Concise total asymmetric synthesis of (S)-2-phenylpiperidin-3-one

Article abstract of DOI:10.1055/s-0029-1218359

Starting from readily available dihydropyridinones, we have developed the first synthesis of (S)-2-phenylpiperidin-3-one. While the scaffold appears relatively common, even in its racemic form, this original product can be considered as a potential precur

Full text of DOI:10.1055/s-0029-1218359

3320
LETTER
Concise Total Asymmetric Synthesis of (S)-2-Phenylpiperidin-3-one
A
symmetric Synth
a
esis of
(
S
)-
v
2-Phenylpipe
i
ridin-3
e
-one r Gaucher, Mouhamad Jida, Jean Ollivier*
Laboratoire de Synthèse Organique et Méthodologie, UMR 8182, Institut de Chimie Moléculaire et des Matériaux d'Orsay,
Université de Paris-Sud XI, 91405 Orsay, France
Fax +33(1)69157252; E-mail: jollivie@icmo.u-psud.fr
Received 27 August 2009
O
Ph
Abstract: Starting from readily available dihydropyridinones, we
have developed the first synthesis of (S)-2-phenylpiperidin-3-one.
While the scaffold appears relatively common, even in its racemic
form, this original product can be considered as a potential precur-
sor of substance P antagonist.
CF3
NH
OMe
F3C
1
HN
Ph
Key words: asymmetric synthesis, conjugation, drugs, piperidines,
radical reactions, ketones
O
Ph
O
Ph
NBoc
NH
NH
3
4
Substance P, discovered in 1931 by Von Euler and Gad-
dum,1 is an undecapeptide belonging to the tachykinin
neuropeptide family that acts as a neurotransmitter and
neuromodulator.2 This protein is closely associated with
certain inflammatory processes and can cause arthritic
pain,3a stress and anxiety responses,3b migraine3c and gas-
trointestinal diseases.3d Functionalized piperidines have
attracted increasing attention as pharmacophores in me-
dicinally active coumpounds.4 These azacyclic com-
pounds, bearing a substituted amine or alcohol moiety at
the 3-position, are active as tachykinine receptor ligands
that exhibit NK-1 receptor antagonist activity.5 Individual
enantiomers prepared from (2S)-phenylpiperidine deriva-
tives are preferred, having advantages over the racemic
mixture.6 Here, we describe a convenient asymmetric syn-
thesis of piperidinone 1, which is a potential intermediate
in the preparation of potent NK-1 antagonists 3 and 4. In-
deed, as shown in Scheme 1, the N-Boc derivative 2 is a
known precursor of these two compounds.7 In contrast to
the previously described processes, this methodology
does not require any resolution8 or asymmetric reaction
processes.9
Recently,10 as depicted in Scheme 2, we have reported the
intramolecular cyclopropanation of phenylglycine deriva-
tives to produce a diastereomeric mixture of azabicyc-
lo[3.1.0]hexanols 5, followed by ring-opening oxidation
to furnish N-benzyldihydropyridinone 6 (path a). Palladi-
um on charcoal catalyzed hydrogenation of this dihydro-
pyridinone 6 gave a mixture of piperidinone 7 and
pyridinol 8 (path b). Surprisingly, when a large excess
(20–50 equiv) of sodium acetate was used in the oxidation
step (path c), an unexpected transfer of the benzylic group
from nitrogen to oxygen was observed that led to the
oxypyridine 9.
2
Scheme 1 Piperidinone 1 as potential precursor to NK-1 antagonists
3 and 4
Bn
Bn
N
Ph
N
Ph
a
c
Bn
OH
O
N
Ph
O
5
7 (68%)
b
c
+
N
Ph
N
Ph
6 (90%)
Bn
OH
8 (16%)
O
9 (66%)
Scheme 2 Reagents and conditions: (a) FeCl3 (2.2 equiv), Et2O,
0 °C then NaOAc (5 equiv), MeOH, 20 °C; (b) H2, 10% Pd/C, EtOAc,
20 °C, 20 h; (c) FeCl3 (0.2–1 equiv), Et2O, 0 °C then NaOAc (20–50
equiv), MeOH, 20 °C.
In order to understand this novel transfer, which is also
observable with N-allyl protection, it is noteworthy that in
a MeOH–Et2O medium, no reaction occurred when the
isolated dihydropyridinone 6 was placed in a large excess
of sodium acetate (20–50 equiv), either in the presence or
absence of ferrous chloride (FeCl2) at room temperature.
However, upon addition of a small amount (from 0.2
equiv.) of iron(III) chloride, the formation of oxypyridine
9 was observed (Scheme 3). Total transformation was
achieved in 24 hours when the dihydropyridinone 6 was
first treated with one equivalent of iron(III) chloride in
Et2O, then with 50 equivalents of sodium acetate in meth-
anol.
As a mechanism (Scheme 3), we propose initial formation
of an enol in tautomeric equilibrium with 6 (stage a)
which, on oxidation with FeCl3, leads to a radical cation
(stage b) that evolves into a new dihydropyridinone radi-
cal (stage c). A further FeCl3-promoted oxidation involves
the formation of a cationic pyridinone (stage d) capable of
undergoing basic deprotonation (stage e), which allows
aromatization and subsequent liberation of the benzyl (or
SYNLETT 2009, No. 20, pp 3320–3322
x
x
.x
x
.2
0
0
9
Advanced online publication: 11.11.2009
DOI: 10.1055/s-0029-1218359; Art ID: D23409ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Synthesis of (S)-2-Phenylpiperidin-3-one
3321
potent NK-1 antagonists.12 We have found that N-benzyl
and N-allyl protected dihydropyridinones are unsuitable
intermediates for generating the desired unprotected pipe-
ridinone. We propose a novel mechanism that proceeds
through the unexpected formation of a benzyl (or allyl)
oxypyridine. Thus, we have demonstrated the extreme im-
portance of the protecting group associated with the nitro-
gen in this type of molecule and have succeeded in the
total synthesis of enantiomerically enriched (S)-2-phe-
nylpiperidin-3-one (1),10 a potential precursor of pharma-
cologically active products.
R
R
N
N
Ph
Ph
O
AcONa
a
6
9
f
OH
R = Bn, allyl
b
e
FeCl3
AcO
H
R
N
R
R
N
Ph
N
Ph
Ph
FeCl3
d
AcONa
c
O
O
OH
Scheme 3 Proposed mechanism for the formation of oxypyridine 9
in the presence of FeCl3
Acknowledgment
allyl) cation, which is trapped by the anionic oxygen
(stage f).
This work was financially supported by the CNRS and the Univer-
sity of Paris-Sud 11, by a grant to X.G. from the Ministère de la
Jeunesse, de l’Education Nationale et de la Recherche.
In order to prepare the unprotected piperidinone 1, we
wished to overcome the inability to realize both debenzy-
lation and reduction of the internal double bond. As a two-
step procedure appeared inevitable, we reasoned that an
N-tosyl protecting group, instead of an N-benzyl group,
would be appropriate. Indeed, its inertness toward palladi-
um-catalyzed hydrogenation and its ease of deprotection
under mild conditions should render it an efficient protect-
ing group for this purpose. Thus, after tosylation of the
(S)-phenylglycinate derivative 10, the resulting sulfonate
11 was induced to undergo subsequent Kulinkovich cy-
clopropanation to afford the separable diastereomeric
mixture (cis/trans ratio 72:28) of azabicyclo[3.1.0]hex-
anols 12a and 12b in 88% yield (Scheme 4).
References and Notes
(1) Von Euler, U. S.; Gaddum, J. H. J. Physiol. 1931, 72, 74.
(2) Otsuka, M.; Yanagisawa, M. Trends Pharmacol. Sci. 1987,
8, 506.
(3) (a) Levine, J. D.; Clark, R.; Devor, M.; Helms, C.;
Moskowitz, M. A.; Basbaum, Al. Science 1984, 226, 547.
(b) Ebner, K.; Singewald, N. Amino Acids 2006, 31, 251.
(c) Sandberg, B. E.; Iversen, L. L. J. Med. Chem. 1982, 25,
1009. (d) Mantyh, P. W.; Mantyh, C. R.; Gates, T.; Vigna,
S. R.; Maggio, J. E. Neuroscience 1988, 25, 817.
(4) Laird, T.; Hermitage, S. A. Org. Process Res. Dev. 2001, 5,
544.
(5) Baker, R.; Harrison, T.; Swain, C. J.; Williams, B. J. (Merck
Sharp & Dohme Ltd.), U.S. Patent WO 1993/004040, 1993;
Chem. Abstr. 1993, 119, 117122.
(6) Arnold, E. P.; Chappie, T. A.; Huang, J.; Humphrey, J. M.;
Nagel, A. A.; O’Neill, B. T.; Sobolov-Jaynes, S. B.; Vincent,
L. A.(Pfizer Products Inc.),U. S. Patent WO/2001/077100,
2001; Chem. Abstr. 2001, 135, 331346.
Ph
Ph
Ts
N
Ph
b
a
OMe
OMe
N
N
H
O
Ts
O
OH
11 (89%)
12a,b (88%)
10
(7) Lee, J.; Askin, D.; Hoang, T. I. (Merck & Co, Inc.), U.S.
Patent 2002/6388083, 2002; Chem. Abstr. 2002, 136,
183710.
Scheme 4 Reagents and conditions: (a) TsCl, pyridine, 20 °C; (b)
Ti(Oi-Pr)4 (1 equiv), i-PrMgCl (5 equiv), THF–Et2O (1:1), 20 °C.
(8) Calvez, O.; Langlois, N. Tetrahedron Lett. 1999, 40, 7099.
(9) (a) Lee, J.; Hoang, T. I.; Lewis, S.; Weissman, S. A.; Askin,
D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 2001, 42,
6223. (b) Takahashi, K.; Nakano, H.; Fujita, R. Tetrahedron
Lett. 2005, 46, 8927.
(10) Jida, M.; Ollivier, J. Eur. J. Org. Chem. 2008, 4041.
(11) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun.
1997, 1017.
(12) 3-Benzyloxy-2-phenylpyridine (9): Yield: 76%;
deliquescent yellow solid; 1H NMR (250 MHz, CDCl3): d =
7.82–7.72 (m, 2 H), 7.56–7.20 (m, 8 H), 7.04 (dd, J = 1.5,
2.5 Hz, 1 H), 6.79 (dd, J = 1.5, 4.3 Hz, 1 H), 6.23 (dd,
J = 2.5, 4.3 Hz, 1 H), 5.70 (s, 2 H); 13C NMR (62.9 MHz,
CDCl3): d = 149.8, 142.5, 139.9, 138.3, 131.5, 130.9, 129.3,
128.7, 128.6, 128.2, 127.9, 123.6, 108.7, 52.4; IR (neat):
3063, 3030, 1600 cm–1; MS (EI): m/z (%) = 261 (78) [M+],
156 (67), 91 (100), 77 (20); HRMS: m/z calcd for C18H15NO:
261.11480; found: 261.11437.
Saegusa oxidation performed on the mixture of cyclopro-
panols 12 afforded the expected dihydropyridinone 13
which, on charcoal palladium hydroxide catalyzed hydro-
genation, yielded the N-tosyl piperidinone 14. Subsequent
magnesium-promoted ultrasonic detosylation11 allowed
the enantiomerically enriched novel piperidinone 1 to be
isolated and characterized (Scheme 5).
Ts
N
Ts
N
H
Ph
Ph
N
Ph
a
b
c
12a,b
O
O
O
13 (90%)
14 (68%)
1 (68%)
Scheme 5 Reagents and conditions: (a) FeCl3 (2.2 equiv), Et2O,
0 °C, 1 h then NaOAc (5 equiv), MeOH, 20 °C; (b) H2, 10% Pd(OH)2/
C, EtOAc, 20 °C; (c) Mg, MeOH, 20 °C, 24 h.
Methyl (2S)-Allyl(4-methylphenylsulfonyl)amino-
20
(phenyl)acetate(11): Yield: 89%; colorless liquid; [a]D
–203 (c 0.6, CH2Cl2); 1H NMR (300 MHz, CDCl3): d = 7.77–
In conclusion, we have developed a concise route to 1 and
examined the limitations of the method. Compound 1 is a
useful chiral intermediate for the efficient preparation of
7.20 (m, 9 H), 5.82 (s, 1 H), 5.47–5.36 (m, 1 H), 4.80–4.74
(m, 2 H), 3.98–3.81 (m, 2 H), 3.63 (s, 3 H), 2.45 (s, 3 H); 13
C
NMR (75.5 MHz, CDCl3): d = 170.4, 143.5, 138.3, 136.9,
Synlett 2009, No. 20, 3320–3322 © Thieme Stuttgart · New York

3322
X. Gaucher et al.
LETTER
134.8, 129.6, 129.2, 128.8, 128.7, 127.5, 116.5, 62.7, 52.1,
48.3, 21.6; IR (neat): 3052, 3031, 2949, 1725, 1648, 1600
cm–1; MS (EI): m/z (%) = 359 (6) [M+], 186 (100), 144 (86),
118 (38), 91 (52); HRMS (ESI+): m/z calcd for
C19H21NO4SNa: 382.10840; found: 382.10906.
(1S,2S)-3-(4-Methylphenylsulfonyl)-2-phenyl-3-
azabicyclo[3.1.0]hexan-1-ol (12a): Yield: 63%;
(2S)-1-(4-Methylphenylsulfonyl)-2-phenyl-1,6-dihydro-3
(2H)-pyridinone (13): Yield: 25%; yellow oil; [a]D20 –145
(c 0.3, CH2Cl2); 1H NMR (360 MHz, CDCl3): d = 7.64–7.25
(m, 9 H), 6.71 (td, J = 4.7, 10.4 Hz, 1 H), 5.95 (td, J = 2.5,
10.4 Hz, 1 H), 5.63 (s, 1 H), 4.49 (ddd, J = 2.5, 4.7, 20.1 Hz,
1 H), 3.85 (ddd, J = 2.5, 4.7, 20.1 Hz, 1 H), 2.41 (s, 3 H); 13
C
NMR (62.9 MHz, CDCl3): d = 192.1, 144.6, 144.5, 136.4,
133.1, 129.9, 128.9, 128.5, 127.6, 127.1, 126.8, 64.0, 41.7,
21.6; IR (neat): 3064, 3032, 2964, 1687, 1633, 1598 cm–1;
MS (EI): m/z (%) = 327 (9) [M+], 207 (18), 196 (75), 194
(35), 172 (86), 146 (100), 118 (43), 91 (78); HRMS (ESI+):
m/z calcd for C18H18NO3S: 328.10270; found: 328.10218.
(2S)-1-(4-Methylphenylsulfonyl)-2-phenylpiperidin-3-
one (14): Yield: 68%; deliquescent solid; [a]D20 +5 (c 0.2,
CH2Cl2); 1H NMR (300 MHz, CDCl3): d = 7.74–7.28 (m, 9
H), 5.58 (s, 1 H), 3.87 (td, J = 5.1, 13.8 Hz, 1 H), 3.45 (td,
J = 4.2, 14.1 Hz, 1 H), 2.44 (s, 3 H), 2.38 (td, J = 4.2, 14.1
Hz, 1 H), 2.20 (td, J = 5.1, 13.8 Hz, 1 H), 1.76–1.68 (m, 2 H);
13C NMR (62.9 MHz, CDCl3): d = 204.4, 143.8, 142.6,
133.9, 130.0, 129.1, 128.1, 127.1, 125.7, 66.8, 41.8, 36.7,
23.5, 21.6; IR (neat): 3063, 2957, 1722, 1598 cm–1; MS (EI):
m/z (%) = 329 (9) [M+], 224 (29), 174 (93), 146 (100), 118
(46), 91 (77); HRMS (ESI+): m/z calcd for C18H19NO3SNa:
352.09780; found: 352.09813.
deliquescent solid; [a]D20 –305 (c 0.7, CH2Cl2); 1H NMR
(360 MHz, CDCl3): d = 7.40–7.12 (m, 9 H), 4.98 (s, 1 H),
3.76 (dd, J = 3.6, 10.1 Hz, 1 H), 3.53 (d, J = 10.1 Hz, 1 H),
2.37 (s, 3 H), 1.79 (br s, 1 H), 1.72 (td, J = 4.5, 9.0 Hz, 1 H),
1.30–1.15 (m, 1 H), 0.46 (t, J = 4.5 Hz, 1 H); 13C NMR (62.9
MHz, CDCl3): d = 143.0, 137.9, 131.8, 129.4, 128.9, 128.3,
127.8, 126.8, 66.1, 64.9, 49.8, 23.1, 21.5, 15.8; IR (KBr):
3473, 3063, 3033, 2928, 2881, 1599 cm–1; MS (EI): m/z
(%) = 329 (8) [M+], 301 (49), 155 (78), 146 (32), 118 (32),
91 (100); HRMS (ESI+): m/z calcd for C18H20NO3S:
330.11580; found: 330.11529.
(1R,2S)-3-(4-Methylphenylsulfonyl)-2-phenyl-3-
azabicyclo[3.1.0]hexan-1-ol (12b): Yield: 25%;
deliquescent solid; [a]D20 –194 (c 0.5, CH2Cl2); 1H NMR
(250 MHz, CDCl3): d = 7.60–7.10 (m, 9 H), 4.11 (s, 1 H),
3.48 (d, J = 9.5 Hz, 1 H), 3.26 (dd, J = 4.5, 9.5 Hz, 1 H), 2.50
(br s, 1 H), 2.36 (s, 3 H), 1.56 (td, J = 4.5, 9.0 Hz, 1 H), 1.11–
1.03 (m, 1 H), 0.68 (dd, J = 4.5, 9.0 Hz, 1 H); 13C NMR (62.9
MHz, CDCl3): d = 144.3, 137.9, 132.0, 129.9, 129.0, 128.6,
128.2, 127.5, 68.4, 67.9, 52.2, 21.9, 21.8, 15.5; IR (KBr):
3465, 3062, 3031, 2928, 2872, 1599 cm–1; MS (EI): m/z
(%) = 329 (8) [M+], 224 (28), 207 (42), 174 (82), 146 (100),
118 (51), 91 (86). HRMS (ESI+): m/z calcd for C18H20NO3S:
330.11580; found: 330.11525.
(2S)-2-Phenylpiperidin-3-one (1): Yield: 68%;
deliquescent solid; [a]D20 +12 (c 0.1, CH2Cl2); 1H NMR (300
MHz, CDCl3): d = 7.36–7.22 (m, 5 H), 4.88 (s, 1 H), 2.66–
2.45 (m, 4 H), 2.44 (br s, 1 H), 1.68–1.52 (m, 2 H); 13C NMR
(62.9 MHz, CDCl3): d = 205.2, 134.9, 124.9, 128.7, 127.1,
72.2, 43.2, 33.6, 26.1; IR (neat): 3059, 2955, 1720, 1598
cm–1; MS (EI): m/z (%) = 175 (24) [M+], 147 (34), 146
(100), 131 (60), 121 (70), 120 (53); HRMS (ESI+): m/z calcd
for C11H13NONa: 198.18840; found: 198.18834.
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