Enantioselective synthesis of NK-1 receptor antagonists (+)-CP-99,994 and (+)-CP-122,721

Article abstract of DOI:10.1016/S0040-4039(02)01832-4

An enantioselective total synthesis of NK-1 receptor antagonists, (+)-CP-99,994 and (+)-CP-122,721, is described. The key steps are diastereoselective addition of vinyllithium to a chiral benzaldehyde oxime ether and diastereoselective borane reduction of

Full text of DOI:10.1016/S0040-4039(02)01832-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7979–7982
Enantioselective synthesis of NK-1 receptor antagonists
(+)-CP-99,994 and (+)-CP-122,721
Naoki Yamazaki, Masakazu Atobe and Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 24 July 2002; revised 22 August 2002; accepted 23 August 2002
Abstract—An enantioselective total synthesis of NK-1 receptor antagonists, (+)-CP-99,994 and (+)-CP-122,721, is described. The
key steps are diastereoselective addition of vinyllithium to a chiral benzaldehyde oxime ether and diastereoselective borane
reduction of a cyclic oxime ether. © 2002 Elsevier Science Ltd. All rights reserved.
The neuropeptide substance P (SP) is involved in a
variety of biological actions, including pain transmis-
sion, vasodilatation, smooth muscle contraction, and
neurogenic inflammation.1 It binds preferentially to the
neurokinin-1 (NK-1) receptor. Although the physiologi-
cal role of the NK-1 receptor remains to be more
clearly defined, selective SP receptor antagonists might
be of potential therapeutic value. Recently, the search
for nonpeptide antagonists of the NK-1 receptor led to
the discovery of CP-99,994 (1), which has been shown
We have recently reported that chiral arylaldehyde
to bind with high affinity to the human and rodent
oxime ethers on treatment with methyllithium undergo
NK-1 receptors and to possess potent anti-emetic activ-
efficient nucleophilic addition leading to an enantiose-
ity.2 Since the discovery of 1, numerous 3-amino or
lective preparation of 1-(aryl)ethylamines.5 This
3-alkoxy-2-phenylpiperidines have been tested, and it
methodology has been applied to an enantioselective
has been established that a cis relationship between the
synthesis of the calcium receptor agonist NPS R-568
and its thio analog.5 Here we report further extension
of this methodology to an enantioselective total synthe-
sis of the NK-1 antagonists CP-99,994 (1)6,7 and CP-
122,721 (2).8
two substituents on the piperidine ring and 2S,3S
configurations are required for high affinity binding to
the human NK-1 receptor.3 More recently, the tri-
fluoromethoxy analog, CP-122,721 (2), was developed
as a second-generation NK-1 receptor antagonist,
which shows a significant increase in efficacy for in vivo
blockade of NK-1 receptor-mediated responses,
together with its potent anti-emetic activity.4 These
nonpeptide ligands 1 and 2 were indicated to be much
more potent NK-1 receptor antagonists than the enan-
tiomerical antipodes designated as CP-100,263 (ent-1)
and CP-132,687 (ent-2), respectively.2,4
Our first objective toward the synthesis of (+)-CP-
99,994 was the enantioselective formation of (1R)-1-
phenyl-2-propen-1-amine (7). To this end, the
benzaldehyde oxime ether 4, prepared using (R)-1-
phenyl-1,2-ethanediol [(R)-3] as a chiral auxiliary
according to the procedure previously reported from
our laboratory,5 was subjected to treatment with vinyl-
lithium (5 equiv.) in toluene at 0°C, resulting in a 5:1
diastereomeric mixture (79% combined yield) of the
1-vinyl adducts favoring the 1R epimer 5 (Scheme 1),
which was isolated in a pure form by silica gel chro-
matography using hexane–AcOEt (70:20).
Keywords: chiral oxime ethers; NK-1 receptor antagonist; CP-99,994;
CP-122,721.
* Corresponding author. Fax: 81-426-76-4475; e-mail: kibayasi@
ps.toyaku.ac.jp
The re face selectivity observed in this reaction can be
accounted for in terms of a six-membered lithium-coor-
dinated transition state consistent with our previous
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01832-4

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N. Yamazaki et al. / Tetrahedron Letters 43 (2002) 7979–7982
results in nucleophilic addition of methyllithium to
chiral oxime ethers.5 Accordingly, a chair-like chelated
transition state 6 can be invoked, which activates the
imino group with respect to nucleophilic addition of
vinyllithium. Thus, the second molecule of vinyllithium
coordinates to the oxygen atom at an axial position to
avoid the 1,3-allylic strain,9 and a subsequent internal
delivery of the vinyl group could occur to the re face of
the imino group, leading predominantly to the 1R
adduct 5.10
The 1R-vinyl adduct 5 underwent NꢀO bond cleavage
using Zn–AcOH to give the amine 7 with recovery of
the antipodal chiral auxiliary (S)-3, allowing us to
confirm the absolute configuration of the newly formed
stereocenter of 7 to be desired R based on comparison
of the optical rotation of synthetic 7, [h]2D5 +10.2 (c 1,
CHCl3), with the published value,11 [h]D25 +10.23 (c 4,
CHCl3).
Scheme 2.
After protection of 7 as its N-Boc derivative 8, the
olefinic double bond was cleaved by a two-step
sequence via OsO4-catalyzed dihydroxylation followed
by oxidation with NaIO4 to afford the aldehyde 9 in an
almost quantitative yield (Scheme 2). Allylation of 9
with allylmagnesium bromide (Et2O, −80°C) provided a
diastereomeric mixture of the secondary alcohols (a-
OH:b-OH=1.2:1), which was protected as the TBDMS
ether to give 10 as a diastereomeric mixture. Hydrobo-
ration of 10 using siamylborane followed by a hydrogen
peroxide basic working-up yielded the primary alcohol
11 (94%).
THF complex in THF at 45°C, stereoselective reduc-
tion of the imine moiety proceeded along with reductive
cleavage of the NꢀO bond, affording the 2,3-cis-disub-
stituted piperidine derivative 16, as
a
major
diastereomer, and its trans-isomer in 10:1 ratio and
70% combined yield. The configuration and conforma-
tion of 16 were determined by the coupling constants
and NOE difference data (Fig. 1).
The stereoselectivity observed in the reduction of 15
can be rationalized by invoking a chair-like conforma-
tion 15A with an axially disposed phenyl group, which
Mesylation of the primary alcohol of 11 afforded the
corresponding mesylate, which underwent t-BuOK-
mediated cyclization at room temperature to provide
the piperidine derivative 12 in 96% overall yield
(Scheme 3). After deprotection of the TBDMS group
with TBAF, the hydroxypiperidine derivative 13 was
subjected to Dess–Martin oxidation12 to form the
ketone 14 (88%). Treatment of 14 with O-methylhy-
droxylamine hydrochloride and pyridine at room tem-
perature yielded (E)-oxime ether 15 (95%) as a single
geometrical isomer. Upon treatment of 15 with borane–
Scheme 1.
Scheme 3.

N. Yamazaki et al. / Tetrahedron Letters 43 (2002) 7979–7982
7981
minimizes the unfavorable 1,3-allylic interactions9 exist-
ing in the alternative conformation 15B. The bottom
face of the CꢁN bond of the conformation 15A is
sterically hindered by the axial phenyl group, so that
the approach of borane can take place preferentially
from the less hindered top face.
TiCl4 (3 equiv.) in benzene at 0°C, the resulting
iminium ion was treated with a methanol solution of
sodiumcyanoborohydride at room temperature. In this
manner, the yield of the reductive amination product 20
was significantly improved up to 78%. Deprotection of
the N-Boc group in HCl–MeOH furnished in 89% yield
CP-122,721 (2) as the hydrochloride salt (2·2HCl), mp
275–276°C (EtOH–Et2O) (lit.8 mp 277–278°C); [h]2D6
+75.6 (c 1.0, MeOH) [lit.8 [h]2D0 +71.2 (c 1.0, MeOH)]
(Scheme 4).
The 3-aminopiperidine derivative 16 thus obtained was
converted to 18 via reductive amination with 2-
methoxybenzaldehyde (17) under conditions using so-
diumcyanoborohydride in HCl–MeOH at room tem-
perature. Deprotection of the N-Boc group with HCl–
MeOH provided CP-99,994 hydrochloride (1·2HCl),
mp 254.5°C (EtOH) [lit.6a mp 255°C (EtOH)]; [h]2D5
+75.5 (c 1.1, MeOH) [lit.6a [h]D25 +77 (c 1.0, MeOH)], in
In conclusion, we have developed a new and efficient
route for the enantioselective synthesis of the NK-1
receptor antagonists, (+)-CP-99,994 and (+)-CP-
122,721, based on diastereoselective addition of vinyl-
lithium to the chiral benzaldehyde oxime ether and
diastereoselective borane reduction of the cyclic oxime
ether.
1
83% yield. The H NMR data for the free base 1 was
identical with those reported6a for racemic 1 in the
literature.
The same protocol was applied to the preparation of
CP-122,721 (2). Thus, 3-aminopiperidine 16 was sub-
jected to reductive amination using 5-trifluoromehyl-2-
methoxybenzaldehyde (19) and sodiumcyanoboro-
hydride (HCl–MeOH, rt) to give an unsatisfactory yield
of 20 (38%). The low yield of this reaction most likely
results from the presence of the electron-withdrawing
5-trifluoromethyl group in 19, which decreases the elec-
trophilicity of the intermediary imine. The electrophilic-
ity of the imine can be enhanced by complexation with
a Lewis acid to form a reactive iminium salt.13 There-
fore after treatment of 16 with 19 in the presence of
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Scheme 4.

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