A diastereoselective synthesis of 2,4-disubstituted piperidines: scaffolds for drug discovery.

Article abstract of DOI:10.1021/ol006589o

A method for the diastereoselective synthesis of 2,4-disubstituted piperidines has been developed which enables the complete control of reaction selectivity merely by changing the order of the reaction sequence. These targets provide convenient platforms

Full text of DOI:10.1021/ol006589o

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3679-3681
A Diastereoselective Synthesis of
2,4-Disubstituted Piperidines: Scaffolds
for Drug Discovery
Paul S. Watson,* Bin Jiang, and Brian Scott
Dupont Pharmaceuticals Company, Route 141 and Henry Clay Road,
Wilmington, Delaware 19880
paul.s.watson@dupontpharma.com
Received September 13, 2000
ABSTRACT
A method for the diastereoselective synthesis of 2,4-disubstituted piperidines has been developed which enables the complete control of
reaction selectivity merely by changing the order of the reaction sequence. These targets provide convenient platforms for drug discovery
which contain easily modified points of diversity.
The piperidine ring continues to be a common moiety in
pharmaceutical research. A search of the chemical and patent
literature reveals thousands of references to this simple ring
system in clinical and preclinical research.1 Not surprisingly,
1,4-disubstitution of the piperidine ring dominates the liter-
ature due to the ease of synthesis and the absence of com-
plicating stereochemical issues. Since 1993 four new com-
mercial products have appeared that possess this substitution
pattern as the central component (Figure 1). Aricept (done-
pezil), an acetylcholinesterase inhibitor,2 is currently being
prescribed for the treatment of Alzheimer’s disease. Naramig
(naratriptan, 2), an agonist of 5-HT1D and 5-HT1B, has shown
promise in the treatment of migraine headaches.3 Finally,
Risperdal (risperidone, 3) and Serdolect (sertindole, 4), both
nonselective 5-HT/D2 antagonists, are currently being utilized
in the treatment of schizophrenia.4 Due to the established
clinical value of these drugs, synthetic approaches to this
simple ring system have drawn a great deal of attention.
A literature search of 2,4-disubstituted piperidines revealed
a paucity of interest in both clinical and preclinical develop-
ment. The added synthetic difficulties and potentially
heightened development costs of this substitution pattern
(1) A substructure search of the piperidine ring using the electronic
version of the Drug Data Report (MDL Drug Data Report) which includes
data from July 1988 through December 1998 revealed over 12 000 discrete
piperidine entities that have been mentioned in clinical or preclinical studies.
(2) Yamanishi, Y.; Ogura, H.; Kosasa, T. Tanpakushitsu Kakusan Koso
2000, 45 (6), 1047-1051.
Figure 1. Recent product launches containing a 1,4-disubstituted
piperidine ring as one of its major components.
(3) Yevich, J. P.; Yocca, F. D. Curr. Med. Chem. 1997, 4, 295-312.
10.1021/ol006589o CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

could be the reason for the inactivity in this area of synthesis
and drug discovery. Despite these perceived liabilities, it was
our belief that the added structural information (available
due to the different conformations produced with this
alternate structural constitution) and the third site of diversity
in this ring system would provide a powerful scaffold for
further investigation (Figure 2).
means of generating the thermodynamic reaction products.
The synthesis of the required substrates was accomplished
by utilizing methodology previously described (Scheme 1).7
Scheme 1. Synthesis of the Required Reduction Precursorsa
Figure 2. 2,4-Disubstituted piperidines can provide valuable
structural information and an additional site of diversity.
Our strategy for the diastereoselective construction of 2,4-
disubstituted piperidines relies on a well-known yet underuti-
lized property of N-acylpiperidine (Figure 3).5 Spectroscopic
a Reaction Conditions: (a) PhOC(O)Cl, THF, -20 °C; RMgCl,
-78 °C; 10% HCl, 23 °C; (b) MeONa, MeOH, 23 °C; (c) Boc2O,
DMAP, MeCN, 23 °C; (d) Zn, HOAc, 50 °C; (e) t-BuOK,
PhCH2P(Ph)3Cl, THF, 23 °C or (Ph)3PdCHCO2Et, toluene, reflux
or 2 equiv of t-BuOK, 4-ZHN-PhCH2P(Ph)3Cl, THF, -78 to 23
°C.
Several commercially available Grignard reagents (allyl, i-Pr,
and Bn) were added to the acylpyridinium salt of 4-meth-
oxypyridine (5). We chose to execute this addition reaction
via the intermediacy of the acylpyridinium ion generated
from phenyl chloroformate. The synthetically more tractable
tert-butylurethane could then be prepared by base hydrolysis
and reprotection of the resulting amide. This sequence
resulted in the production of vinylogous imides 8a-c in good
overall yields. Conjugate reduction of the olefin with zinc
in acetic acid provided piperidones 9a-c.8 These conditions
proved to be superior and more reliable on a large scale than
previously published protocols.9 Wittig olefination provided
styrenes 10a-c and R,â-unsaturated esters 11a-c and 12a10
in good overall yields.
Reduction of the styryl derivatives 10a-c (as 1:1 mixtures
of E- and Z-olefins, Table 1) using typical conditions for
dissolving metal reductions (50 equiv of Li, NH3, THF, -78
to -28 °C) followed by removal of the nitrogen protecting
group provided the trans-piperidines (13a-c) with excellent
diastereoselectivity and overall yields.11 Transformation of
the R,â-unsaturated esters 11a-c using the same protocol
provided the corresponding amino alcohols (13d-f) with
comparable selectivities and slightly reduced yields.12 Amino
alcohol 13d, containing three chemically orthogonal moieties,
can be used to prepare highly diverse and unique derivatives.
Figure 3. Pseudo A1,3-strain in 2-substituted acylated heterocycles
controls the ground state conformation (the Paulson effect).
evidence6 suggests that resonance structure B contributes
significantly to the ground state conformation of N-acylated
piperidine. This electronic effect, coupled with a pendant
2-substituent on the ring, creates a scenario where pseudo
allylic strain (A1,3) governs the ground state conformation
of the heterocycle. Thus, conformation D, which minimizes
the pseudo allylic strain, is the lowest energy conformation
and should dictate the stereochemical outcome of a thermo-
dynamically controlled reaction pathway that generates an
additional stereogenic center on the ring. Removal of this
control element (nitrogen deprotection) should reverse the
diastereochemical outcome of this transformation.
Our initial efforts in this area focused on the dissolving
metal reduction of R,â-unsaturated esters and styrenes as a
(4) For sertindole, see: Targum S.; Zborowski, J.; Henry, M.; Schmitz,
P.; Sebree, T.; Wallin B. Eur. Neuropsychopharmacol. 1995, 5, 4-71. For
resperidone, see: Schotte, A.; Janssen, P. F. M.; Gommeren, W.; Luyten,
W. H. M. L.; Van Gompel, P.; Lesage, A. S.; De Loore, K.; Leysen, J. E.
Psychopharmacology 1996, 124, 57-73.
(5) For two examples that use this control element in an intermolecular
fashion, see: (a) Krow, G. R.; Alston, P. V.; Szczepanski, S. W.;
Raghavachari, R.; Cannon, K. C.; Carey, J. T. Synth. Comm. 1990, 20(13),
1949-1958. (b) Polniaszek, R. P.; Dillard, L. W. J. Org. Chem. 1992, 57,
4103-4110.
(6) Paulson, H.; Todt, K. Angew. Chem., Int. Ed. Engl. 1966, 5 (10),
899-900.
(7) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986, 27 (38), 4549-
4552. An auxiliary-mediated process has also been developed to provide
these substrates in optically pure form. See: Comins, D. L.; Goehring, R.
R.; Joseph, S. P.; O′Connor, S. J. Org. Chem. 1990, 55, 2574-2576.
(8) We wish to thank Professor Daniel Comins for making us aware of
this reaction.
(9) (a) Comins, D. L.; Dehgani, A. Tetrahedron Lett. 1992, 33, 6299-
6302. (b) Waldman, H.; Braun, M. J. Org. Chem. 1992, 57, 444.
3680
Org. Lett., Vol. 2, No. 23, 2000

The conformational flexibility imparted to these substrates
after the removal of the nitrogen protecting group compli-
cated the assignment of the relative stereochemistry. How-
ever, this problem was addressed by rigidifying the entire
system by conversion to the quinolizinone ring system. Thus,
acylation of allyl derivatives 13a and 14a followed by ring-
closing metathesis (Figure 4) provided quinolizinones 15 and
Table 1. Reduction of the N-Acylated Piperidines
Reduction of olefin 12a conveniently removes the aniline
protecting group, unveiling an additional site of chemical
diversity.
Congruent with our original goals, changing the order of
the synthetic operations is predicted to reverse the selectivity
of these reductions. Thus, acid-catalyzed removal of the tert-
butylurethane from 10a (Table 2) followed by dissolving
Figure 4. Structural assignment of each diastereomer.
16, respectively. This represents a novel approach to the quin-
olizidine ring system.13 These bicycles now possessed pre-
dictable and definitive spectroscopic properties necessary for
an unambiguous assignment of the relative stereochemistry.14
In conclusion, a highly diastereoselective synthesis of 2,4-
disubstituted piperidines has been developed which provides
access to both diastereomers simply by changing the order
of the reaction sequence. These substrates are easily acces-
sible in optically enriched form and should be useful
intermediates for the assembly of novel diverse piperidine
scaffolds. Further application of this methodology is under-
way and will be reported in due course.
Table 2. Reduction of the Free Amines
Acknowledgment. We thank Dr. Paul Anderson, Dr.
George Trainor, and Dr. Soo Ko for their support of this
research. We thank Greg Nemeth for his help in the
assignment of the relative stereochemistry of these com-
pounds. We thank Mike Haas for his valuable help with
providing mass spectral data for these compounds.
metal reduction afforded the cis-diastereomer with excellent
diastereoselectivity and excellent overall yield. Further
examination of Table 2 reveals that comparable selectivities
and yields were obtained with the remaining examples
studied (10b-c, 11a-c, 12a). Merely by changing the order
of the synthetic operations one can dictate which stereo-
chemical outcome the reaction will afford. This protocol
provides for simple access to all four stereoisomers and
should be applicable to other similar ring systems.
Supporting Information Available: Representative ex-
perimentals and spectral data (1H NMR, 13C NMR, IR, and
high-resolution mass spectra) for all new compounds and
the structural assignments for compounds 15 and 16. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL006589O
(10) The synthesis and use of this Wittig reagent will be described
elsewhere.
(11) Catalytic hydrogenation (H2, 10% Pd/C, EtOAc) provided a slight
preference (2:1) for the cis-diastereomer as measured by 1H NMR
spectroscopy.
(12) The chemical yields of these substrates tended to be lower due to
side reactions (amide formation and incomplete ester reduction) associated
with the ester functionality.
(13) Our work in this area will be disclosed in a separate Letter. For a
similar approach to R,â-unsaturated-2-piperidinones, see: Rutjes, F. P. J.
T.; Schoemaker, H. E. Tetrahedron Lett. 1997, 38, 677-680.
(14) For 15: An NOE between the proton adjacent to the nitrogen (Ha)
and the benzylic protons (Hb) confirmed the trans relationship between the
substituents. For 16: An NOE between the proton adjacent to the nitrogen
(Ha) and the proton adjacent to the 4-substituent (Hb) confirmed the cis
relationship between the substituents.
Org. Lett., Vol. 2, No. 23, 2000
3681