 5H).
(4aS,5S,5aS,6R,8aR,9aS)-6-Methyl-8-oxodecahydrofuro[3,4-
g]quinoline-1,5-dicarboxylic Acid 1-Ethyl Ester (40). Compound
39 (1.7 g, 4.11 mmol) was dissolved in EtOAc, palladium on carbon
(10 wt %, 170 mg) was added, and the mixture was stirred under
1 atm of H2 for 2 h. The mixture was filtered through celite, and
the solvent was removed under reduced pressure. The resulting
residue (1.4 g) was taken up in MeOH (25 mL), and PtO2 (140
mg) was added. The mixture was shaken using a parr apparatus
under 50 psi of H2 for 48 h. The catalyst was removed by filtration,
and the solvent was removed under reduced pressure to give 1.36
g of 40 (98%). 1H NMR (400 MHz, CDCl3) δ 1.09 (m, 1H), 1.26
(t, J ) 7.3 Hz, 3H), 1.35 (d, J ) 5.86 Hz, 3H), 1.57-1.74 (m,
3H), 1.81-1.92 (m, 2H), 1.95-2.04 (m, 1H), 2.41-2.46 (m, 1H),
2.53-2.63 (m, 2H), 2.84 (quintet, J ) 6.6 Hz, 1H), 3.14-3.28 (m,
2H), 3.77-3.83 (m, 1H), 4.14 (q, J ) 7.3 Hz, 2H), 4.70-4.77 (m,
1H).
Ethyl (4aS,5S,5aS,6R,8aR,9aS)-5-[(E)-2-[5-(2-Fluorophenyl)-
2-pyridinyl]ethenyl]-decahydro-6-methyl-8-oxofuro[3,4-g]quino-
line-1(2H)-carboxylate (43b). 1H NMR (400 MHz, CDCl3) δ
1.00-1.09 (m, 1H), 1.26 (t, J ) 7.3 Hz, 3H), 1.45 (d, J ) 5.86
Hz, 3H), 1.57-1.87 (m, 5H), 2.34-2.39 (m, 1H), 2.43-2.54 (m,
2H), 2.86 (quintet, J ) 6.6 Hz, 1H), 3.08-3.16 (m, 1H), 3.31 (td,
J ) 11.7, 2.2 Hz, 1H), 3.78-3.84 (m, 1H), 4.14 (q, J ) 7.3 Hz,
2H), 4.75-4.82 (m, 1H), 6.53-6.63 (m, 2H), 7.16-7.23 (m, 1H),
7.25-7.27 (m, 2H), 7.35-7.46 (m, 2H), 7.84 (d, J ) 8.05 Hz,
1H), 8.74 (s, 1H); MS (CI) m/z 479 (MH+, 100%); HRMS calcd
for C28H31FN2O4 (MH+), 479.2346; found, 479.2350; Anal. (C28H31-
FN2O4‚HCl‚1.5H2O) C, H, N.
Ethyl (4aS,5S,5aS,6R,8aR,9aS)-5-[(E)-2-[5-(2-Methylphenyl)-
2-pyridinyl]ethenyl]-decahydro-6-methyl-8-oxofuro[3,4-g]quino-
line-1(2H)-carboxylate (43c). 1H NMR (400 MHz, CDCl3) δ
1.00-1.08 (m, 1H), 1.27 (t, J ) 7.2 Hz, 3H), 1.46 (d, J ) 6.04
Hz, 3H), 1.56-1.91 (m, 5H), 2.30 (s, 3H), 2.33-2.56 (m, 3H),
2.86 (quintet, J ) 6.04 Hz, 1H), 3.07-3.17 (m, 1H), 3.32 (td, J )
11.5, 2.2 Hz, 1H), 3.77-3.85 (m, 1H), 4.15 (q, J ) 7.2 Hz, 2H),
4.75-4.84 (m, 1H), 6.56-6.58 (m, 2H), 7.18-7.32 (m, 5H), 7.61
(dd, J ) 8.2, 2.2 Hz, 1H), 8.54 (d, J ) 2.2 Hz, 1H); MS (CI) m/z
475 (MH+, 100%); HRMS calcd for C29H34N2O4 (MH+), 475.2597;
found, 475.2591; Anal. (C29H34N2O4‚HCl‚1.5H2O) C, H, N.
Ethyl (4aS,5S,5aS,6R,8aR,9aS)-5-[(E)-2-[5-(3-Cyanophenyl)-
2-pyridinyl]ethenyl]-decahydro-6-methyl-8-oxofuro[3,4-g]quino-
line-1(2H)-carboxylate (43d). 1H NMR (400 MHz, CDCl3) δ
0.98-1.09 (m, 1H), 1.25 (t, J ) 7.3 Hz, 3H), 1.43 (d, J ) 5.8 Hz,
3H), 1.58-1.89 (m, 5H), 2.33-2.39 (m, 1H), 2.43-2.55 (m, 2H),
2.86 (quintet, J ) 6.6 Hz, 1H), 3.09-3.17 (m, 1H), 3.31 (td, J )
11.7, 2.2 Hz, 1H), 3.77-3.83 (m, 1H), 4.08-4.17 (m, 2H), 4.75-
4.82 (m, 1H), 6.54-6.66 (m, 2H), 7.28 (d, J ) 8.05 Hz, 1H), 7.43-
7.47 (m, 1H), 7.52-7.69 (m, 2H), 7.79-7.84 (s, 2H), 8.75 (s, 1H);
(4aS,5S,5aS,6R,8aR,9aS)-5-Formyl-6-methyl-8-oxodecahydro-
furo[3,4-g]quinoline-1-carboxylic Acid Ethyl Ester (41). Com-
pound 40 (1 g, 3.076 mmol) was suspended in CH2Cl2 (17 mL),
and (COCl)2 (0404 mL, 1.5 equiv) was added, followed by a drop
of DMF. The mixture was stirred for 1 h and then concentrated
under reduced pressure. The resulting residue was dissolved in
PhMe (15 mL) and cooled to 0 °C. Pd(Ph3P)4 (355.5 mg, 10 mol
%) was added followed by dropwise addition of Bu3SnH (1.24 mL,
1.5 equiv). The mixture was stirred at 0 °C for 30 min followed by
1 h at room temperature. The reaction mixture was purified by silica
gel chromatography (hexane/EtOAc 10:1-2:1) to give 570 mg of
41 (60%). 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J ) 7.3 Hz, 3H),
1.35 (d, J ) 5.86 Hz, 3H), 1.62-1.73 (m, 3H), 1.80-1.93 (m,
2H), 2.10 (m, 1H), 2.42-2.48 (m, 1H), 2.60-2.68 (m, 2H), 2.85
(quintet, J ) 6.6 Hz, 1H), 3.13-3.27 (m, 2H), 3.73-3.78 (m, 1H),
4.14 (q, J ) 7.3 Hz, 2H), 4.61-4.67 (m, 1H), 9.76 (d, J ) 2.2 Hz,
1H).
(4aS,5S,5aS,6R,8aR,9aS)-5-[(E)-2-(5-Bromopyridin-2-yl)vinyl]-
6-methyl-8-oxodecahydrofuro[3,4-g]quinoline-1-carboxylic Acid
Ethyl Ester (42). Compound 32 (896 mg, 2.91 mmol, 2 equiv)

5160 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Chelliah et al.
MS (CI) m/z 486 (MH+, 100%); HRMS calcd for C29H31N3O4
(MH+), 486.2393; found, 486.2399; Anal. (C29H31N3O4‚HCl) C,
H, N.
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(25) After intravenous administration of a radiolabeled sample of 2 in
cynomolgus monkey, recovery of the radioactivity required more than
ten days.
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(27) (R)-3-Butyn-2-ol (ee > 97%) was purchased from DSM Fine
Chemicals, 217 Rt. 46W., Saddle Brook, NJ.
Ethyl (4aS,5S,5aS,6R,8aR,9aS)-5-[(E)-2-[3,3′-Bipyridin]-6-
ylethenyl]decahydro-6-methyl-8-oxo-furo[3,4-g]quinoline-1(2H)-
carboxylate (43e). 1H NMR (400 MHz, CDCl3) δ 1.00-1.07 (m,
1H), 1.27 (t, J ) 7.3 Hz, 3H), 1.44 (d, J ) 6.6 Hz, 3H), 1.56-1.89
(m, 5H), 2.33-2.40 (m, 1H), 2.43-2.55 (m, 2H), 2.86 (quintet, J
) 5.9 Hz, 1H), 3.08-3.16 (m, 1H), 3.31 (td, J ) 10.9, 2.9 Hz,
1H), 3.78-3.83 (m, 1H), 4.14 (q, J ) 7.3 Hz, 2H), 4.75-4.82 (m,
1H), 6.53-6.65 (m, 2H), 7.29 (d, J ) 8.05 Hz, 1H), 7.39-7.42
(m, 1H), 7.83-7.89 (m, 2H), 8.64 (d, J ) 4.4 Hz, 1H), 8.78 (s,
1H), 8.84 (s, 1H); MS (CI) m/z 462 (MH+, 100%); HRMS calcd
for C27H31N3O4 (MH+), 462.2393; found, 462.2387.
Acknowledgment. The authors like to thank Drs. Catherine
Strader, John Piwinski, Ashit Ganguly, Paul Mcnamara, Michael
Graziano, Richard Morrison, and Ronald White for helpful
discussions, Drs. Birendra Pramanik and Pradip Das for mass
spectral data, and Wenqing Feng and Dr. Mohindar Puar for
NMR data.
Supporting Information Available: Results of elemental
analyses. This material is available free of charge via the Internet
at http://pubs.acs.org.
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JM070704K