An efficient stereoselective synthesis of (2S,3S)-3-hydroxy-2- phenylpiperidine

Article abstract of DOI:10.1016/j.tetlet.2003.11.103

A concise enantioselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2- phenylpiperidine 1 is described starting from L-phenyl-glycine and using a Grignard reaction as a key step.

Full text of DOI:10.1016/j.tetlet.2003.11.103

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 987–988
An efficient stereoselective synthesis of (2S,3S)-3-hydroxy-
2-phenylpiperidine
Mandar S. Bodas, Puspesh K. Upadhyay and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 17 September 2003; revised 10 November 2003; accepted 21 November 2003
Abstract—A concise enantioselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine 1 is described starting from
L
-phenyl-glycine and using a Grignard reaction as a key step.
Ó 2003 Elsevier Ltd. All rights reserved.
Functionalised piperidines constitute one of the major
classes of naturally occurring compounds, and interest
in their chemistry continues unabated because of their
usefulness as biologically active agents. Consequently
numerous methods have been developed for the
synthesis of substituted piperidines in a stereo- and
enantioselective manner.1 N-Boc-(2S,3S)-3-hydroxy-2-
phenylpiperidine 1 is an important intermediate from
which nonpeptide neurokinin NK1 receptor antagonists
22 and 33 have been prepared (Fig. 1).
H
N
OH
OMe
N
N
H
Ph
(+)-(2S,3S)-CP-99, 994
Boc
1
2
CF3
O
CF3
N
Ph
These nonpeptide ligands 2 and 3 are known to exhibit a
variety of biological activities including neurogenic
inflammation,4 pain transmission and regulation of the
immune response.5 They have been implicated in a
variety of disorders including migraine,6 rheumatoid
arthritis7 and pain.8 It has been established that the cis-
relationship between the two substituents on the piper-
idine ring and 2S,3S configurations are essential for
A
few reports have appeared on the asymmetric synthesis
of 1. These involve the use of Sharpless asymmetric di-
hydroxylation of a silyl enol ether,10a -glutamic acid10b
L
H
(2S,3S)-L-733, 060
3
Figure 1.
ested in developing a simple and feasible route to N-
Boc-3-hydroxy-2-phenylpiperidine 1. Here we report a
new and highly enantio- and diastereoselective synthesis
of 1 employing a Grignard reaction as a key step.
high-affinity binding to the human NK1 receptor.2b;3;9
or (S)-N-methoxy-N-methylpyroglutamide10c as chiral
pool materials, the intramolecular ring opening of a
chiral epoxide followed by ring expansion10d and the
application of ring-closing metathesis10e for the prepa-
ration of enantiopure 1. As part of our research pro-
gram aimed at developing enantioselective syntheses of
naturally occurring amino alcohols,11 we became inter-
The synthesis of the target compound 1 commenced
from commercially available
L-phenylglycine 4 as
depicted in Scheme 1. Compound 4 was first converted
into the N-Boc derivative and subsequently esterified
with methyl iodide to give N-Boc methyl ester 5 in
excellent yield. The ester 5 was reduced to alcohol 6
using LiAlH4. The essential feature of our synthetic
strategy was the presumption that the aldehyde derived
from alcohol 6 would undergo chelation-controlled
carbonyl addition12 and provide preferentially the
desired threo amino alcohol 7 in a stereoselective
manner. Thus, Swern oxidation of 6 followed by in situ
* Corresponding author. Tel.: +91-20-589-3300x2050; fax: +91-20-
589-3614; e-mail: tripathi@dalton.ncl.res.in
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.103

988
M. S. Bodas et al. / Tetrahedron Letters 45 (2004) 987–988
References and notes
NH2
COOH
NHBoc
COOCH3
b
a
1. Lasschat, S.; Dickner, T. Synthesis 2000, 13, 1781–1813,
and references cited therein.
2. (a) Baker, R.; Harrison, T.; Hollingworth, G. J.; Swain, C.
J.; Williams, B. J. 1993, EP 528,495 A1; (b) Harrison, T.;
Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med.
Chem. Lett. 1994, 4, 2545–2550.
3. Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K.
P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911–4913.
4. Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1988,
241, 1218–1221.
5. Perianan, A.; Snyderman, R.; Malfroy, B. Biochem.
Biophys. Res. Commun. 1989, 161, 520–524.
6. Moskowitz, M. A. Trends. Pharmacol. Sci. 1992, 13, 307–
311.
4
5
NHBoc
NHBoc
OH
d
OTHP
c
OH
6
7
NHBoc
OH
e
OH
N
OH
8
1
Boc
7. Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1987,
235, 893–895.
Scheme 1. Reagents and conditions: (a) (i) (Boc)2O, 1 N NaOH,
dioxane, 2 h, 0 °C–rt, 95%, (ii) K2CO3, DMF, CH3I, 1 h, 0 °C–rt, 85%;
(b) LiAlH4, THF, 1 h, 0 °C–rt, 89%; (c) DMSO, (COCl)2, DCM,
i-Pr2NEt then BrMg (CH2)3OTHP, THF, 2 h, rt, 58%; (d) TsOH,
MeOH, 2 h, rt, 85%; (e) (i) MsCl, Et3N, DCM, 3 h, 0 °C–rt, (ii) NaH,
THF, rt, 78%.
8. Otsuka, M.; Yanagisawa, M. J. Physiol. (London) 1988,
395, 255–270.
9. (a) Giardina, G. A. M.; Raveglia, L. F.; Grugni, M. Drugs
Future 1997, 22, 1235–1257; (b) Chandrasekhar, S.;
Mohanty, P. K. Tetrahedron Lett. 1999, 40, 5071–5072.
10. (a) Stadler, H.; Bos, M. Heterocycles 1999, 51, 1067–1071;
(b) Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org.
Lett. 2003, 5, 1927–1929; (c) Calvez, O.; Langlois, N.
Tetrahedron Lett. 1999, 40, 7099–7100; (d) Lee, J.; Hoang,
T.; Lewis, S.; Weissman, S. A.; Askin, D.; Volante, R. P.;
Reider, P. J. Tetrahedron Lett. 2001, 42, 6223–6225; (e)
Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44, 915–
917.
reaction of the resulting aldehyde with 3-(tetrahydro-
pyran-2-yloxy)propylmagnesium bromide afforded the
amino alcohol 7 as a single diastereomer13 in favour of
the syn isomer, which is in accordance with the reported
observation.14 The THP group of 7 was removed using
p-toluenesulfonic acid to give the amino diol 8 in 85%
yield. The primary hydroxyl group was then mesylated
followed by in situ cyclisation using NaH to furnish
N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine 1 in 78%
11. (a) Fernandes, R. A.; Kumar, P. Tetrahedron: Asymmetry
1999, 10, 4797–4802; (b) Fernandes, R. A.; Kumar, P. Eur.
J. Org. Chem. 2000, 3447–3449; (c) Fernandes, R. A.;
Kumar, P. Tetrahedron Lett. 2000, 41, 10309–10312; (d)
Pandey, R. K.; Fernandes, R. A.; Kumar, P. Tetrahedron
Lett. 2002, 43, 4425–4426; (e) Naidu, S. V.; Kumar, P.
Tetrahedron Lett. 2003, 44, 1035–1037; (f) Kandula, S. V.;
Kumar, P. Tetrahedron Lett. 2003, 44, 1957–1958; (g)
Pandey, R. K.; Upadhyay, P. K.; Kumar, P. Tetrahedron
Lett. 2003, 44, 6245–6246; (h) Gupta, P.; Fernandes, R.
A.; Kumar, P. Tetrahedron Lett. 2003, 44, 4231–4232.
12. For the stereocontrolled addition of organometallic com-
pounds to optically active N-protected a-amino aldehydes
see, review: Jurczak, J.; Golebiowski, A. Chem. Rev. 1989,
89, 149–164.
20
D
25
D
yield, ½aꢀ +35.41° (c 1.2, CHCl3) [Lit.10e ½aꢀ +38.30°
(c 1.92, CHCl3)]. The physical and spectroscopic data of
1 were in full agreement with the literature values.10e The
intermediate 1 could easily be transformed into the
nonpeptidic neurokinin NK1 receptor antagonists 2 and
3 as previously reported.10b;e
In summary, a highly enantio- and stereoselective syn-
thesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine 1
has been accomplished. The short reaction sequence and
high overall yield of the target compound render our
strategy a good alternative to the known methods.
13. The diastereoselectivity was determined based on 13C
20
D
NMR spectral data. Spectral data of 7: ½aꢀ +13.73° (c
0.82, CHCl3) IR (CHCl3, cmꢁ1) 3480, 3350, 2936, 2840,
1
1680, 1550, 1448; H NMR (200 MHz, CDCl3): d 1.47 (s,
9H), 1.52–1.68 (m, 8H), 2.04–2.35 (m, 2H), 3.41–3.79 (m,
5H), 4.21–4.24 (m, 1H), 4.58 (m, 1H), 5.46 (br s, 1H), 7.30
(m, 5H); 13C NMR (75 MHz, CDCl3): d 19.05, 25.08,
28.24, 30.22, 32.50, 34.93, 56.50, 63.82, 65.84, 79.65, 94.36,
98.60, 126.53, 127.26, 128.40, 140.02, 156.23; Mass (ESI):
397 (M+NHþ4 ), 380 (M+1), 356, 279, 246.
Acknowledgements
Mandar S. Bodas thanks CSIR, New Delhi for the
award of Senior Research Fellowship. We are grateful
to Dr. M. K. Gurjar for his support and encouragement.
This is NCL Communication No. 6655.
14. For related examples, see: Denis, J. N.; Correa, A.;
Greene, A. E. J. Org. Chem. 1991, 56, 6939–6942, and
references cited therein.