A concise and practical catalytic asymmetric synthesis of (-)-CP-99,994 and (-)-L-733,061

Article abstract of DOI:10.1016/j.tetlet.2005.10.054

A concise and practical catalytic asymmetric synthesis of (-)-CP-99,994 and (-)-L-733,061 was achieved. Key features involve the Pd-catalyzed asymmetric allylic amination and the ring-closing metathesis as key steps.

Full text of DOI:10.1016/j.tetlet.2005.10.054

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8927–8930
A concise and practical catalytic asymmetric synthesis of
(ꢀ)-CP-99,994 and (ꢀ)-L-733,061
Kouichi Takahashi, Hiroto Nakano* and Reiko Fujita
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Received 9 August 2005; revised 17October 2005; accepted 17October 2005
Available online 8 November 2005
Abstract—A concise and practical catalytic asymmetric synthesis of (ꢀ)-CP-99,994 and (ꢀ)-L-733,061 was achieved. Key features
involve the Pd-catalyzed asymmetric allylic amination and the ring-closing metathesis as key steps.
Ó 2005 Elsevier Ltd. All rights reserved.
Substance P1 (SP), an undecapeptide belonging to the
tachykinin family of peptides, has extremely important
biological activities involving binding to the neuro-
kinin-1 (NK1) receptor. It has been established that
the release of SP is closely related to the transmission
of pain and the induction of neurogenic inflammatory
responses.2 Therefore, the SP antagonist3 is expected
to act as a remedy for a wide range of diseases, including
arthritis, asthma, and migraines. It has recently been
reported that the piperidine analogues CP-99,994 (1)4
and L-733,060 (2)5 have excellent affinity and selectivity
with human NK1 receptor. Due to their important
potential pharmacological applications, there have been
several reports on the synthesis of 1 and 2 in both race-
mic6,7 and optically active forms.8,9
odologies that uses a chiral template or a diastereoselec-
tive reaction as a key step for the asymmetric induction.
As an other methodology, catalytic enantioselective syn-
thesis is strongly desirable for the synthesis of 1 and 2.
However, only one example for the catalytic asymmetric
synthesis of 1 using the catalytic asymmetric nitro-Man-
nich reaction as a key step has been reported by Shiba-
saki and co-workers.10 Their results, however, cannot
necessarily be considered satisfactory due to the moder-
ate enantioselectivity of the nitro-Mannich reaction and
the low over all yield (6%).
Most recently, we have reported the highly enantio-
selective Pd-catalyzed asymmetric allylic amination of
common allylacetate 3 using our polymer-supported
phosphinooxathiane ligand 5 to afford the amino prod-
uct 4 in excellent enantioselectivity.11 Although the
substrate 3 has been used as most general substrate of
Pd-catalyzed allylic alkylation and amination,12 only a
few studies have utilized 4 as a chiral building block in
CF3
H
N
O
CF3
OMe
Ph
Ph
N
N
H
H
Ligand 5
[PdCl(η3-C3H5)]2
CP-99,994 (1)
Figure 1.
L-733,060 (2)
OAc
Ph
NHBn
Ph
Ph
Ph
PhCH2NH2
CH2Cl2, 0 oC, 24 h
3
4 : 90%, 99%ee
O-DES-PS
As a synthetic methodology of optically active forms,
previous most reported studies have included the meth-
O
S
Keywords: (ꢀ)-CP-99,994; (ꢀ)-L-733,061; Pd-catalyzed asymmetric
allylic amination; Chiral phosphinooxathiane ligand; Substance P
antagonists.
H
PPh2
polymer-supported chiral ligand (5)
*
Corresponding author. Tel.: +81 22 234 4181; fax: +81 22 275
2013; e-mail: hnakano@tohoku-pharm.ac.jp
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.054

8928
K. Takahashi et al. / Tetrahedron Letters 46 (2005) 8927–8930
a stereocontrolled synthesis.13 However, 4 includes a
chiral a-phenyl amine unit, and it should be easily con-
verted to chiral 2-phenylpiperidones. Our intent, there-
fore, was turned to synthesize 1 and 2 using 4 as a key
starting material (Scheme 1).
H-
H
Bn
Bn
O
O
H
N
Ph
N
Ph
H
Ph
3
H
H
H
N
O
O
O
HO
Bn
A
B
9
Herein, we report a concise and practical catalytic asym-
metric synthesis of (ꢀ)-CP-99,994 (ent-1) and (ꢀ)-L-
733,061 (ent-2) using Pd-catalyzed asymmetric allylic
amination and ring-closing metathesis as key steps
(Fig. 1).
Figure 2.
4 was converted to diene 7 in quantitative yield by the
reaction with 3-butenoic acid in the presence of DCC.
The RCM of 7 using the second-generation Grubbs
catalyst proceeded smoothly to afford the desired 2-phen-
ylpiperidinone 6 in 94% yield.14 Furthermore, the epoxi-
dation of 6 with m-chloroperbenzoic acid (mCPBA)
gave the corresponding epoxide (8)15 in 63% yield as
a single stereoisomer. Reduction of amide moiety
followed by regioselective ring opening of the epoxide
in 8 with lithium aluminum hydride (LAH) afforded
trans-N-Bn-hydroxyphenyl piperidine 915 in 78% yield.
The reaction might be through the conformer A that
has a less steric interaction between a benzyl group on
nitrogen and a phenyl group at 2-position rather than
conformer B. Then the hydride anion might attack from
the b-axial site at 3-position to afford the desired trans-
product 9 (Fig. 2).16 Then, product 9 was easily con-
verted to the desired N-Boc-2-phenyl-hydroxyphenyl
piperidine (10) in 98% yield.
Our retrosynthetic route for ent-1 and ent-2 is outlined
in Scheme 2. These compounds were traced to 2-phenyl-
piperidinone (6), which is constructed by the ring-clos-
ing metathesis (RCM) of 7. Furthermore, the starting
building block 7 was obtained by Pd-catalyzed asym-
metric allylic amination using our explored chiral poly-
mer-supported phosphinooxathiane ligand 5.
First, the synthesis of 2-phenylpiperidinol (10) was
examined (Scheme 3). The Pd-catalyzed asymmetric
allylic amination of allylacetate 3 using chiral ligand 5
afforded allylamine 4 in 90% yield and 99% ee. Product
O
NBn
ent-1 and ent-2
O
N
Ph
Ph
Ph
Next, the synthesis of ent-1 was examined. We planned
to access compound ent-1 by the oxidation of 10, fol-
lowed by imine formation using 11 and reduction of
imine 12, as shown in Scheme 4. Although this is a
convenient pathway and some research groups carried
out this synthetic route to 1, it has been known that
2-phenyl-piperidinone 11 is prone to racemization.17
Therefore, we examined the derivation to N-Boc-13
without isolation of either ketone 11 or imine 12. Thus,
the Swern oxidation of 10 and imine formation with
2-methoxybenzylamine at ꢀ20 °C, followed by the
Bn
6
7
NHBn
Ph
3
Ph
4
Scheme 2.
O
O
N
a
b
NHBn
NBn
Ph
b
d
10
a
OMe
O
N
Ph
Ph
N
N
Ph
Ph
Ph
Ph
Bn
Boc
Boc
4
7
6
11
12
c
c
O
OH
Ph
OH
Ph
e
H
N
d
O
N
N
N
Ph
ent -1 · 2HCl
OMe
Bn
Boc
Bn
Ph
N
Boc
10
9
8
13
Scheme 3. Reagents and conditions: (a) 3-butenoic acid, DCC,
DMAP, CH2Cl2, room temperature, 24 h, 99%; (b) GrubbsÕ catalyst,
CH2Cl2, reflux, 24 h, 94%; (c) mCPBA, CH2Cl2, room temperature,
24 h, 63%; (d) LAH, THF, room temperature, 24 h, 78%; (e) (Boc)2O,
Pd(OH)2, H2, AcOEt, 45 °C, 24 h, 98%.
Scheme 4. Reagents and conditions: (a) Swern oxidation; (b) 2-
methoxybenzylamine, TiCl4, ꢀ20 °C, 24 h; (c) NaCNBH3, MeOH,
ꢀ20 °C, 12 h, 49% (three steps); (d) HCl, CH2Cl2, room temperature,
24 h, 99%.

K. Takahashi et al. / Tetrahedron Letters 46 (2005) 8927–8930
8929
5. Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G.
Bioorg. Med. Chem. Lett. 1994, 4, 2545.
O
OH
Ph
a
b
10
6. For the synthesis of racemic CP-99,994: (a) Desai, M. C.;
Thadeio, P. F.; Lefkowitz, S. L. Tetrahedron Lett. 1993,
34, 5831; (b) Rosen, T.; Seeger, T. F.; Mclean, S.; Desai,
M. C.; Guiarino, K. J.; Byrce, D.; Pratt, K.; Heym, J. J.
Med. Chem. 1993, 36, 3197.
N
N
Ph
Boc
Boc
11
14
7. For the synthesis of racemic L-733,060: Tomooka, K.;
Nakazaki, A.; Nakai, T. J. Am. Chem. Soc. 2000, 122, 408.
8. For the enantioselective synthesis of CP-99,994: (a)
Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett.
1999, 40, 5071; (b) Atobe, M.; Yamazaki, N.; Kibayashi,
C. J. Org. Chem. 2004, 69, 5595; (c) Liu, L.-X.; Ruan,
Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem. 2004, 69,
6001; (d) Lemire, A.; Grenon, M.; Pourashraf, M.;
Charette, A. B. Org. Lett. 2004, 6, 3517.
9. For the enantioselective synthesis of L-733,060: (a) Bhas-
kar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44, 915; (b)
Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org.
Lett. 2003, 5, 1927; (c) Yoon, Y.-J.; Joo, J.-E.; Lee, K.-Y.;
Kim, Y.-H.; Oh, C.-Y.; Ham, W.-H. Tetrahedron Lett.
2005, 46, 739; (d) Baker, R.; Harrison, T.; Hollingworth,
G. J.; Swain, C. J.; Williams, B. J. EP 0528,495A1, 1993.
10. For the catalytic asymmetric synthesis of CP-99,994:
Tsuritani, N.; Yamada, K.; Yoshikawa, N.; Shibasaki,
M. Chem. Lett. 2002, 276.
11. Nakano, H.; Takahashi, K.; Suzuki, Y.; Fujita, R.
Tetrahedron: Asymmetry 2005, 16, 609.
12. (a) Johannsen, M.; Jorgensen, K. A. Chem. Rev. 1998, 98,
1689; (b) Heumann, A. In Transition Metals for Organic
Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Wein-
heim, 1998; p 251.
13. (a) Jumnah, R.; Williams, A. C.; Williams, J. M. J. Synlett
1995, 821; (b) Bower, J. F.; Jumnah, R.; Williams, A. C.;
Williams, J. M. J. J. Chem. Soc., Perkin Trans. 1 1997,
1411.
c
CF3
d
ent -2 · HCl
O
CF3
Ph
N
Boc
15
Scheme 5. Reagents and conditions: (a) Swern oxidation; (b)
L-Selectride, THF, ꢀ20 °C, 83% (two steps); (c) NaH, 3,5-bistrifluoro-
methylbenzyl bromide, DMF, room temperature, 24 h, 77%; (d) HCl,
CH2Cl2, room temperature, 24 h, 98%.
stereoselective reduction of imine (12) using sodium
cyanoborohydride, gave the desired N-Boc-ent-1 in
49% yield from 10. Using this method, the racemization
of 11 was not observed. Finally, the removal of the Boc
group with HCl afforded ent-1 in 99% yield.18
Furthermore, this methodology was applied to the syn-
thesis of ent-2. Thus, the Swern oxidation of 10, followed
by the stereoselective reduction of 11, using L-Selectride
at ꢀ20 °C gave the desired N-Boc-2,3-cis-hydroxy piper-
idine 14 in 83% yield from 10. Furthermore, the reaction
of 14 with bistrifluoromethyl bromide using NaH as a
base afforded N-Boc-ent-2 in 77% yield, which was then
easily converted to ent-2 in 98% yield (Scheme 5).19
14. For the experimental details of (6S)-N-benzyl-6-phenyl-
3,6-dihydropyridin-2-one (6): a mixture of 7 (1380 mg,
3.76 mmol) and second-Grubbs catalyst (39 mg,
0.046 mmol) in dry dichloromethane (500 mL) was stirred
at 60 °C under argon. After 24 h, the solvent was
evaporated under reduced pressure. The residue was
chromatographed on a column of silica gel (1:1 AcOEt–
hexane) to give 6 (1138 mg, 94%) as a white solid. HPLC
analysis indicated that the enantiomeric excess of 6 was
98% [Chiralcel OD-H; hexane–2-propanol = 9:1; flow
rate = 0.5 mL/min; tR = 14.5 (major), 17.1 (minor) min].
In conclusion, we demonstrated both the catalytic asym-
metric synthesis of ent-1 and the first catalytic asymmet-
ric synthesis of ent-2 using the Pd-catalyzed asymmetric
allylic amination and the ring closing metathesis as key
steps. All of reactions proceeded stereo- and regioselec-
tively in the synthetic route. The synthesis of ent-1 com-
pleted in 10 steps and the overall yield was 26%, which is
better than the result (6%) of ShibasakiÕs group. In addi-
tion, the synthesis of ent-2 also completed the overall
yield of ent-2 was 20%. Further applications of this
methodology using chiral building block 4 will be
reported in due course.
20
Mp 103 °C; ½aꢁD ꢀ97.76 (c 5.23, CHCl3, 98% ee); IR
1
(KBr) 701, 1451, 1640, 3023 cmꢀ1; H NMR (CDCl3) d:
3.12–3.33 (m, 2H), 3.41 (d, J = 15.0 Hz, 1H), 4.79–4.83
(m, 1H), 5.61 (d, J = 15.0 Hz, 1H), 5.65–5.79 (m, 2H),
7.15–7.21 (m, 4H), 7.25–7.38 (m, 6H); 13C NMR (CDCl3):
d 32.11, 46.29, 61.65, 120.50, 126.36, 127.04 (2C), 127.41,
128.19, 128.24 (2C), 128.61 (2C), 129.10 (2C), 136.76,
140.06, 167.56; MS m/z 263 (M+); HRMS calcd for
C18H17NO (M+) 263.1310, found: 263.1312.
References and notes
15. Spectral data for some key compounds: compound 8:
HPLC analysis indicated that the enantiomeric excess of 8
was 98% [Chiralcel OD-H; hexane–2-propanol = 9:1; flow
rate = 0.5 mL/min; tR = 31.9 (major), 45.3 (minor) min].
1. (a) von Euler, U. S.; Gaddum, J. H. J. Physiol. 1931, 72,
74; (b) Chang, M. M.; Leeman, S. E.; Niall, H. D. Nat.
New Biol. 1971, 232, 86.
2. (a) Snijdelaar, D. G.; Dirksen, R.; Slappendel, R.; Crul, B.
J. P. Eur. J. Pain 2000, 4, 121; (b) Datar, P.; Srivastava, S.;
Coutinho, E.; Govil, G. Curr. Top. Med. Chem. 2004, 4, 7 5.
3. (a) Takeuchi, Y.; Berkley Shands, E. F.; Beusen, D. D.;
Marshall, G. R. J. Med. Chem. 1998, 41, 3609; (b) Swain,
C. J. Prog. Med. Chem. 1998, 35, 57 .
20
Mp 120 °C; ½aꢁD ꢀ21.80 (c 2.73, CHCl3, 98% ee); IR
(KBr) 698, 746, 1226, 1434, 1598 cmꢀ1 1H NMR
;
(CDCl3): d 3.02 (d, J = 18.5 Hz, 1H), 3.24 (d, J =
18.5 Hz, 1H), 3.32 (s, 1H), 3.42 (s, 1H), 3.48 (d, J =
15.5 Hz, 1H), 4.79 (s, 1H), 5.54 (d, J = 15.3 Hz, 1H),
7.19–7.35 (m, 7H), 7.37–7.46 (m, 3H); 13C NMR (CDCl3):
d 33.14, 47.33, 50.91, 53.74, 59.46, 126.75 (2C), 127.28,
127.60 (2C), 128.57 (2C), 128.65, 129.33 (2C), 135.85,
136.74, 166.02; MS m/z 279 (M+); HRMS calcd for
4. Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K.
P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911.

8930
K. Takahashi et al. / Tetrahedron Letters 46 (2005) 8927–8930
C18H17NO2 (M+) 279.1259, found: 279.1257. Compound
16. Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983; pp 209–290.
17. Williams, B. J.; Cascieri, M. A.; Chicchi, G. G.; Harrisson,
T.; Owens, A. P.; Owen, S. N.; Rupiniak, N. M. J.;
Tattersall, D. F.; Williams, A.; Swain, C. J. Bioorg. Med.
Chem. Lett. 2002, 12, 2719.
9: HPLC analysis indicated that the enantiomeric excess of
9 was 98 % [Chiralcel OD-H; hexane–2-propanol = 9:1;
flow rate = 0.5 mL/min; tR = 9.5 (major), 10.3 (minor)
20
min]. Mp 105 °C; ½aꢁD ꢀ26.95 (c 1.30, CHCl3, 98% ee); IR
(KBr) 704, 761, 2937, 3437 cmꢀ1 1H NMR (CDCl3): d
;
20
1.38–1.48 (m, 2H), 1.55–1.70 (m, 2H), 1.90–2.00 (m, 1H),
2.09–2.15 (m, 1H), 2.83–2.95 (m, 3H), 3.58–3.63 (m, 1H),
3.67(d, J = 13.4 Hz, 1H), 7.19–7.33 (m, 6H), 7.36–7.41
(m, 2H), 7.52 (d, J = 6.9 Hz, 2H); 13C NMR (CDCl3): d
23.29, 32.42, 52.39, 59.24, 73.92, 75.96, 126.64 (2C),
127.96, 128.04 (2C), 128.51 (2C), 128.81, 128.85 (2C),
139.53, 140.95; MS m/z 267(M +); HRMS calcd for
C18H21NO (M+) 267.1623, found: 267.1607.
18. Mp 236 °C (lit.4 255 °C); ½aꢁD ꢀ73.0 (c 1.00, MeOH)
20
{lit.4 ½aꢁD +77 (c 1.0, MeOH) for (2S,3S)-CP-99,994}. The
spectra data of (2R,3R)-CP-99,994 are identical with those
of (2S,3S)-CP-99,994.8b,9b
20
19. Mp 210 °C (lit.9d 215–216 °C); ½aꢁD ꢀ86.0 (c 1.00, MeOH)
23
{lit.9d ½aꢁD ꢀ86.9 (c 1.0, MeOH)}. The spectra data of
(2R,3R)-L-733,061 are identical with those of (2S,3S)-L-
733,060.9b