A stereoselective route to cis-2-phenyl-3-piperidinol

Article abstract of DOI:10.1016/j.tetlet.2005.08.060

Enantiopure cis-2-phenyl-3-piperidinol is a commonly used synthon for the obtention of a potent class of neurokinin substance P receptor antagonists. Starting from (R)-phenylglycine, the present report describes an efficient route for the stereoselective

Full text of DOI:10.1016/j.tetlet.2005.08.060

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7221–7223
A stereoselective route to cis-2-phenyl-3-piperidinol
Ningning Liang, Pusuluri Srinivas and Apurba Datta*
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA
Received 2 August 2005; accepted 15 August 2005
Available online 2 September 2005
Abstract—Enantiopure cis-2-phenyl-3-piperidinol is a commonly used synthon for the obtention of a potent class of neurokinin sub-
stance P receptor antagonists. Starting from (R)-phenylglycine, the present report describes an efficient route for the stereoselective
synthesis of the above piperidinol structural core.
Ó 2005 Elsevier Ltd. All rights reserved.
Chiral polysubstituted piperidine structural frame-
work is a common feature present in a large number
of natural and nonnatural compounds of biological
significance.1 Consequently, development of new and
efficient methods for the stereoselective synthesis of
functionalized piperidines continues to be an active area
of research.2,3 In the search for nonpeptidic neurokinin
NK-1 receptor antagonists, the 2,3-disubstituted piperi-
dine derivatives 2 and 3 (Scheme 1) were found to dis-
play potent and selective antagonist activity at the
human NK-1 receptor site.4,5
2 and 3 is required for optimum binding activity.7 In
the majority of the synthetic studies reported so far,
appropriately protected piperidinol 1 has been a com-
monly utilized precursor for the synthesis of the corre-
sponding aryl ether derivative 2.6 Interestingly, the
piperidinol 1 could also be stereoselectively transformed
to the corresponding 3-amino derivative toward synthe-
sizing the 3-aminoaryl analog 3.6e,g In continuation of
our studies on amino acid chiral template assisted stereo-
selective synthesis of bioactive compounds,8 we report
herein an efficient route to the enantiopure 2-phenyl-3-
piperidinol structural core.
In recent years, several methods have been developed to-
wards the synthesis and structural modification studies
of the above compounds.6 Structure–activity relation-
ship studies have shown that the cis-relationship be-
tween C2 and C3 substituents on the piperidine ring of
Our plan for the construction of the piperidine frame-
work is shown below (Fig. 1). The key bond forming
reactions in the delineated strategy are envisioned to
be (i) a chelation controlled, stereoselective addition of
an appropriate Grignard reagent to enantiopure N-
Boc-phenylglycinal and (ii) an oxidative cyclization of
the resulting d-alkenylcarbamate 5 toward formation
of the target piperidine core 4.
OH
Ph
3
2
Ar
X
N
H
N
Ph
H
Following a known procedure, readily available (R)-
phenylglycine was converted to N-Boc-phenylglycinol
(6, Scheme 2) in good yield.9 The next step in the
sequence required stereoselective construction of the
2, X = O; Ar = 3,5-(CF3)2C6H3:
[(+)-L-733,060]
1
3a, X = NH; Ar = 2-(MeO)C6H4:
[(+)-CP-99,994]
3b, X = NH; Ar = 2-(MeO)-5-
(OCF3)C6H3: [(+)-CP-122,721]
H
Ph
N
Scheme 1.
NH2
CO2H
Boc NH
Ph
Ph
HO
Keywords: Piperidine; Bioactive; Phenylglycine; Stereoselective;
Chelation controlled.
(R)-Phenyl-
glycine
OR
5
4
*
Corresponding author. Tel.: +1 785 864 4117; fax: +1 785 864
5326; e-mail: adutta@ku.edu
Figure 1. Retrosynthetic strategy and approach.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.060

7222
N. Liang et al. / Tetrahedron Letters 46 (2005) 7221–7223
In conclusion, starting from easily available (R)-phenyl-
i. Swern oxidn.
ii.
Boc NH
Ph
NH2
CO2H
i. LiAlH4
ii. Boc2O
glycine and utilizing an elegant oxidative heterocycliza-
tion of an appropriately functionalized d-alkenyl-
carbamate intermediate, an efficient route to enantio-
pure cis-2-phenyl-3-piperidinol has been developed. In
terms of brevity and efficiency, the present synthesis
compares well with the earlier reported methods6 and
is expected to offer an attractive alternative route to
the title compound. Furthermore, as chiral nonracemic
piperidines are common structural subunits found in
a variety of compounds of pharmaceutical significance,
the strategy and the approach described herein can
be easily extended towards synthesizing various
functionalized piperidines of potential biomedical
application.
MgBr
Ph
73%
64%
(syn:anti > 9:1)
OH
(R)-Phenyl-
glycine
6
Boc
OsO4, NaIO4,
2,6-lutidine
Boc NH
Ph
Ph
N
OH
69%
TBSO
OR
5, R = H
7, R = TBS
8
TBDMSCl,
Im, CH2Cl2
82%
Boc
N
Et3SiH,
HCl
H
•
aq. HCl,
reflux
Ph
Ph
N
BF3 Et O
•
2
85%
(9a --> 10)
RO
HO
97%
10
TBAF,
THF
88%
9a, R = TBS
9b, R = H
References and notes
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Scheme 2.
syn-1,2-aminoalcohol functionality as depicted in the de-
sired intermediate 5. In a previous research from our
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the fully protected 2-phenyl-3-piperidinol derivative 9a.
At this stage, partial deprotection via selective removal
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25
20
data {½aꢀD ꢁ50.4 (c 1, CHCl3): Lit.6c ½aꢀD ꢁ51.1 (c 1,
CHCl3)} of which were found to be in good agreement
with the reported values, thereby confirming the as-
signed structure and absolute configuration of 9b and
its precursors. In a separate experiment, simultaneous
removal of both the O- and N-protecting groups by
treatment of 9a with refluxing aq HCl culminated in
an efficient route to the hydrochloride salt of cis-2-phen-
yl-3-hydroxypiperidine (10/ent-1).13
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Chem. 1997, 5, 535–547.
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1991, 56, 6939–6942.

N. Liang et al. / Tetrahedron Letters 46 (2005) 7221–7223
7223
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7611; (b) Ravi Kumar, J. S.; Datta, A. Tetrahedron Lett.
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13. Spectral and analytical data of compound 10: light yellow
25
flaky solid; mp 264–268 °C; ½aꢀD ꢁ62.54 (c 1.03, H2O); 1H
NMR (400 MHz, D2O): d 1.69–1.99 (m, 4H), 3.07–3.13
(m, 1H), 3.40–3.43 (m, 1H), 4.12 (br s, 1H), 4.32 (br s, 1H),
7.24–7.57 (m, 5H); 13C NMR (100.6 MHz, D2O): d 16.0,
28.8, 45.1, 62.6, 66.7, 126.3, 128.2, 128.9, 129.0, 129.5,
134.8; HRMS Calcd for C11O16NO (free amine) m/z
(M+H) 178.1232, found 178.1224.
12. Pedregal, C.; Ezquerra, J.; Escribano, A.; Carreno, M. C.;
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