Concise synthesis of (2S,3R)-3-hydroxy-2-phenylpiperidine: An advanced key intermediate of human non-peptide NK-1 receptor antagonists

Article abstract of DOI:10.1055/s-0029-1218308

The rapid, high-yielding synthesis of (25,3R)-3-hydroxy-2-phenylpiperidine, a known advanced key intermediate of some non-peptide human NK-1 receptor antagonists such as (+)CP-99,994, (+)-CP-122,721 and (+)-LP-733,060, is reported. This synthesis involves

Full text of DOI:10.1055/s-0029-1218308

LETTER
3115
Concise Synthesis of (2S,3R)-3-Hydroxy-2-phenylpiperidine: An Advanced
Key Intermediate of Human Non-Peptide NK-1 Receptor Antagonists
S
ynthesis of (2
S,
e
R
)-3-Hydr
n
oxy-2-pheny
o
lpiperidine ît Hélal, Franck Ferreira,* Candice Botuha, Fabrice Chemla,* Alejandro Pérez-Luna
UPMC–Univ Paris 06, CNRS UMR 7201, Institut Parisien de Chimie Moléculaire (FR 2769), Case 183, 4 Place Jussieu, 75005 Paris,
France
Fax +33(1)44277567; E-mail: franck.ferreira@upmc.fr; E-mail: fabrice.chemla@upmc.fr
Received 24 July 2009
Thus, in 1992, (+)-CP-99,994 (Figure 1) was shown to ex-
Abstract: The rapid, high-yielding synthesis of (2S,3R)-3-hy-
hibit high affinity for human NK-1 receptors11 and to pos-
droxy-2-phenylpiperidine, a known advanced key intermediate of
some non-peptide human NK-1 receptor antagonists such as (+)-
CP-99,994, (+)-CP-122,721 and (+)-LP-733,060, is reported. This
sess potent anti-emetic activity.12 Since the discovery of
(+)-CP-99,994, other 3-amino- and 3-alkoxy-2-phenyl-
synthesis involves the stereoselective addition of racemic 3-(meth- piperidine derivatives, such as (+)-CP-122,721,13 (+)-LP-
733,06014 and the oxaazaspirodecane 1,15 have been dem-
oxymethoxy)allenylzinc bromide to enantiopure (RS,E)-N-2-ben-
zylidene-2-methylpropane-2-sulfinamide and
a
ring-closing
onstrated to be of potential therapeutic value (Figure 1).
All the biological studies on these compounds have estab-
lished that both the cis-relationship between the two sub-
stituents on the piperidine ring and the (2S,3S)-
configuration are crucial for high bioactivity.16
metathesis reaction as the key steps. Following this procedure,
(2S,3R)-3-hydroxy-2-phenylpiperidine is obtained in seven steps in
56.2% overall yield.
Key words: metathesis, piperidines, ring-closure, stereoselective
synthesis, zinc
Amongst the various approaches reported for the prepara-
tion of such 3-hydroxy-2-phenylpiperidine deriva-
tives,17,18 some involve the formation of (2S,3R)-N-tert-
butyl 3-hydroxy-2-phenylpiperidine-1-carboxylate (2),19
which can be regarded as an advanced versatile and
valuable precursor of (+)-CP-99,994,20 (+)-CP-122,721,20
(+)-LP-733,06014 and 115b,c (Scheme 1).
The neuropeptide substance P is an undecapeptide be-
longing to the tachykinin family that binds preferentially
to the endogenous neurokinin-1 (NK-1) receptor.1 Sub-
stance P is involved in complex mechanisms related to the
transmission of pain information in the central nervous
system. It is associated with the regulation of mood disor-
ders, anxiety, stress,2 reinforcement,3 neurogenesis,4
respiratory rhythm,5 neurotoxicity, nausea/emesis,6 mi-
graine,7 neurogenic inflammation,8 pain and nociception.9
Due to the various activities in which substance P is im-
plicated, the search for non-peptide NK-1 receptor antag-
onists has been investigated in recent years.10
(+)-CP-99,994
(+)-CP-122,721
ref. 20
Boc
N
ref. 15b,c
ref. 14
(+)-LP-733,060
1
Ph
2
OH
HN
Scheme 1 Advanced key intermediate 2 for the synthesis of (+)-CP-
99,994, (+)-CP-122,721, (+)-LP-733,060 and 1
Ph
Y
Rn
In the course of our studies on the synthesis of biological-
ly active compounds, we were interested in preparing 2
using a reaction developed in our group (i.e. the stereose-
lective addition of a racemic allenylzinc to an enantiopure
N-tert-butylsulfinyl imine21) and a ring-closing metathe-
sis as two key steps. Analogous allylsulfone addition to
(S)-p-toluenesulfinylimine and ring-closing metathesis
has been described before as an entry into optically active
2-arylpiperidines.22
(+)-CP-99,994
(+)-CP-122,721
(+)-LP-733,060
Y = NH, R = 2-MeO
Y = NH, R = 2-MeO, 3-OCF3
Y = O, R = 3,5-CF3
HN
Ph
OCF3
O
1
O
Our synthesis then began with the reaction between race-
mic allenylzinc ( )-3 and N-tert-butylsulfinyl imine (RS)-
4, which is easily prepared in diastereo- and enantiomeri-
cally pure form from commercially or readily synthetical-
ly available (RS)-tert-butylsulfinyl amide.23 Addition of
(RS)-4 to ( )-3 (4 equiv) allowed a high dynamic kinetic
resolution to take place; the (aR)-enantiomer of 3 reacted
Figure 1 Some non-peptide human NK-1 receptor antagonists
SYNLETT 2009, No. 19, pp 3115–3118
x
x
.x
x
.2
0
0
9
Advanced online publication: 23.10.2009
DOI: 10.1055/s-0029-1218308; Art ID: G25109ST
© Georg Thieme Verlag Stuttgart · New York

3116
B. Hélal et al.
LETTER
MOMO
H
ZnBr
TMS
•
S
S
S
O
HN
TMS
O
HN
O
N
( )-3 (4 equiv)
1. TBAF, THF, 0 °C, 40 min
Ph
2. H2 (1 atm), Lindlar Pd
acetone–hexane, r.t., 4 h
Ph
Et2O, –80 °C, 1 h
Ph
H
OMOM
5 94%, single
OMOM
6 98%
(RS)-4
>99% ee, >98:2 E/Z
S
S
1. NaH, THF–HMPA, 0 °C
then r.t., 30 min
O
O
N
Grubbs II catalyst (2 x 4 mol%)
CH2Cl2 (0.003 M) , 40 °C, 40 h
N
2. allyl bromide, r.t., 40 min
Ph
Ph
OMOM
8 95%
OMOM
7 72%
Boc
Ph
S
N
H2 (1 atm), Raney Ni
MeOH, r.t., 16 h
O
1. HCl (5 equiv), MeOH, 65 °C, 1 h
N
2. Et3N (15 equiv), Boc2O (5 equiv)
MeOH, 65 °C, 3 h
Ph
OH
2 98%
OMOM
9 91%
Scheme 2 Synthesis of (2S,3R)-3-hydroxy-2-phenylpiperidine derivative 2
with (RS)-4 faster [(aR)-3⋅(RS)-4 matched pair] than the tatively recovered), the desired product 926 was obtained
(aS)-antipode [(aS)-3⋅(RS)-4 mismatched pair]. After acid- in 91% yield within 16 hours at room temperature in the
ic workup, the desired acetylenic anti-(2S,3R)-sulfinyla- presence of Raney nickel in MeOH (Scheme 2).
midoalkyl ether 5 was isolated as a single isomer in 94%
Finally, acid-mediated removal of the tert-butylsulfinyl
auxiliary and MOM-ether deprotection were concomi-
yield (Scheme 2).24
Treatment of 5 with TBAF (1.05 equiv) in THF resulted tantly accomplished by treatment with anhydrous HCl (4
in the clean protodesilylation of the acetylenic position M in 1,4-dioxane, 5 equiv) at 65 °C in MeOH for one
within 40 minutes at 0 °C. The resulting crude product hour. Successive addition of Et3N (15 equiv) and Boc2O
was subjected to semihydrogenation (1 atm H2) for four (5 equiv) to the reaction mixture, followed by additional
hours in the presence of Lindlar palladium catalyst (20 heating at 65 °C for three hours afforded the target mole-
wt% of Pd) and 3,5-dithia-1,2-octanediol (4 wt%) in ace- cule 2 in 98% yield after usual work-up, intensive extrac-
tone–hexane (5%).21b Compound 6 was thus obtained in tion with EtOAc and silica gel flash chromatography
98% isolated yield over the two steps (Scheme 2).
(Scheme 2). It is worth noting that compound 2, thus ob-
tained, exhibited spectroscopic data {[a]D22 +64.1 (c 0.96,
CHCl3)} in excellent agreement with those reported for
the (2R,3S)-antipode19c {[a]D20 –66.1 (c 0.9, CHCl3)}, pre-
sumably indicating its optical purity.
Continuing the synthesis, intermediate 6 was added to
NaH (4 equiv) in a mixture of THF–HMPA (85:15) at
0 °C, and the resulting suspension was stirred at room
temperature for 30 minutes. The formed sodium sulfinyl
amide was subsequently treated with allyl bromide (10 In conclusion, (2S,3R)-N-tert-butyl 3-hydroxy-2-phe-
equiv) for 40 minutes at room temperature. After the usual nylpiperidine-1-carboxylate, a known advanced key inter-
workup, the expected allyl N-tert-butylsulfinyl amine 7 mediate of several non-petide human NK-1 receptor
was obtained in 72% yield (Scheme 2).
antagonists, has been obtained in seven steps and 56.2%
overall yield. This concise and high-yielding synthesis,
which involves the stereoselective addition of a racemic
3-alkoxy allenylzinc to an enantiopure (RS)-N-tert-butyl-
sulfinyl imine and a ring-closing metathesis reaction as
the key steps, represents a competitive alternative to pre-
viously reported approaches.
At this stage, we expected to construct the piperidine ring
system of the target molecule by subjecting 7 to ring-
closing metathesis with Grubbs II catalyst. Indeed, per-
forming the reaction with 8 mol% of ruthenium catalyst
(added as two portions each of 4 mol% separated by a pe-
riod of 20 h) in CH2Cl2 (0.003 M solution) at 40 °C for 40
hours, resulted in the formation of the desired compound
8
25 in 95% yield (Scheme 2).
References and Notes
In order to obtain the piperidine derivative 9, we under-
took the hydrogenation of the C–C double bond. While
carrying out the hydrogenation (1 atm) in the presence of
Pd/C failed to produce 9 (starting material 8 being quanti-
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Synlett 2009, No. 19, 3115–3118 © Thieme Stuttgart · New York

LETTER
Synthesis of (2S,3R)-3-Hydroxy-2-phenylpiperidine
3117
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(24) Procedure for the formation of 5: Under a nitrogen
atmosphere, to a stirred solution of 3-[(methoxymethoxy)-
prop-1-ynyl]trimethylsilane (8.40 mL, 48.00 mmol) and
TMEDA (0.66 mL, 4.80 mmol) in anhydrous Et2O (400 mL)
at –80 °C, was added dropwise s-BuLi (1.3 M in cyclo-
hexane–hexane, 92:8, 36.90 mL, 48.00 mmol). The resulting
clear orange mixture was stirred for 1 h at –80 °C and then a
solution of ZnBr2 (1 M in Et2O, 48.00 mL, 48.00 mmol) was
added. The resulting white slurry of allenylzinc ( )-3 was
stirred at –80 °C for an additional 20 min before imine 4
(2.51 g, 12.00 mmol) in anhydrous Et2O (48 mL) was added
dropwise. The mixture was stirred for 1 h at –80 °C, then
HCl (1 M, 200 mL) was added and the mixture was warmed
to room temperature. The layers were separated and the
aqueous phase was extracted with Et2O (3 × 200 mL). The
combined organic layers were washed with sat. NaHCO3 (60
mL), water (2 × 120 mL) and brine (120 mL), dried over
MgSO4 and concentrated in vacuo. The residual oil was
purified by flash chromatography on silica gel (EtOAc–
cyclohexane, 20→50%) to produce the desired compound 5
(4.32 g, 94%) as a pale-yellow solid. The physical and
spectroscopic data of 5 were in good agreement with those
previously reported for its antipode.21h
(14) Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G.
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B. J. Org. Lett. 2001, 3, 667. (b) Baker, R.; Curtis, N. R.;
Elliott, J. M.; Harrisson, T.; Hollingworth, G. J.; Jackson, P.
S.; Kulagowski, J. J.; Rupniak, N. M.; Seward, E. M.; Swain,
C. J.; Williams, B. J. Use of NK-1 receptor antagonists for
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Chem. 2008, 73, 3307. (b) Davis, F. A.; Zhang, Y.; Li, D.
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2007, 18, 982. (c) Kandula, S. R. V.; Kumar, P.
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3118
B. Hélal et al.
LETTER
spatulas) was added. The flask was flushed with H2 (3×).
(25) Procedure for the formation of 8: Under an argon
atmosphere, to a stirred solution of 7 (1.12 g, 3.20 mmol) in
anhydrous CH2Cl2 (1 L), was added Grubbs II catalyst (109
mg, 0.128 mmol). After 20 h stirring at 40 °C, additional
Grubbs II catalyst (109 mg, 0.128 mmol) was added. The
mixture was stirred for an additional 20 h and then cooled to
room temperature. Removal of the solvent in vacuo gave a
dark oil, which was purified by flash chromatography on
silica gel (EtOAc–cyclohexane, 30→50%) to yield 8 (984
mg, 95%) as a brown oil; [a]D20 +13.4 (c 1.11, CHCl3). 1H
NMR (400 MHz, CDCl3): d = 7.43–7.26 (m, 5 H), 6.11–6.02
(m, 2 H), 4.78 (AB system, J = 7.0 Hz, 1 H), 4.74 (AB
system, J = 7.0 Hz, 1 H), 4.62 (d, J = 3.3 Hz, 1 H), 4.51–
4.47 (m, 1 H), 3.77–3.60 (m, 2 H), 3.36 (s, 3 H), 1.18 (s,
9 H). 13C NMR (100 MHz, CDCl3): d = 137.7, 129.4, 129.3,
128.4, 128.2, 127.8, 125.3, 95.0, 71.3, 63.8, 59.3, 55.51,
55.50, 40.1, 23.2. IR (ATR diamond): 3033, 2948, 2887,
1657, 1601, 1028, 699 cm–1. HRMS (ESI): m/z [M + H+]
calcd for C17H26NO3S: 324.1628; found: 326.1620.
After 16 h stirring at room temperature under 1 atm of H2,
the reaction mixture was filtered through a short pad of flash
silica gel (EtOAc–cyclohexane, 30%). The solvents were
removed and the residue was filtered through a short pad of
flash silica gel eluting with EtOAc. Removal of the solvent
gave 9 (1.23 g, 91%) as a colorless viscous oil; [a]D20 +105.3
(c 0.82, CHCl3). 1H NMR (400 MHz, CDCl3): d = 7.46 (d,
J = 8.0 Hz, 2 H), 7.40 (t, J = 8.0 Hz, 2 H), 7.31–7.26 (m,
1 H), 4.63 (AB system, J = 6.8 Hz, 1 H), 4.57 (AB system,
J = 6.8 Hz, 1 H), 4.39 (d, J = 5.0 Hz, 1 H), 4.14–4.09 (m,
1 H), 3.43 (ddd, J = 13.1, 9.4, 3.5 Hz, 1 H), 3.31–3.22 (m,
1 H), 3.27 (s, 3 H), 2.02–1.91 (m, 1 H), 1.86–1.77 (m, 1 H),
1.76–1.65 (m, 1 H), 1.61–1.51 (m, 1 H), 1.18 (s, 9 H). 13
C
NMR (100 MHz, CDCl3): d = 138.1, 128.6, 128.1, 127.3,
94.6, 74.6, 64.6, 59.6, 55.4, 41.1, 27.2, 23.4, 21.3. IR (ATR
diamond): 3059, 3028, 2927, 2862, 1601, 1032, 914 cm–1.
HRMS (ESI): m/z [M + H+] calcd for C17H28NO3S:
326.1784; found: 326.1768.
(26) Procedure for the formation of 9: To a solution of 8 (1.35
g, 4.18 mmol) in absolute MeOH (100 mL), Raney Ni (5
Synlett 2009, No. 19, 3115–3118 © Thieme Stuttgart · New York