CL-150940
Received: October 10, 2015 | Accepted: October 30, 2015 | Web Released: November 10, 2015
Asymmetric Synthesis of CP-99,994 by Ring-expanding Amination of Monosubstituted Prolinols
Noriyuki Yamagiwa,* Sayaka Watanuki, Takahiro Nishina, Yutaka Suto, and Genji Iwasaki
Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui, Takasaki, Gumma 370-0033
(E-mail: Yamagiwa@takasaki-u.ac.jp)
A stereospecific synthesis of the biologically active com-
NR3
pound (+)-CP-99,994 was achieved. The key step in this process
was a ring-expansion rearrangement, in which threo-fused
monosubstituted prolinol was effectively transformed to 2,3-
disubstituted piperidine with a cis-relationship, without loss
of enantiomeric excess. Finally, D-proline methyl ester was
successfully transformed to (+)-CP-99,994 in 10 steps (total
yield of 23%).
Ring-Expansion
Rearrangement
2
H
H
N
R1
N
R1
N
R1
OH
OH
HNR3
2
2
Scheme 1. The ring-expansion rearrangement of prolinol.
Nu
path A
Functionalized piperidines are widely found in artificial
drugs and biologically active compounds. Typical examples are
tachykinin receptor 1 (NK-1) antagonists, (+)-(2S,3S)-CP-
99,994 (1), and (+)-(2S,3S)-CP-122,721 (Figure 1) as well as
their analogs.1 These small molecules strongly prevent the
activation of the NK-1 receptor by the neuropeptide, substance P,
and are expected to act as antidepressants, anxiolytics, and
antiemetics.
In CP-99,994 and CP-122,721 and their analogs, the aryl
group and alkylamino groups are connected to the central
piperidine ring at the C-2 and C-3 positions, respectively, to
form contiguous stereocenters.2 Among the various stereo-
isomers, only the cis-2S,3S-relationship has been found to show
high affinity binding to the human NK-1 receptor. Therefore,
stereoselective construction of the contiguous stereocenters of
2,3-disubstituted piperidines has received much attention over
the past two decades. Several methods, including chiral
synthone-based,3 chiral auxiliary-based,4 and catalytic asym-
metric syntheses,5 have been developed so far and applied to
CP-99,994. However, synthesis from simple amino acids would
be a preferable route, although to date, only one method starting
from L-glutamic acid has been reported.3b Many opportunities
for new synthesis are yet to be investigated in this area.
The ring-expansion rearrangement of prolinols, developed by
Cossy et al., is one solution for the synthesis of 3-substituted
N
R1
R2
H
H
Nu
– OH
R2
piperidine
N
R1
N
R1
R2
OH
H
2
path B
bicyclic intermediate
R2
N
R1
threo-pyrrolidine
Nu
H
path C
Nu
– OH
R2
Nu
N
R1
erythro-pyrrolidine
Figure 2. Proposed mechanism of the ring-expansion rear-
rangement of monosubstituted prolinols.
as the starting point, especially 1-phenyl-1-(1-alkylpyrrolidine-
2-yl)methanol (2); however, this synthesis is yet to be reported.
Here, we report the stereospecific synthesis of CP-99,994
through a ring-expansion rearrangement of a monosubstituted
prolinol.
The ring-expansion rearrangements of prolinol are known to
produce some by-products in a competitive manner. The
treatment of 2 with a hydroxy group activator immediately
affords a bicyclic intermediate through neighboring group
participation of the adjacent nitrogen atom (Figure 2). The
attack of a nucleophile (Nu) toward the bicyclic intermediate
generates not only the desired ring-expansion product with a
piperidine backbone (path A), but also an undesired pyrrolidine
derivative with a threo relationship (path B). Moreover, through
direct substitution of the activated hydroxy group, without
neighboring group participation, it is possible to generate the
erythro-pyrrolidine isomer (path C). Therefore, optimized
reaction conditions are required to obtain the desired piperidine
structure with high selectivity.
piperidines from prolines in
a
stereospecific manner
(Scheme 1).6 This process might also be applied for the
synthesis of CP-99,994 if a chiral prolinol derivative is used
OCF3
NH OCH3
NH OCH3
First, we examined different hydroxy group activators.
Methanesulfonyl chloride with triethylamine effectively acti-
vated the hydroxy group but afforded the desired piperidine
derivative in only 18% yield, and the threo-pyrrolidine isomer
was obtained as a major product in 58% yield (method A in
Table 1). XtalFluor-Eμ is known to be an effective activator
of hydroxy groups according to Cossy’s reports.6 However,
using XtalFluor-E produced the erythro-pyrrolidine as the major
N
N
H
H
(+)-CP-99,994 (1)
(+)-CP-122,721
Figure 1. Structure of tachykinin receptor 1 (NK-1) antago-
nists, i.e., (+)-(2S,3S)-CP-99,994 (1) and (+)-(2S,3S)-CP-
122,721.
© 2016 The Chemical Society of Japan
Yamagiwa, Noriyuki
