A direct stereoselective approach to trans-2,3-disubstituted piperidines: Application in the synthesis of 2-Epi-CP-99,994 and (+)-epilupinine

Article abstract of DOI:10.1021/ol800722a

(Chemical Equation Presented) A simple synthesis of enantiomerically pure piperidine esters is described, offering a straightforward access to the trans-2,3-disubstituted piperidine skeleton which is present in a broad range of biologically active compounds.

Full text of DOI:10.1021/ol800722a

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2473-2476
A Direct Stereoselective Approach to
trans-2,3-Disubstituted Piperidines:
Application in the Synthesis of
2-Epi-CP-99,994 and (+)-Epilupinine
M’hamed Ahari, Amandine Perez, Christine Menant, Jean-Luc Vasse, and
Jan Szymoniak*
Institut de Chimie Mole´culaire de Reims, CNRS (UMR 6229), UniVersite´ de Reims,
51687 Reims Cedex 2, France
jan.szymoniak@uniV-reims.fr
Received March 31, 2008
ABSTRACT
A simple synthesis of enantiomerically pure piperidine esters is described, offering a straightforward access to the trans-2,3-disubstituted
piperidine skeleton which is present in a broad range of biologically active compounds.
The piperidine skeleton is common to a number of natural
products and medicinal drugs and constitutes an important class
of building blocks for the synthesis of a broad range of
alcaloids.1 Although many asymmetric syntheses of piperidine
derivatives have been reported,2 the development of new
synthetic strategies opening the way to optically pure piperidines
is still important. In this paper we present a hydrozirconation
strategy that allows an easy access to optically pure piperidines
having a trans-2,3-disubstituted skeleton.3 It was inspired by
our diastereoselective syntheses of both enantiomeric 2-substi-
tuted pyrrolidines from N-allyloxazolidines and homoallylic
amines (Scheme 1).4,5 These reactions involve (i) hydro-
zirconation-Lewis acid mediated cyclization and (ii) hydro-
zirconation-iodination and subsequent intramolecular N-
Scheme 1
.
Access to Enantiomerically Pure 2-Substituted
Pyrrolidines
(1) (a) Daly, J. W.; Garraffo, H. M.; Spande T. F. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon Press: New
York, 1999; Vol. 13, pp 1-161. (b) Watson, P. S.; Jiang, B.; Scott, B.
Org. Lett. 2000, 2, 3679–3681. (c) Pu, X.; Ma, D. J. Org. Chem. 2003, 68,
4400–4405. (d) Vazzana, I.; Budriesi, R.; Terranova, E.; Ioan, P.; Ugenti,
M. P.; Tasso, B.; Chiarini, A.; Sparatore, F. J. Med. Chem. 2007, 50, 334–
343.
10.1021/ol800722a CCC: $40.75
Published on Web 05/14/2008
2008 American Chemical Society

alkylation. In the second pathway, CdC double bond
hydrozirconation is performed in the presence of a secondary
amine.
The synthetic strategy presented herein takes advantage
of both the remarkable chemoselectivity of hydrozirconation6
and the sequential generation of an electrophilic site (via
halogenation), followed by that of a nucleophilic site to
promote the cyclization step (Scheme 2).
amide C to the R,ꢀ-unsaturated tert-butyl ester D.8 According
to this strategy, the allylic fragment is not used as a protecting
group (as it is in the Davies approach), but as an electrophilic
site precursor, and thus is included in the core structure of
the target molecule.
N-Allyl ꢀ-amino ester 2a was first prepared in a totally
diastereoselective manner.8 The hydrozirconation reaction
was next performed in CH2Cl2, by using 1 equiv of the
Schwartz reagent, followed by the addition of iodine (1
equiv). The expected iodo ester 2′a was obtained quantita-
tively. Subsequent treatment with LiHMDS in THF at -78
°C afforded 3a in 77% yield as a unique stereoisomer (g95%
de). Generation of the second stereocenter in a totally
diastereoselective manner, during ring closure, demonstrates
the synthetic utility of this method. Subsequent catalytic
hydrogenolysis afforded the piperidine ester 4a in good yield
(Scheme 4). A one-pot procedure was also tested by simply
Scheme 2. Synthetic Strategy
Scheme 4. Synthesis of Piperidine Ester 4a
The flexibility of such an approach is illustrated here by
a three step synthesis of piperidine esters A which can be
obtained from B by applying the hydrozirconation/halogena-
tion/base-mediated cyclization sequence (Scheme 3).7 The
Scheme 3. Disconnective Approach to Piperidine Esters (A)
carrying out the hydrozirconation/iodination in THF, fol-
lowed by the addition of the base at -78 °C. Comparable
yields are obtained without altering the diastereoselectivity.
This methodology was further extended to diversely
substituted piperidine esters. First, ꢀ-amino esters 2b-h were
prepared. These reactions proceeded with total diastereose-
lectivity, except for 2h (84% de) where the major diastere-
omer was easily purified by flash chromatography. The
hydrozirconation/iodination sequence followed by LiHMDS-
mediated ring closure was next applied to 2, leading to the
trans-piperidine esters 3 (Table 1).9
configuration of the R carbon in compound B is controlled
through diastereoselective Davies 1,4-addition of the chiral
(2) (a) Cossy, J.; Vogel, P. In Studies in Natural Products Chemistry,
Part H; Atta-ur-Raman, Ed.; Elsevier: Amsterdam, 1993; Vol. 12, pp
275-363. (b) Angle, S. R.; Breittenbucher, J. G. In Studies in Natural
Products Chemistry, Part J; Atta-ur-Raman, Ed;. Elsevier: Amsterdam,
1995; Vol. 16, pp 453-502. (c) Laschat, S.; Dickner, T. Synthesis 2000,
178, 1–1813. (d) Guilloteau-Bertin, B.; Compe`re, D.; Gil, L.; Marazano,
C.; Das, B. C. Eur. J. Org. Chem. 2000, 139, 1–1399. (e) Weintraub, P. M.;
Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953–
2989. (f) Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729. (g) Agami,
C.; Dechoux, L.; Hebbe, S. J. Org. Chem. 2002, 67, 7573–7576. (h) Davis,
F. A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855–3857. (i) Davis,
F. A.; Zhang, J.; Li, Y.; Xu, H.; DeBrosse, C. J. Org. Chem. 2005, 70,
5413–5419. (j) Amat, M.; Escolano, C.; Lozano, O.; Gomez-Esque´, A.;
Griera, R.; Molins, E.; Bosch, J. J. Org. Chem. 2006, 71, 3804–3815. (k)
Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Org. Lett. 2007, 9,
2473–2476. (l) Noe¨l, R.; Vanucci-Bacque´, C.; Fargeau-Bellassoued, M.-
C.; Lhommet, G. Eur. J. Org. Chem. 2007, 476–486.
Piperidine esters bearing phenyl or substituted phenyl
groups (entries 1 and 2), heteroaromatic groups (entries 3-5),
(4) Vasse, J.-L.; Joosten, A.; Denhez, C.; Szymoniak, J. Org. Lett. 2005,
7, 4887–4889.
(5) Ahari, M.; Joosten, A.; Vasse, J.-L.; Szymoniak, J. Synthesis 2008,
61–68.
(6) Reviews: (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853–12910.
(b) Lipshutz, B. H.; Pfeiffer, S. S.; Noson, K.; Tomioka, T. In Titanium
and Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; p 110. (c) Wipf, P.; Kendall, C. In Topics in Organometallic
Chemistry; Takahashi, T., Ed.; Springer-Verlag: New York, 2005; Vol. 8,
p 1.
(3) For recent syntheses of 2,3-disubstituted piperidines, see: (a)
Kanayama, T.; Yoshida, K.; Miyabe, H.; Kimachi, T.; Takemoto, Y. J.
Org. Chem. 2004, 68, 6197–6201. (b) Suga, S.; Nishida, T.; Nagaki, A.;
Yoshida, J.-I. J. Am. Chem. Soc. 2004, 126, 14338–14339. (c) Pedersen,
C. M.; Bols, M. Tetrahedon 2005, 61, 115–122. (d) Takahashi, M.;
Macalizio, G. C. J. Am. Chem. Soc. 2007, 129, 7514–7516.
(7) The hydrozirconation compatibility with tert-butyl esters is known;
see ref 6a.
(8) High level of asymmetric induction was reported with tert-butyl
esters, see: (a) Davies, S. G.; Fenwick, D. R. J. Chem Soc., Perkin Trans.
1 1995, 110, 9–1110. (b) Davies, S. G.; Smyth, G. D.; Chippindale, A. M.
J. Chem. Soc., Perkin Trans. 1 1999, 3089–3104.
2474
Org. Lett., Vol. 10, No. 12, 2008

Piperidine esters 3 are versatile building blocks, offering
an easy access to the 2,3-disubstituted piperidine skeleton,
which is present in numerous biologically active com-
pounds.1,2 Among them, 3-amino 2-substituted piperidines
are key structural features of natural products and pharma-
ceutical drugs.10 Whereas the synthesis of cis-3-amino
2-substituted piperidines has widely been established,11 only
a few examples of trans analogues have been reported.12
The described method offers a rapid access to such com-
pounds, as exemplified with a simple synthesis of the trans
(2R,3S) analogue (6) of CP-99,994, a highly potent substance
P antagonist.10a–d This was acomplished in a straightforward
manner from the piperidine ester 3a through a Curtius type
rearrangement, deprotection and reductive amination (Scheme
6). Furthermore, an easy access to trans-fused polycyclic
Table 1. Synthesis of Piperidine Esters 3
entry
R
2 (yield, %)a
3 (yield, %)a
1
2
Ph
2a(87)
2b(82)
2c(90)
2c(90)
2d(76)
2e(84)
2f (81)
2g(68)
2h(75)
3a(77)
3b(72)
3c(79)
3c(65)
3d(51)
3e(55)
3f (64)
3g(58)
3h(69)
4F-C6H4
2-thienyl
2-thienyl
3-pyridyl
Me
iPr
Bn
3
4b
5
6
7c
8
9
cinnamyl
a Isolated yields. b Obtained according to the one-pot procedure. c LDA
was used as base.
Scheme 6
.
Synthesis of 2-epi-CP-99,994 (6) and
Octahydrobenzoquinoline 8
as well as alkyl or alkenyl groups (entries 6-9) on the C2
atom, were obtained in good to moderate yields. Interestingly,
compound 3h was selectively obtained from the ꢀ-amino
ester 2h with two alkene chains having a different degree of
substitution (entry 9). In all cases, the unique stereochemistry
obtained was due to the highly diastereoselective 1,4-addition
and cyclization steps.
The high level of stereoselectivity observed during the
ring-closure step is postulated to result from a chairlike
transition state involving a nonchelated E-enolate (Scheme
5). The control in enolate conformation could be a result of
piperidines is possible and is exemplified by the synthesis
of the octahydrobenzoquinoline derivative 8.13 Compound
7 was first obtained in two steps starting from 3g via TFA-
mediated hydrolysis followed by Friedel-Crafts annulation.
Starting from 7, diastereoselective reduction of the oxo group
Scheme 5. Stereochemical Pathway Explaining the Formation of 3
(10) (a) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.;
Snider, M. J. Med. Chem. 1992, 35, 4911–4913. (b) Rosen, T.; Seeger,
T. F.; McLean, S.; Desai, M. C.; Guarino, K. J.; Bryce, D.; Pratt, K.; Heym,
J.; Chalabi, P. M.; Windels, J. H.; Roth, R. W. J. Med. Chem. 1993, 36,
3197–3201. (c) Lemire, A.; Grenon, M.; Pourashraf, M.; Charette, A. B.
Org. Lett. 2004, 4, 3517–3520. (d) Davis, F. A.; Zhang, Y.; Li, D.
Tetrahedron Lett. 2007, 48, 7838–7840. (e) Ward, P.; Armour, D. R.; Bays,
D. E.; Evans, B.; Giblin, G. M. P.; Heron, N.; Hubbard, T.; Liang, K.;
Middlemiss, D.; Mordaunt, J.; Naylor, A.; Pegg, N. A.; Vinader, V.; Watson,
S. P.; Bountra, C.; Evans, D. C. J. Med. Chem. 1995, 38, 4985–4992.
(11) (a) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F. Tetrahedron Lett.
1993, 34, 5831–5834. (b) Diez, A.; Voldoine, A.; Lopez, I.; Rubralta, M.;
Segarra, V.; Pages, L.; Palacios, J. M. Tetrahedron 1995, 51, 5143–5156.
(c) Laschat, S.; Fox, T. Synthesis 1997, 475–479. (d) Oshitari, T.; Mandai,
T. Synlett 2006, 3395–3398. (e) Kokotos, C. G.; Aggarwal, V. K. Chem
Commun. 2006, 2156–2158.
(i) the R group’s almost perpendicular orientation with
respect to the enolate plan and (ii) an efficient discrimination
in favor of the less sterically hindered rotameric form of the
enolate.
(12) (a) Liu, L.-X.; Huang, P.-Q. Tetrahedron: Asymmetry 2006, 17,
3265–3272. (b) Kokotos, C.; Aggarwal, V. K. Org. Lett. 2007, 9, 2099–
2102.
(9) The trans configuration in 3 was deduced from the J2-3 coupling
constants and NOE study of the compond 3h.
(13) Trans- and cis-fused octahydrobenzoquinolines are known to exhibit
various biological properties; see: (a) Cannon, J. G.; Amoo, V. E. D.; Long,
J. P.; Bhatnagar, R. K.; Flynn, J. R. J. Med. Chem. 1986, 29, 2529–2534.
(b) Smissman, E. E.; El-Antabbly, S.; Hedrich, L. W.; Walaszek, E. J.;
Tseng, L.-F. J. Med. Chem. 1973, 16, 109–113. (c) Thermos, K.; Froudakis,
G. E.; Tagmatarchis, N.; Katerinopoulos, H. E. Bioorg. Med. Chem. Lett.
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Org. Lett., Vol. 10, No. 12, 2008
2475

afforded 8 in which three contiguous stereogenic centers are
controlled.
function afforded (+)-epilupinine ([R]D +30.7 (c 1.4, EtOH),
optical purity 95% based on literature data: [R]D +32 (c 1.49,
EtOH).17
In summary, we have described an efficient diastereose-
lective approach to enantiomerically pure piperidine esters
based on a simple three step hydrozirconation/iodination and
base-mediated ring-closure sequence. This methodology
opens a wide access to the trans-2,3-disubstituted piperidine
skeleton and has potential for the synthesis of biologically
active piperidine derivatives.
The described methodology can also be applied to the
preparation of quinolizidine alkaloids as illustrated by the
asymmetric synthesis of naturally occurring (+)-epilupinine
(Scheme 7).14 The reaction of R,ꢀ-unsaturated ester 915 with
Scheme 7. Asymmetric Synthesis of (+)-Epilupinine
Acknowledgment. We thank the CNRS and the Ministe`re
de l’Education Nationale et de la Recherche for their financial
support.
Supporting Information Available: Experimetal proce-
dures and characterization of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL800722A
(14) For the synthesis of optically active epilupinine, see: (a) Nagao,
Y.; Wei, M.; Mashahito, T.; Tsukagoshi, S.; Fujita, E. J. Am. Chem. Soc.
1988, 110, 289–290. (b) Hua, D. H.; Miao, S. W.; Bravo, A. A. Synthesis
1991, 970–974. (c) West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1994,
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ArkinoV 2002, 62–77. (h) Agami, C.; Dechoux, L.; Hebbe, S.; Menard, C.
Tetrahedron 2004, 60, 5433–5438. (i) Ma, S.; Ni, B. Chem. Eur. J. 2004,
10, 3286–3300.
the amide derived from 1 provided the ꢀ-amino ester 10 in
good yield with total diastereoselectivity. Compound 10 was
next submitted to the hydrozirconation/iodination/LiHMDS-
mediated ring-closure sequence to afford the expected
piperidine 11. Subsequent hydrogenolysis and alcohol con-
version to chloride,16 followed by Et3N treatment, gave the
bicyclic compound 12. Finally, LiAlH4 reduction of the ester
(15) Chang, M.-Y.; Chen, C.-Y.; Chen, S.-T.; Chang, N.-C. Tetrahedron
2003, 59, 7547–7553.
(16) Agami, C.; Couty, F.; Evano, G.; Darro, F.; Kiss, R. Eur. J. Org.
Chem. 2003, 2062–2070.
(17) Nagao, Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi, S.; Fujita, E. J. Am.
Chem. Soc. 1988, 110, 289–291.
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