Conjugate addition of organocuprates to chiral bicyclic delta-lactams. Enantioselective synthesis of cis-3,4-disubstituted and 3,4,5-trisubstituted piperidines.

Article abstract of DOI:10.1021/ol007010p

[reaction: see text] Chiral nonracemic bicyclic lactam 3, easily accessible by cyclodehydration of (R)-phenylglycinol and racemic methyl 4-formylhexanoate, was converted to the unsaturated lactams 5, which undergo the stereoselective conjugate addition of

Full text of DOI:10.1021/ol007010p

ORGANIC
LETTERS
2001
Vol. 3, No. 4
611-614
Conjugate Addition of Organocuprates
to Chiral Bicyclic δ-Lactams.
Enantioselective Synthesis of
cis-3,4-Disubstituted and
3,4,5-Trisubstituted Piperidines
,†
Mercedes Amat,* Maria Pe´rez,† Nu´ria Llor,† Joan Bosch,† Elena Lago,‡ and
Elies Molins‡
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona,
08028-Barcelona, Spain, and Institut de Cie`ncia de Materials (CSIC), Campus UAB,
08193-Cerdanyola, Spain
amat@farmacia.far.ub.es
Received December 18, 2000
ABSTRACT
Chiral nonracemic bicyclic lactam 3, easily accessible by cyclodehydration of (R)-phenylglycinol and racemic methyl 4-formylhexanoate, was
converted to the unsaturated lactams 5, which undergo the stereoselective conjugate addition of lower order cyanocuprates to ultimately lead
to enantiopure cis-3,4-disubstituted and 3,4,5-trisubstituted piperidines.
A large number of piperidine-containing compounds, either
natural or synthetic, are biologically and medicinally interest-
ing.1 As a consequence, the development of new methods
for the enantioselective synthesis of piperidine derivatives
by stereoselective introduction of substituents at the carbon
positions of the heterocycle constitutes an area of current
interest.2 In this context, chiral nonracemic bicyclic lactams
derived from phenylglycinol have proven to be versatile
building blocks for the synthesis of diversely substituted
enantiopure piperidines, giving access to 2-3 and 3-substi-
tuted4 and cis-2,4-,5 cis-2,6-,6 trans-2,6-,7 and trans-3,4-
disubstituted8 piperidines.9 In a further application of (R)-
(2) For reviews, see: (a) Wang, C.-L. J.; Wuonola, M. A. Org. Prep.
Proced. Int. 1992, 24, 585. (b) Angle, S. R.; Breitenbucher, J. G. In Studies
in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
1995; Vol. 16, pp 453-502. (c) Leclercq, S.; Daloze, D.; Braekman, J.-C.
Org. Prep. Proced. Int. 1996, 28, 501. (d) Nadin, A. Contemp. Org. Synth.
1997, 4, 387. (d) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem.
Commun. 1998, 633.
(3) (a) Amat, M.; Llor, N.; Bosch, J. Tetrahedron Lett. 1994, 35, 2223.
(b) Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7084. (c)
Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7086.
(4) Amat, M.; Pschenichnyi, G.; Bosch, J.; Molins, E.; Miravitlles, C.
Tetrahedron: Asymmetry 1996, 7, 3091.
(5) Dwyer, M. P.; Lamar, J. E.; Meyers, A. I. Tetrahedron Lett. 1999,
40, 8965.
(6) (a) Munchhof, M. J.; Meyers, A. I. J. Am. Chem. Soc. 1995, 117,
5399. (b) Amat, M.; Llor, N.; Hidalgo, J.; Herna´ndez, A.; Bosch, J.
Tetrahedron: Asymmetry 1996, 7, 977.
(7) Amat, M.; Hidalgo, J.; Llor, N.; Bosch, J. Tetrahedron: Asymmetry
1998, 9, 2419.
† University of Barcelona.
‡ Institut de Cie`ncia de Materials.
(1) (a) Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W. Ed.; Wiley: New York, 1985; Vol. 3, Chapter
1, pp 1-90. (b) Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1987;
Vol. 5, Chapter 1, pp 1-54. (c) Takahata, H.; Momose, T. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: San Diego, 1993; Vol. 44, Chapter
3, pp 189-256. (d) Schneider, M. J. In Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Pergamon: Oxford, 1996; Vol. 10,
Chapter 2, pp 155-299.
10.1021/ol007010p CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/19/2001

phenylglycinol-derived lactams, we present here a synthetic
route for the preparation of enantiopure cis-3,4-disubstituted
piperidines and open up a route to more complex enantiopure
3,4,5-trisubstituted piperidines.
derived R,â-unsaturated lactams depicted in Scheme 2 and
demonstrated that the configuration of the stereocenter at
the angular position (C-8a) determines if the attack of the
nucleophile takes place on the si or the re face of the
electrophilic carbon of the conjugated double bond. These
conjugate additions constitute the key step of an enantio-
divergent synthesis of both enantiomers of the antidepressant
drug paroxetine (a trans-3,4-disubstituted piperidine).8
The conjugate addition of carbon nucleophiles to γ-sub-
stituted R,â-unsaturated γ-lactams (2-pyrrolidones), either
simple10 or bicyclic,11 is a well-documented reaction that has
been reported to stereoselectively give trans-4,5-disubstituted
2-pyrrolidones. In contrast, the addition of stabilized anions12
and organocuprates13 to γ-substituted R,â-unsaturated δ-lac-
tams (2-piperidones) has been scarcely used as a method for
the stereoselective synthesis of piperidine derivatives. In the
few reported examples, all of them dealing with simple
unsaturated δ-lactams, the 1,4-addition also leads to the trans
isomers as a consequence of either the thermodynamic
control (from â-carbonyl enolates) or the kinetic axial attack
of the nucleophile (from copper derivatives) upon a confor-
mation in which the γ-substituent is pseudoaxial in order to
avoid A(1,2) strain with the olefinic hydrogen atom (Scheme
1).14
Scheme 2
Scheme 1. Conjugate Additions to Simple γ-Substituted
R,â-Unsaturated δ-Lactams
In this paper we want to disclose the effect that a
substituent at the γ position of the unsaturated bicyclic lactam
2 has on the stereoselectivity of the conjugate addition of
organocuprates and report a method for the enantioselective
synthesis of cis-3,4-disubstituted and 3,4,5-trisubstituted
piperidines. The required unsaturated lactams 5 were pre-
pared, via the selenides 4, from the enantiopure bicyclic
lactam 3, which was easily accessible by cyclodehydration
of (R)-phenylglycinol and racemic methyl 4-formylhex-
anoate.15 The alkoxycarbonyl group not only enhances the
reactivity of the conjugated system, thus allowing the
subsequent conjugate addition of an organocuprate, but also
can later be manipulated to ultimately lead to 3,4,5-
trisubstituted piperidines. Thus, sequential treatment of 3 with
2.2 equiv of LHMDS, the appropriate chloroformate, and
PhSeCl, followed by ozonolysis of the resulting selenides
under neutral conditions, led to the unsaturated lactams 5a
and 5b (Scheme 3). Addition of lithium methyl- or phenyl-
cyanocuprate to these lactams at low temperature stereo-
selectively afforded compounds 6a,b and 7a,b as mixtures
of epimers at the isomerizable stereocenter adjacent to the
ester and lactam carbonyl goups (approximate ratio of CO2R
R:â isomers, 7:3 for 6 and 4:1 for 7).16 The high facial
stereoselectivity of the conjugate addition was confirmed
after removal of the benzyloxycarbonyl substituent. Thus,
hydrogenolysis of the benzyl esters 6a and 7a by treatment
with hydrogen in the presence of Pd-C, followed by
Recently, we have studied the conjugate addition of lower
order cyanocuprates to the diastereomeric (R)-phenylglycinol-
(8) Amat, M.; Bosch, J.; Hidalgo, J.; Canto´, M.; Pe´rez, M.; Llor, N.;
Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65,
3074.
(9) For a review, see: Meyers, A. I.; Brengel, G. P. Chem. Commun.
1997, 1.
(10) (a) Nagashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K. Tetrahedron
Lett. 1985, 26, 657. (b) Hagen, T. Synlett 1990, 63. (c)Langlois, N.;
Andriamialisoa, R. Z. Tetrahedron Lett. 1991, 32, 3057. (d) Woo, K.-C.;
Jones, K. Tetrahedron Lett. 1991, 32, 6949. (e) Herdeis, C.; Hubmann, H.
P. Tetrahedron: Asymmetry 1992, 3, 1213. (f) Koot, W.-J.; Hiemstra, H.;
Speckamp, W. N. Tetrahedron Lett. 1992, 33, 7969. (g) Hashimoto, M.;
Hashimoto, K.; Shirahama, H. Tetrahedron 1996, 52, 1931. (h) Diaz, A.;
Siro, J. G.; Garc´ıa-Nav´ıo, J. L.; Vaquero, J. J.; Alvarez-Builla, J. Synthesis
1997, 559. (i) Baussanne, I.; Royer, J. Tetrahedron Lett. 1998, 39, 845. (j)
Luker, T.; Koot, W.-J.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1998,
63, 220. (k) Cossy, J.; Cases, M.; Gomez-Pardo, D. Synlett 1998, 507.
(11) (a) Hanessian, S.; Ratovelomanana, V. Synlett 1990, 501. (b)
Baldwin, J. E.; Moloney, M. G.; Shim, S. B. Tetrahedron Lett. 1991, 32,
1379. (c) Meyers, A. I.; Snyder, L. J. Org. Chem. 1992, 57, 3814. (d)
Meyers, A. I.; Snyder, L. J. Org. Chem. 1993, 58, 36. (e) Goswami, R.;
Moloney, M. G. Chem. Commun. 1999, 2333.
(14) The same trans relative stereochemistry is obtained in the conjugate
addition to γ-substituted R,â-unsaturated δ-lactones: Yoda, H.; Naito, S.;
Takabe, K.; Tanaka, N.; Hosoya, K. Tetrahedron Lett. 1990, 31, 7623. See
also refs 10g and 13b.
(15) Amat, M.; Llor, N.; Hidalgo, J.; Bosch, J. Tetrahedron: Asymmetry
1997, 8, 2237.
(12) (a) Takano, S.; Sato, M.; Ogasawara, K. Heterocycles 1981, 16,
799. (b) Fujii, T.; Ohba, M.; Akiyama, S. Chem. Pharm. Bull. 1985, 33,
5316. (c) Fujii, T.; Ohba, M.; Sakaguchi, J. Chem. Pharm. Bull. 1987, 35,
3628.
(13) (a) Herdeis, C.; Kaschinski, C.; Karla, R.; Lotter, H. Tetrahedron:
Asymmetry 1996, 7, 867. See also: (b) Fleming, I.; Reddy, N. L.; Takaki,
K.; Ware, A. C. J. Chem. Soc., Chem. Commun. 1987, 1472.
(16) All yields are from material purified by column chromatography.
Satisfactory spectral (IR, 1H and 13C NMR), analytical, and/or HRMS data
were obtained for all new compounds.
612
Org. Lett., Vol. 3, No. 4, 2001

Oxazolopiperidone 9 was converted into cis-5-ethyl-4-
phenyl-2-piperidone (11) by reductive cleavage of the C-O
bond of the oxazolidine ring with triethylsilane and TiCl4,
followed by treatment of the resulting piperidone 10 with
sodium in liquid ammonia (Scheme 4). Alternatively, alane
Scheme 3. Conjugate Addition to Bicyclic γ-Substituted
R,â-Unsaturated δ-Lactams Derived from (R)-Phenylglycinola
Scheme 4. Synthesis of Enantiopure cis-3,4-Disubstituted
Piperidinesa
a Reagents and conditions: (a) LHMDS, ClCO2R, PhSeCl, THF,
-78 °C, 86% (4a), 89% (4b); (b) O3, CH2Cl2, -78 °C; (c)
R′Cu(CN)Li, THF, -78 °C. Yields from 4a: 38% (6a), 80% (7a).
Yields from 4b: 40% (6b), 75% (7b). (d) H2, Pd-C, 25 °C, then
toluene, reflux, 72% (8), 82% (9).
a Reagents and conditions: (a) Et3SiH, TiCl4, CH2Cl2, reflux,
51%; (b) Na, liq NH3, THF, -33 °C, 94%; (c) AlCl3, LiAlH4, THF,
25 °C, 89%; (d) H2, (Boc)2O, Pd(OH)2, AcOEt, 25 °C, 73%; (e)
TFA, CH2Cl2, 25 °C, 86%.
decarboxylation of the resulting â-keto acids by heating in
refluxing toluene, afforded lactams 8 and 9, respectively, as
single isomers.
reduction of 9 afforded the cis-3,4-disubstituted piperidine
12, which was subjected to hydrogenolysis in the presence
of di-tert-butyl dicarbonate to give the N-Boc-protected
piperidine 13. Finally, treatment of 13 with TFA gave cis-
3-ethyl-4-phenylpiperidine (14). Thus, the above route ef-
ficiently provides an enantioselective entry to cis-3,4-
disubstituted piperidines, which are not easily accessible by
alternative methods.17 It is worth commenting that cis-3-
alkyl-4-phenylpiperidines possess dopaminergic activity and
are currently being investigated for the treatment of cocaine
abuse.18
The stereoselectivity in the attack of organocuprates to
both the unsaturated lactams 5a,b and the deethyl lactams 1
and 2 can be rationalized by considering that these lactams
are conformationally rigid as a result of the presence of an
amide bond in a bicyclic system, the conformation of the
six-membered ring being determined by the configuration
of C-8a. As a consequence, they adopt the pseudochair
conformations depicted in Figure 1, which implies the
Alane reduction of the mixture of epimers 7b brought
about the cleavage of the C-O bond of the oxazolidine ring
and the simultaneous reduction of the lactam and ester
carbonyl groups to give a 4:1 epimeric mixture of trans-
trans and cis-cis 3-piperidinemetanols, 15a19 and 15b,
respectively, which were transformed into the N-Boc-
protected trisubstituted piperidines 16a and 16b by catalytic
hydrogenation in the presence of di-tert-butyl dicarbonate
(Scheme 5). Removal of the N-Boc protecting group of 16a
by treatment with TFA gave piperidine 17a.
Figure 1. Stereoelectronic control in the conjugate addition to
bicyclic R,â-unsaturated δ-lactams derived from (R)-phenylglycinol.
In summary, in contrast with the usual stereochemical
outcome of conjugate additions to cyclic γ-substituted
pseudoequatorial disposition of the ethyl substituent in 5a,b.
This was confirmed by 1H NMR analysis since H-8a appears
as a doublet with J ) 10.8 Hz. A stereoelectronically
preferred axial attack of the organocuprate at the electrophilic
carbon, which occurs cis with respect to the ethyl substituent
in 5a,b, accounts for the resulting stereochemistry.
(19) The configuration of 15a was unambiguously confirmed by X-ray
crystallography. The experiment was done on an Enraf-Nonius CAD4
diffractometer using graphite monochromated Mo KR radiation. The
structure was solved by direct methods (SHELXS-86) after applying Lorentz,
polarization, and absorption (empirical PSI scan method; maximum and
minimum transmission factors were 0.9737 and 0.9298, respectively)
corrections. Full-matrix least squares refinement (SHELXL-93) using
anisotropic thermal parameters for non-H atoms and riding thermal
parameters for H-atoms (positioned at calculated positions) converged to a
R factor of 0.047 (calculated for the reflections with I > 2σ(I)). Crystal
data: C22H29NO2, monoclinic, space group C2, a ) 16.570(4) Å, b )
10.150(4) Å, c ) 11.597(2) Å, V ) 1937.4(8) Å3, µ (MoKR) ) 0.073
mm-1, Dc ) 1.164 g/cm3. Approximate dimensions: 0.7 × 0.5 × 0.18
mm3. Data collection was up to a resolution of 2θ ) 56.8° producing 2659
reflections. Maximum and minimum heights at the final difference Fourier
(17) For examples in the racemic series, see: (a) McErlane, K. M. J.;
Casy, A. F. Can. J. Chem. 1972, 50, 2149. (b) Pridgen, L. N. J. Org. Chem.
1974, 39, 3059. (c) Gless, R. D.; Rapoport, H. J. Org. Chem. 1979, 44,
1324.
(18) Kozikowski, A. P.; Araldi, G. L.; Boja, J.; Meil, W. M.; Johnson,
K. M.; Flippen-Anderson, J. L.; George, C.; Saiah, E. J. Med. Chem. 1998,
41, 1962.
synthesis were 0.133 and -0.147 e Å-3
.
Org. Lett., Vol. 3, No. 4, 2001
613

provides easy access to enantiopure 3,4,5-trisubstituted
piperidines bearing a functionalized one-carbon substituent
at the â-position of the ring.
Scheme 5. Synthesis of Enantiopure 3,4,5-Trisubstituted
Piperidinesa
Acknowledgment. Financial support from the DGICYT,
Spain (projects PB94-0214 and BQU2000-0651) and the
“Comissionat per a Universitats i Recerca”, Generalitat de
Catalunya (grant 1999-SGR-00079) is gratefully acknowl-
edged. Thanks are also due to the Ministry of Education,
Culture and Sport for a fellowship to M.P. We thank DSM
Deretil (Almer´ıa, Spain) for the generous gift of (R)-
phenylglycine.
a Reagents and conditions: (a) AlCl3, LiAlH4, THF, 25 °C, 64%
(15a) and 16% (15b); (b) H2, (Boc)2O, Pd(OH)2, AcOEt, 25 °C,
75% (16a), 62% (16b); (c) TFA, CH2Cl2, 25 °C, 55%.
Supporting Information Available: General procedure
for the preparation of unsaturated lactams 5 from 3 and for
the conjugate additions leading to 6 and 7; copies of 1H and
13C NMR spectra of compounds 3-17; complete X-ray
crystallographic data for 15a. This material is available free
of charge via the Internet at http://pubs.acs.org.
unsaturated carbonyl compounds (in particular lactams), the
conjugate addition to chiral bicyclic γ-substituted R,â-
unsaturated lactams 5 stereoselectively leads to the cis
isomers, thus providing an enantioselective route to cis-3,4-
disubstituted piperidines. By appropriate manipulation of the
activating alcoxycarbonyl group, the above route also
OL007010P
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Org. Lett., Vol. 3, No. 4, 2001