Synthesis of (±)-1-phenyl-2-azabicyclo[2.2.1]heptane derivatives - Novel NK1 receptor ligands

Article abstract of DOI:10.1055/s-2006-926221

The synthesis of the 1-phenyl-2-azabicyclo[2.2.1]heptane derivative 2, a potential NK₁ receptor ligand, is reported. Ring-closing metathesis of diene 10 and regio- and stereoselective opening of the oxirane ring in 14 are key steps in the synth

Full text of DOI:10.1055/s-2006-926221

LETTER
271
Synthesis of ( )-1-Phenyl-2-azabicyclo[2.2.1]heptane Derivatives – Novel NK1
Receptor Ligands
Synthesis of
(
i
)-1-Ph
o
enyl-2-azabi
t
c
yclo[2
r
.2.1]heptane
DR
erivatives aubo,*a Janusz J. Kulagowski,a Gary G. Chicchib
a
Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, CM20 2QR, UK
Fax +44(1279)440187; E-mail: piotr_raubo@merck.com
b
Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA
Received 31 October 2005
vomiting. Since 1991, when the first non-peptidic antago-
nist (CP-96,345) was reported,3 numerous selective and
structurally diverse NK1 modulators have been identified
and subsequently developed (Figure 1).1,4 As part of an
ongoing programme we were interested in examining the
conformationally restricted piperidine derivative 2.
Abstract: The synthesis of the 1-phenyl-2-azabicyclo[2.2.1]hep-
tane derivative 2, a potential NK1 receptor ligand, is reported. Ring-
closing metathesis of diene 10 and regio- and stereoselective open-
ing of the oxirane ring in 14 are key steps in the synthetic sequence.
Key words: bicyclic compounds, ring-closing olefin metathesis,
McMurry coupling, opening of epoxides, NK1 receptor
Substituted 3-hydroxy piperidines, such as 1, were
reported5 from our laboratory as high affinity ligands at
the human NK1 receptor. The bicyclic analogue of 1, 1-
phenyl-2-azabicyclo[2.2.1]heptane (2), was selected for
synthesis and biological evaluation. In this communica-
tion, we report a synthesis of the bicyclic ether 2 and dis-
close its NK1 binding affinity data.
Neurokinin-1 (NK1) receptor antagonists are of continu-
ing interest since the natural ligand for the NK1 receptor –
Substance P – has been implicated in the pathophysiology
of a wide range of disease conditions including neuro-
genic inflammation, transmission of pain, emesis and de-
pression.1 A demonstration of antidepressant activity by
NK1 receptor antagonists2 significantly accelerated efforts
in identification of new selective NK1 receptor ligands.
Furthermore, the Merck NK1 antagonist, aprepitant
(Emend®), has recently been approved for the prevention
of acute and delayed chemotherapy-induced nausea and
We envisaged that the bicyclic scaffold in 3 (Scheme 1)
should be accessible from the cyclopentene derivative 5
through stereoselective manipulation of the double bond
and subsequent lactamisation of the amino ester 4. In turn,
5 could be obtained through ring-closing metathesis of
diene 6.
CF3
CF3
CF3
MeO
CF3
CF3
CF3
O
N
O
NH
O
O
N
N
N
H
H
N
F
HN
O
NH
Emend®
2
1
CP-96,345
Figure 1
CF3
CF3
RO2C
RO2C
RO2C
O
HN
Ph
OH
O
N
H
H2N
Ph
Ph
Ph
3
6
4
5
2
Scheme 1
SYNLETT 2006, No. 2, pp 0271–0274
0
1.
0
2.
2
0
0
6
Advanced online publication: 24.01.2006
DOI: 10.1055/s-2006-926221; Art ID: D33005ST
© Georg Thieme Verlag Stuttgart · New York

272
P. Raubo et al.
LETTER
EtO2C
The synthesis began with bromination of a-methylstyrene
(7) using N-bromosuccinimide (Scheme 2), giving a 4.5:1
mixture of the allyl bromide 8 and the vinyl bromide 9.
This mixture was allowed to react with the lithium enolate
of ethyl pent-4-enoate providing the diene 10 in 61%
EtO2C
a
EtO2C
O
O
Ph
14
Ph
Ph
13
12
overall
yield.
Ruthenium-catalysed
ring-closing
b
metathesis6 (RCM) of the diene 10 smoothly gave the
cyclopentene 12 in 80% yield. Alternatively to the RCM
procedure, a two-step sequence was developed. This in-
volved ozonolysis of the diene 10 followed by McMurry
coupling7 of the resulting keto aldehyde 11 using titanium
tetrachloride and zinc powder in the presence of pyridine
to afford 12 in 40% overall yield.8,9
EtO2C
O
c, d, e
OTBS
OH
HN
Ph
N3
Ph
15
16
Scheme 3 Reagents and conditions: a) MCPBA, Na2HPO4, CH2Cl2,
r.t., 30 min, 81%, 13:14 = 1:3; b) NaN3, 18-crown-6, NH4Cl, EtOH,
reflux, 20 h, 96%; c) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 2 h, 99%;
d) Ph3P, H2O, 1,4-dioxane, reflux, 40 h; e) xylene, reflux, 6 h, 95%.
Br
EtO2C
Ph
ence of disodium hydrogen phosphate (Scheme 3). This
reaction proceeded with only modest diastereocontrol,
providing a readily separable 3:1 mixture of isomeric ep-
oxides 14 and 13 in favour of the desired anti isomer 14.10
a
b
8
Ph
Br
Ph
7
Ph
10
9
c
Regioselective opening of the oxirane ring in 14 with so-
dium azide in the presence of 18-crown-6 and ammonium
chloride occurred, at the benzylic position, furnishing the
required azido alcohol 15 in 96% yield. For operational
expediency, the hydroxyl group in 15 was protected as its
tert-butyldimethylsilyl ether and the azide was reduced to
the primary amine using the Staudinger reaction.11
Thermal cyclisation of the amino ester afforded the de-
sired bicyclic lactam 16 in excellent overall yield.
d
EtO2C
O
EtO2C
e
O
Ph
Ph
11
12
Scheme 2 Reagents and conditions: a) NBS, PhCl, reflux, 15 min,
80%, 8:9 = 4.5:1; b) LiHMDS, ethyl pent-4-enoate, THF, –78 °C to
–50 °C, 3.5 h, 77%; c) [Ru carbene] catalysed metathesis, PhMe, r.t.,
20 h, 80%; d) O3, CH2Cl2, MeOH, then Me2S, –78 °C to r.t., 63%; e)
TiCl4, Zn, THF, pyridine, reflux, 18 h, 64%.
Reduction of the lactam 16 (Scheme 4) with lithium alu-
minium hydride, followed by protection of the amine as a
tert-butyl carbamate and subsequent removal of the tert-
butyldimethylsilyl protecting group, yielded the endo-al-
cohol 1712 in 74% yield. Swern oxidation of the alcohol 17
followed by stereoselective reduction of the resulting
ketone 18 with sodium borohydride gave the exo-alcohol
19 as a single diastereoisomer in excellent overall yield.
Formation of the desired 1-phenyl-2-azabicyc-
lo[2.2.1]heptane ring was accomplished by a five-step se-
quence beginning with epoxidation of the double bond in
12 using m-chloroperbenzoic acid (MCPBA) in the pres-
O
a, b, c
d
e
OH
OTBS
BocN
Ph
BocN
Ph
BocN
Ph
HN
Ph
O
OH
16
17
18
19
Scheme 4 Reagents and conditions: a) LiAlH4, THF, reflux, 2 h, 97%; b) Boc2O, CH2Cl2, r.t., 5 h, 99%; c) TBAF, NH4OAc, THF, reflux, 2.5
h, 76%; d) (COCl)2, DMSO, CH2Cl2, then Et3N, 2 h, 96%; e) NaBH4, MeOH, 15 min, 99%.
CF3
CF3
CF3
CF3
O
O
a, b
OH
a, b
BocN
Ph
BocN
Ph
N
N
OH
H
H
17
19
20
2
Scheme 5 Reagents and conditions: a) NaH, 3,5-bis(trifluoromethyl)benzyl bromide, DMF, 60 °C, 20 min, 94–99%; b) TFA, CH2Cl2, r.t., 30
min, 53%.
Synlett 2006, No. 2, 271–274 © Thieme Stuttgart · New York

LETTER
Synthesis of (±)-1-Phenyl-2-azabicyclo[2.2.1]heptane Derivatives
273
(3) Snider, R. M.; Constantine, J. W.; Lowe, J. A. III.; Longo,
K. P.; Lebel, W. S.; Woody, H. A.; Drozda, S. E.; Desai, M.
C.; Vinick, F. J.; Spencer, R. W.; Hess, H.-J. Science 1991,
251, 435.
Both epimeric alcohols 17 and 19 were then converted
into their 3,5-bis(trifluoromethyl)benzyl ethers and the
Boc protecting group removed by treatment with tri-
fluoroacetic acid to give bicyclic amines 20 and 2, respec-
tively (Scheme 5).
(4) For recent advances, see: (a) Shaw, D.; Chicchi, G. G.;
Elliott, J. M.; Kurtz, M.; Morrison, D.; Ridgill, M. P.; Szeto,
N.; Watt, A. P.; Williams, A. R.; Swain, C. J. Bioorg. Med.
Chem. Lett. 2001, 11, 3031. (b) Elliott, J. M.; Castro, J. L.;
Chicchi, G. G.; Cooper, L. C.; Dinnell, K.; Hollingworth, G.
J.; Ridgill, M. P.; Rycroft, W.; Kurtz, M. M.; Shaw, D. E.;
Swain, C. J.; Tsao, K.-L.; Yang, L. Bioorg. Med. Chem. Lett.
2002, 12, 1755. (c) Cooper, L. C.; Carlson, E. J.; Castro, J.
L.; Chicchi, G. G.; Dinnell, K.; Di Salvo, J.; Elliott, J. M.;
Hollingworth, G. J.; Kurtz, M. M.; Ridgill, M. P.; Rycroft,
W.; Tsao, K.-L.; Swain, C. J. Bioorg. Med. Chem. Lett.
2002, 12, 1759. (d) Seward, E. M.; Carlson, E.; Harrison, T.;
Haworth, K. E.; Herbert, R.; Kelleher, F. J.; Kurtz, M. M.;
Moseley, J.; Owen, S. N.; Owens, A. P.; Sadowski, S. J.;
Swain, C. J.; Williams, B. J. Bioorg. Med. Chem. Lett. 2002,
12, 2515. (e) Williams, B. J.; Cascieri, M. A.; Chicchi, G.
G.; Harrison, T.; Owens, A. P.; Owen, S. N.; Rupniak, N. M.
J.; Tattersall, F. D.; Williams, A.; Swain, C. J. Bioorg. Med.
Chem. Lett. 2002, 12, 2719. (f) Gale, J. D.; O’Neill, B. T.;
Humphrey, J. M. Expert Opin. Ther. Pat. 2001, 11, 1837.
(5) Harrison, T.; Wiliams, B. J.; Swain, C. J.; Ball, R. G. Bioorg.
Med. Chem. Lett. 1994, 4, 2545.
The NK1 receptor binding affinity for both bicyclic ethers
2 and 20 was determined (Table 1).13 Similar IC50 values
were found for the bicyclic ether 2 and piperidine ana-
logue 1. The exo ether 2 (hNK1 IC50 2.7 nM) was about
100-fold more potent then the endo epimer 20 in this
assay. These results suggest that the 1-phenyl-2-aza-
bicyclo[2.2.1]heptane ring could be considered as a 2-
phenylpiperidine mimic in NK1 receptor modulators.
Table 1 The NK1 Receptor Binding Affinity
Compound
Structurea
hNK1 IC50 (nM)b
1.45
1
OR
N
H
Ph
2
21
20
2.7
3005
370
OR
(6) (a) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012.
(b) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
(7) McMurry, J. E. Chem. Rev. 1989, 89, 1513.
N
H
Ph
OR
(8) Experimental Procedure for the Preparation of 11.
Ozone was passed through a stirred mixture of 10 (30.5 g,
124 mmol), MeOH (1.4 mL) and CH2Cl2 (350 mL) at –70 °C
to –65 °C until the reaction mixture turned blue. Then, DMS
(90 mL, 1.24 mol) was added keeping the temperature of the
reaction mixture below –60 °C. The mixture was slowly
warmed up to r.t. and stirred for an additional 48 h. Then the
mixture was filtered through a pad of Celite® and concen-
trated. The residue was purified on silica gel (i-hexane–
EtOAc, 0–30%) to give the keto aldehyde 11 as an oil (19.5
g, 63%). 1H NMR (400 MHz, CDCl3): d = 1.23 (3 H, t, J =
7.1 Hz), 2.81 (1 H, ddd, J = 1.0, 5.4, 18.2 Hz), 2.99 (1 H, ddd,
J = 1.0, 6.2, 18.1 Hz), 3.25 (1 H, dd, J = 8.1, 19.4 Hz), 3.48–
3.54 (2 H, m), 4.16 (2 H, q, J = 7.2 Hz), 7.46 (2 H, m), 7.58
(1 H, m), 7.96 (2 H, m), 9.80 (1 H, s).
(9) Experimental Procedure for the Preparation of 12.
TiCl4 (15.5 mL, 140 mmol) was added dropwise to THF
(800 mL) to form a yellow slurry. Zinc dust (21 g, 325
mmol) was added in one portion to this slurry. The resulting
mixture was stirred for 1 h and pyridine (13 mL, 160 mmol)
was added. The mixture was stirred for 30 min and a solution
of 11 (19.3 g, 78 mmol) in THF (30 mL) was added. The
resulting black mixture was stirred at reflux overnight. After
cooling to r.t., Et3N (75 mL) and EtOH (75 mL) were added
and the mixture stirred for 30 min. Then, H2O (15 mL) and
EtOAc (800 mL) were added and the mixture was stirred
until a white solid was formed. This mixture was filtered
through a pad of Celite® and concentrated. The residue was
purified on silica gel (i-hexane–Et2O, 0–30%) to give the
cyclopentene 12 as an oil (10.8 g, 64%). 1H NMR (400 MHz,
CDCl3): d = 1.28 (3 H, t, J = 7.2 Hz), 2.83 (2 H, m), 2.97–
3.11 (2 H, m), 3.28 (1 H, m), 4.18 (2 H, q, J = 7.2 Hz), 6.08
(1 H, m), 7.23 (1 H, m), 7.31 (2 H, m), 7.42 (2 H, m).
(10) Experimental Procedure for the Preparation of 14.
MCPBA (60%, 5 g) was added to a stirred mixture of 12
(1.62 g, 7.5 mmol), Na2HPO4 (5 g, 35 mmol) and CH2Cl2 (50
mL). The mixture was stirred for 30 min and a solution of
Na2SO3 (10 g) in H2O (50 mL) was added. The mixture was
N
H
Ph
OR
N
H
Ph
a Racemate; R = 3,5-bis(trifluoromethyl)benzyl.
b Displacement of labelled [125I] Substance P from the cloned receptor
expressed in CHO cells. Data are mean of three independent determi-
nations.13
In conclusion, the stereoselective synthesis of novel
NK1 antagonists based upon the 1-phenyl-2-azabicy-
clo[2.2.1]heptane framework was developed and binding
affinity of selected compounds at the human NK1 receptor
determined. The bicyclic ether 2 exhibited similar binding
affinity at the NK1 receptor to the known piperidine deriv-
ative 1, providing a novel class of NK1 receptor modula-
tors confirming the relative topology of the binding site.
References and Notes
(1) Seward, E. M.; Swain, C. J. Expert Opin. Ther. Pat. 1999, 9,
571.
(2) Kramer, M. S.; Cutler, N.; Feighner, J.; Shrivastava, R.;
Carman, J.; Sramek, J. J.; Reines, S. A.; Liu, G.; Snavely, D.;
Wyatt-Knowles, E.; Hale, J. J.; Mills, S. G.; MacCoss, M.;
Swain, C. J.; Harrison, T.; Hill, R. G.; Hefti, F.; Scolnick, E.
M.; Cascieri, M. A.; Chicchi, G. G.; Sadowski, S.; Williams,
A. R.; Hewson, L.; Smith, D.; Carlson, E. J.; Hargreaves, R.
J.; Rupniak, N. M. J. Science 1998, 281, 1640.
Synlett 2006, No. 2, 271–274 © Thieme Stuttgart · New York

274
P. Raubo et al.
LETTER
extracted into i-hexane (150 mL) and an organic layer was
washed with 2 M aq NaOH solution and brine, then dried
(Na2SO4) and concentrated. The residue was purified on
silica gel (i-hexane–Et2O, 0–20%) to give the epoxide 14
(1.1 g, 63%) and the epoxide 13 (0.33 g, 18%). 1H NMR of
14 (400 MHz, CDCl3): d = 1.28 (3 H, t, J = 7.2 Hz), 2.08 (1
H, dd, J = 10.2, 14.0 Hz), 2.45 (1 H, dd, J = 8.0, 14.0 Hz),
2.53 (2 H, d, J = 9.2 Hz), 2.86 (1 H, pent., J = 9.2 Hz), 3.61
(1 H, s), 4.17 (2 H, q, J = 7.1 Hz), 7.26–7.39 (5 H, m).
Relative stereochemistry of 14 was assigned by 1H NMR/
NOE experiments. 1H NMR of 13 (400 MHz, CDCl3):
d = 1.27 (3 H, t, J = 7.1 Hz), 2.06 (1 H, dd, J = 8.5, 14.5 Hz),
2.44 (1 H, dd, J = 8.8, 14.0 Hz), 2.81 (1 H, d, J = 14.4 Hz),
2.84 (1 H, m), 2.91 (1 H, d, J = 14.1 Hz), 3.56 (1 H, s), 4.16
(2 H, q, J = 7.1 Hz), 7.27–7.37 (5 H, m).
(11) Vaultier, M.; Knouzi, N.; Carrie, R. Tetrahedron Lett. 1983,
24, 763.
(12) Relative stereochemistry of 17 was assigned by 1H NMR/
NOE experiments. 1H NMR (400 MHz, CDCl3): d = 1.11 (9
H, s), 1.67 (1 H, m), 1.88 (1 H, br), 2.08–2.13 (3 H, m), 2.52
(1 H, m), 3.19 (1 H, dd, J = 1.6, 9.3 Hz), 3.50 (1 H, dt, J =
2.5, 9.4 Hz), 4.56 (1 H, d, J = 6.2 Hz), 7.25 (1 H, m), 7.32 (2
H, m), 7.58 (2 H, m).
(13) Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.; Bansal,
A.; Swain, C. J.; Seward, E. M.; Frances, B.; Burns, D.;
Strader, C. D. Mol. Pharmacol. 1992, 47, 458.
Synlett 2006, No. 2, 271–274 © Thieme Stuttgart · New York