Dynamic kinetic resolution of racemic γ-aryl-δ-oxoesters. Enantioselective synthesis of 3-arylpiperidines

Article abstract of DOI:10.1021/jo025894f

Cyclodehydration of racemic γ-aryl-δ-oxoesters with (R)- or (S)-phenylglycinol stereoselectively affords bicyclic δ-lactams, in a process that involves a dynamic kinetic resolution. Subsequent reduction of these lactams leads to enantiopure 3-arylpiperidines. Starting from racemic aldehyde esters, this short sequence has been applied to the synthesis of (R)-3-phenylpiperidine and the antipsychotic drug (-)-3-PPP (an (S)-3-arylpiperidine), whereas starting from racemic ketone esters enantiopure cis-2-alkyl-3-arylpiperidines are prepared.

Full text of DOI:10.1021/jo025894f

Dyn a m ic Kin etic Resolu tion of Ra cem ic γ-Ar yl-δ-oxoester s.
En a n tioselective Syn th esis of 3-Ar ylp ip er id in es
Mercedes Amat,*,† Margalida Canto´,† Nu´ria Llor,† Carmen Escolano,† Elies Molins,‡
Enrique Espinosa,‡ and J oan Bosch*,†
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 (Barcelona), Spain
amat@farmacia.far.ub.es
Received May 2, 2002
Cyclodehydration of racemic γ-aryl-δ-oxoesters with (R)- or (S)-phenylglycinol stereoselectively
affords bicyclic δ-lactams, in a process that involves a dynamic kinetic resolution. Subsequent
reduction of these lactams leads to enantiopure 3-arylpiperidines. Starting from racemic aldehyde
esters, this short sequence has been applied to the synthesis of (R)-3-phenylpiperidine and the
antipsychotic drug (-)-3-PPP (an (S)-3-arylpiperidine), whereas starting from racemic ketone esters
enantiopure cis-2-alkyl-3-arylpiperidines are prepared.
The preparation of a single enantiomer from a race-
mate may be achieved via a conventional resolution or
by exploiting the differences in reactivity (kinetic resolu-
tion). Although enzyme-catalyzed kinetic resolution of
racemates has become a classical approach for the
synthesis of enantiopure compounds,1 it suffers, like
conventional resolution processes, from the drawback
that the maximum yield of one enantiomer is always
limited to 50%. This situation dramatically changes when
the racemic substrate or the two diastereomers resulting
from the initial reaction with a chiral reagent have a
chirally labile stereogenic center capable of undergoing
in situ racemization2 or epimerization during the reaction
to form a chirally stable enantiopure product in up to
100% chemical yield (dynamic kinetic resolution).3 Al-
though these processes represent a viable and useful tool
for preparing enantiopure chiral compounds, they have
been scarcely used in synthetic sequences due to the
particular requirements imposed by the substrate. When
the reaction involves the generation of an additional
stereogenic center, under appropriate conditions this
methodology can convert a racemic compound into one
of four possible enantiopure stereoisomers.
been thoroughly investigated in view of their interesting
dopaminergic activity,5,6 has received very little atten-
tion.7 In fact, the enantiomers of 3-phenylpiperidine8 and
most enantiopure 3-arylpiperidines reported so far have
been obtained by routes involving the conventional
resolution of a racemate.9
In the context of the enantioselective synthesis of
piperidine derivatives, chiral nonracemic bicyclic δ-lac-
tams formed by cyclodehydration of simple δ-oxoesters
and (R)- or (S)-phenylglycinol have proven to be versatile
(4) For reviews, see: (a) Meyers, A. I.; Brengel, G. P. Chem.
Commun. 1997, 1-8. (b) Meyers, A. I.; Andres, C. J .; Resek, J . E.;
Woodall, C. C.; McLaughlin, M. A.; Lee, P. H.; Price, D. A. Tetrahedron
1999, 55, 8931-8952. (c) Groaning, M. D.; Meyers, A. I. Tetrahedron
2000, 56, 9843-9873. (d) Bailey, P. D.; Millwood, P. A.; Smith, P. D.
Chem. Commun. 1998, 633-640. (e) Laschat, S.; Dickner, T. Synthesis
2000, 1781-1813 (f) Angle, S. R.; Breitenbucher, J . G. In Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amster-
dam, The Netherlands, 1995; Vol. 16, pp 453-502. (g) Wang, C.-L.;
Wuonola, M. A. Org. Prep. Proced. Int. 1992, 24, 585-621. (h) Leclerq,
S.; Daloze, D.; Braekman, J .-C. Org. Prep. Proced. Int. 1996, 28, 501-
543. (i) Nadin, A. Contemp. Org. Synth. 1997, 4, 387-414. (j) Husson,
H.-P.; Royer, J . Chem. Soc. Rev. 1999, 28, 383-394.
(5) See for instance: (a) Liljefors, T.; Bøgesø, K. P.; Hyttel, J .;
Wikstro¨m, H.; Svensson, K.; Carlsson, A. J . Med. Chem. 1990, 33,
1015-1022. (b) Sonesson, C.; Lin, C.-H.; Hansson, L.; Waters, N.;
Svensson, K.; Carlsson, A.; Smith, M. W.; Wikstro¨m, H. J . Med. Chem.
1994, 37, 2735-2753. (c) Hansson, L. O.; Waters, N.; Holm, S.;
Sonesson, C. J . Med. Chem. 1995, 38, 3121-3131. (d) Cervetto, L.;
Demontis, G. C.; Giannaccini, G.; Longoni, B.; Macchia, B.; Macchia,
M.; Martinelli, A.; Orlandini, E. J . Med. Chem. 1998, 41, 4933-4938.
(6) The 3-arylpiperidine moiety is also present in jussiaeiine A, an
alkaloid recently isolated from Ulex jussiaei: Ma´ximo, P.; Lourenc¸o,
A. J . Nat. Prod. 2000, 63, 201-204.
(7) (a) Thorberg, S.-O.; Gawell, L.; Cso¨regh, I.; Nilsson, J . L. G.
Tetrahedron 1985, 41, 129-139. (b) Wong, Y.-S.; Marazano, C.; Gnecco,
D.; Ge´nisson, Y.; Chiaroni, A.; Das, B. C. J . Org. Chem. 1997, 62, 729-
733. (c) For the enantioselective synthesis of trans-3,4-diaryl-
piperidines, see: J ohnson, T. A.; Curtis, M. D.; Beak, P. J . Am. Chem.
Soc. 2001, 123, 1004-1005. (d) For a recent synthesis of N-Fmoc
protected (2S,3R)-3-phenylpipecolic acid, see: Liu, D.-G.; Gao, Y.;
Wang, X.; Kelley, J . A.; Burke, T. R., J r. J . Org. Chem. 2002, 67, 1448-
1452.
(8) (a) Morlacchi, F.; D’Ambruoso, M.; Tortorella, V. Chim. Ind.
(Milan) 1974, 56, 465-466. (b) Dukic, S.; Kostic-Rajacic, S.; Sˇosˇkic,
V.; J oksimovic, J . Arch. Pharm. Pharm. Med. Chem. 1997, 330, 25-
28.
Despite the impressive advances in the enantio-
selective synthesis of piperidine derivatives over the last
10 years,4 the preparation of enantiopure 3-aryl-
piperidines, an important group of compounds that has
† Laboratory of Organic Chemistry.
‡ Institut de Cie`ncia dels Materials.
(1) For a review, see: Kagan, H. B.; Fiaud, J . C. Top. Stereochem.
1988, 18, 249-330.
(2) For a review on the controlled racemization of optically active
compounds, see: Ebbers, E. J .; Ariaans, G. J . A.; Houbiers, J . P. M.;
Bruggink, A.; Zwanenburg, B. Tetrahedron 1997, 53, 9417-9476.
(3) For reviews, see: (a) Noyori, R.; Tokunaga, M.; Kitamura, M.
Bull. Chem. Soc. J pn. 1995, 68, 36-56. (b) Ward, R. S. Tetrahedron:
Asymmetry 1995, 6, 1475-1490. (c) Caddick, S.; J enkins, K. Chem.
Soc. Rev. 1996, 25, 447-456. (d) Stecher, H.; Faber, K. Synthesis 1997,
1-16. (e) Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron: Asymmetry
1999, 10, 107-117. (f) Huerta, F. F.; Minidis, A. B. E.; Ba¨ckvall, J .-E.
Chem. Soc. Rev. 2001, 30, 321-331.
10.1021/jo025894f CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/26/2002
J . Org. Chem. 2002, 67, 5343-5351
5343

Amat et al.
SCHEME 1. Syn th esis of En a n tiop u r e
3-P h en ylp ip er id in es
synthons that provide easy access to a variety of enan-
tiopure mono- and disubstituted piperidines by successive
introduction of the substituents taking advantage of the
functionalization and conformational rigidity of the bi-
cyclic lactam system.10 In particular, alkylation of the
enolate derived from the lactam carbonyl takes place with
high stereoselectivity to ultimately give enantiopure
3-alkylpiperidines.10d,11 However, this alkylation method
cannot be extended to the synthesis of 3-arylpiperidines.
In this paper we present an efficient and straight-
forward procedure for the enantioselective synthesis of
3-arylpiperidines, involving as the key step a dynamic
kinetic resolution during cyclodehydration of racemic
γ-aryl-δ-oxoesters with (R)- or (S)-phenylglycinol. To
illustrate the versatility and potential of this methodology
we applied it to the synthesis of the antipsychotic drug
(-)-3-PPP (preclamol),9b,12 as well as several 2-alkyl
substituted analogues (cis-2-alkyl-3-arylpiperidines).
SCHEME 2. Dyn a m ic Kin etic Resolu tion
Resu lts a n d Discu ssion
The required racemic aldehyde ester 1 was prepared
by reaction of the piperidine enamine of phenylacet-
aldehyde with methyl acrylate. Cyclodehydration of 1
with (R)-phenylglycinol was carried out by heating at
reflux in toluene solution to give a major trans 3-C6H5/
8-C6H5 lactam 2 (49% yield), accompanied by minor
amounts (9% yield) of a second diastereomer 3 in which
the two phenyl groups are cis13 (Scheme 1). The trans
H-8/H-8a relationship in both isomers was evident from
1
the coupling constant (∼9 Hz) of these protons in the H
NMR spectra. The above result clearly indicated that a
dynamic kinetic resolution had occurred during the
cyclodehydration reaction. The diastereomeric imines A
and A′ initially formed after the interaction of (R)-
phenylglycinol with racemic oxoester 1 are in equilibrium
via enamine B (Scheme 2). Consequently, a mixture of
four equilibrating oxazolidines (a -d ) at the two chirally
labile stereogenic centers is formed. Subsequent lactam-
ization takes place via a transition state in which the
phenyl substituent of the incipient chairlike six-mem-
bered lactam is equatorial, thus leading to isomers 2
(major) and 3 (minor). The preferential formation of 2 is
a consequence of lactamization occurring faster from the
diastereomeric oxazolidine (c) that allows a less hindered
approach of the ester group to the nitrogen atom.
Lactam 2 was easily converted to (R)-3-phenylpiperi-
dine (5) by LiAlH4 reduction followed by debenzylation
by hydrogenolysis of the resulting N-substituted piperi-
dine 4. A similar reduction from the minor lactam 3 led
to piperidine 6, which was a diastereomer of 4 according
to the NMR data, thus confirming the S configuration
at the piperidine 3-position in the minor lactam 3. The
13C NMR data of piperidines 4 and 6 (as well as the
related 3-arylpiperidines 10 and 14, see below) are in
agreement with the above stereochemical assignment.
Thus, in the preferred conformation, which involves a
hydrogen bond between the nitrogen atom and the
hydroxy group, the phenyl substituent of the phenyl-
glycinol moiety lies near one of the piperidine R carbons,
thus shielding the corresponding signal in the 13C NMR
spectra (Figure 1).
(9) (a) Arnold, W.; Daly, J . J .; Imhof, R.; Kyburz, E. Tetrahedron
Lett. 1983, 24, 343-346. (b) Wikstro¨m, H.; Sanchez, D.; Lindberg, P.;
Hacksell, U.; Arvidsson, L.-E.; J ohansson, A. M.; Thorberg, S.-O.;
Nilsson, J . L. G.; Svensson, K.; Hjorth, S.; Clark, D.; Carlsson, A. J .
Med. Chem. 1984, 27, 7, 1030-1036. (c) Law, H.; Leclerc, G. A.;
Neumeyer, J . L. Tetrahedron: Asymmetry 1991, 2, 989-992. (d)
Grayson, N. A.; Bowen, W. D.; Rice, K. C. Heterocycles 1992, 34, 2281-
2292. (e) Rollema, H.; Mastebroek, D.; Wikstro¨m, H.; Svensson, K.;
Carlsson, A.; Sundell, S. J . Med. Chem. 1986, 29, 1889-1895. (f)
Cannon, J . G.; Kirschbaum, K. S.; Amoo, V. E. D.; J ohnson, A. K.; Long,
J . P. J . Med. Chem. 1993, 36, 2416-2419. (g) Sonesson, C.; Lindborg,
J . Tetrahedron Lett. 1994, 35, 9063-9066. (h) See also ref 7a.
(10) (a) For reviews, see refs 4a-c. (b) Amat, M.; Llor, N.; Bosch, J .
Tetrahedron Lett. 1994, 35, 2223-2226. (c) 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, 3074-3084. (d) Amat,
M.; Llor, N.; Hidalgo, J .; Herna´ndez, A.; Bosch, J . Tetrahedron:
Asymmetry 1996, 7, 977-980. (e) Amat, M.; Hidalgo, J .; Llor, N.; Bosch,
J . Tetrahedron: Asymmetry 1998, 9, 2419-2422.
(11) (a) Micouin, L.; J ullian, V.; Quirion, J .-C.; Husson, H.-P. Tetra-
hedron: Asymmetry 1996, 7, 2839-2846. (b) Amat, M.; Pshenichnyi,
G.; Bosch, J .; Molins, E.; Miravitlles, C. Tetrahedron: Asymmetry 1996,
7, 3091-3094. (c) Micouin, L.; Bonin, M.; Cherrier, M.-P.; Mazurier,
A.; Tomas, A.; Quirion, J .-C.; Husson, H.-P. Tetrahedron 1996, 52,
7719-7726.
(12) (a) Hjorth, S.; Carlsson, A.; Wikstro¨m, H.; Lindberg, P.; Sanchez,
D.; Hacksell, U.; Arvidsson, L.-E.; Svensson, U.; Nilsson, J . L. G. Life
Sci. 1981, 28, 1225-1238. (b) Hacksell, U.; Arvidsson, L.-E.; Svensson,
U.; Nilsson, J . L. G.; Sanchez, D.; Wikstro¨m, H.; Lindberg, P.; Hjorth,
S.; Carlsson, A. J . Med. Chem. 1981, 24, 1475-1482. (c) Drugs Future
1987, 12, 88-89.
(13) For a preliminary account of this part of the work, see: Amat,
M.; Canto´, M.; Llor, N.; Ponzo, V.; Pe´rez, M.; Bosch, J . Angew. Chem.,
Int. Ed. 2002, 41, 335-338.
The above three-step sequence constitutes the first
enantioselective synthesis of (R)-3-phenylpiperidine. Tak-
ing into account that (S)-phenylglycinol is also com-
mercially available, this procedure provides access to
3-arylpiperidines in both enantiomeric series. This was
5344 J . Org. Chem., Vol. 67, No. 15, 2002

Enantioselective Synthesis of 3-Arylpiperidines
SCHEME 4
F IGURE 1. Diagnostic 13C NMR chemical shifts (δ) of
3-arylpiperidines 4, 6, 20, and 18.
1
H-8a coupling constant (∼9 Hz) in the H NMR spectra
of these lactams again was indicative of the trans
relationship of these protons. Moreover, the configuration
at the piperidine 3-position in 8a was confirmed by X-ray
crystallographic analysis of piperidine 10,15 which was
obtained in 67% yield by reduction of 8a with alane.
Piperidine 10 was converted to the target drug (-)-3-PPP
(preclamol) by catalytic hydrogenation in the presence
of propionaldehyde followed by demethylation of the
resulting N-alkylated piperidine 11. Alternatively, hy-
drogenolysis of 10 in the presence of di-tert-butyl dicar-
bonate, followed by removal of the N-Boc protecting group
of 12, gave the N-unsubstituted piperidine 13, which had
previously been converted9b to (-)-3-PPP.16 In a similar
manner, for the sake of comparison,16c the minor lactam
9a was converted to ent-11 via the RS,3R-piperidine 14
(Scheme 4).
SCHEME 3. En a n tioselective Syn th esis of
(-)-3-P P P
We then planned to extend the above methodology to
the synthesis of preclamol analogues bearing an alkyl
(15) The X-ray experiments were done on an Enraf-Nonius CAD4
diffractometer with graphite monochromated Mo KR radiation. The
structure was solved by direct methods (SHELXS-97) after applying
Lorentz, polarization, and absorption (semiempirical PSI scan method)
corrections. Full-matrix least-squares refinement (SHELXL-97) with
anisotropic thermal parameters for non-H atoms and riding thermal
parameters for H-atoms (positioned at calculated positions) converged
to R factors of 0.051 (for 10) and 0.049 (for 16b) (calculated for the
reflections with I > 2σ(I)). 10: crystal data, C20H26ClNO2, monoclinic,
space group P21, a ) 6.610(4) Å, b ) 24.892(8) Å, c ) 11.648(3) Å, V )
1885(1) Å3, Z ) 4, µ(Mo KR) ) 0.214 mm-1, Dc ) 1.226 g/cm3.
Approximate dimensions: 0.10 × 0.18 × 0.35 mm3. Data collection was
up to a resolution of 2θ ) 52.4° producing 4088 reflections. The
asymmetric unit contains two independent molecules. Largest peak
and hole at the final difference Fourier synthesis were 0.233 and
-0.375 e Å-3. 16b: crystal data, C21H23NO3, monoclinic, space group
C2, a ) 19.789(3) Å, b ) 7.393(9) Å, c ) 37.051(11) Å, V ) 5397(7) Å3,
Z ) 12, µ(Mo KR) ) 0.083 mm-1, Dc ) 1.246 g/cm3. Approximate
dimensions: 0.5 × 0.3 × 0.06 mm3. Data collection was up to a
resolution of 2θ ) 60.8° producing 2160 reflections. The asymmetric
unit contains three independent molecules. Largest peak and hole at
exemplified by the synthesis of (-)-3-PPP (preclamol), an
(S)-3-arylpiperidine that acts as a selective dopaminergic
autoreceptor agonist and has been extensively studied
both as a pharmacological tool to investigate dopamin-
ergic mechanisms and from the therapeutic point of
view.5,12 Accordingly, the synthesis of (-)-3-PPP required
starting from (S)-phenylglycinol and racemic δ-oxoester
7a , which bears a m-methoxyphenyl substituent (Scheme
3). This ester was conveniently prepared by reaction of
methyl acrylate with the pyrrolidine enamine of (m-
methoxyphenyl)acetaldehyde. The use of a benzyl or tert-
butyldimethylsilyl protecting group instead of methyl was
not satisfactory due to the difficulties encountered in the
purification of the corresponding δ-oxoesters 7b and 7c.14
As expected, heating a toluene solution of (S)-phenyl-
glycinol and racemic oxoester 7a stereoselectively led to
lactam 8a in 59% yield (Scheme 3). Minor amounts (10%)
of the isomeric lactam 9a were also isolated. The H-8/
the final difference Fourier synthesis were 0.317 and -0.234 e Å-3
.
(16) (a) For syntheses of (-)-3-PPP via resolution of a racemate, see
refs 7a and 9a-d. (b) For a previous enantioselective synthesis of (-)-
3-PPP, see ref 7a. (c) An enantioselective synthesis of (-)-3-PPP has
also been reported in ref 7b. This synthesis proceeds via the intermedi-
ates ent-10, ent-13, and ent-11, with an
R configuration at the
piperidine 3-position. In fact, the sign and absolute value of specific
rotation of ent-13‚HCl in this synthesis are in agreement with the data
reported in the literature for the R enantiomer,9b,d whereas the [R]
values of ent-10 and ent-11 reveal that these compounds are enanti-
omers of intermediates 10 and 11, respectively, in our synthesis.
Furthermore, the 1H and 13C NMR data reported for ent-10 are
identical with those of 10 (RR,3S; absolute configuration confirmed
by X-ray crystallography)15 but different from those of the diastereomer
14 (RS,3R). The R configuration of intermediates ent-10, ent-13, and
ent-11 is correctly depicted in the scheme of reference 7b, although
these compounds are named as 3S in the Experimental Section. The
above intermediates should unambiguously lead to the R enantiomer
of 3-PPP, which is known7a,9a-c to be (X-ray) dextrorotatory. However,
surprisingly, the article talks about the formation of levorotatory 3-PPP
(depicted with the R configuration in the scheme but named as S in
the Experimental Section).
(14) Cyclodehydration of crude mixtures containing esters 7b and
7c with (S)-phenylglycinol also occurred stereoselectively to give
bicyclic lactames 8b and 8c, respectively, as the major products (85:
15 approximate 8/9 ratios).
J . Org. Chem, Vol. 67, No. 15, 2002 5345

Amat et al.
SCHEME 5. En a n tioselective Syn th esis of
SCHEME 6
cis-2-Alk yl-3-a r ylp ip er id in es
Lactams 16a and 16b proved to be convenient precur-
sors of enantiopure cis-2-methyl-3-arylpiperidines. Thus,
treatment of 16a or 16b with alane brought about both
the reduction of the carbonyl lactam and the stereo-
selective opening of the oxazolidine ring, with retention
of configuration,17b to give the respective cis-piperidines
18a and 18b in excellent yields. Only trace amounts of
the corresponding epimers at C-2 were detected by NMR
from the crude reaction mixtures. The cis relationship
between the substituents at the piperidine 2 and 3
positions in 18 (and 20, see below) was evident from the
chemical shifts of the methyl and piperidine R carbons
in the 13C NMR spectra (Figure 1). Removal of the chiral
auxiliary by hydrogenolysis with simultaneous introduc-
tion of the propyl substituent by reductive amination with
propionaldehyde, followed by demethylation, led to the
target preclamol analogues 19a and 19b. The above route
constitutes an enantioselective entry to cis-2-alkyl-3-
arylpiperidines. In a similar manner, the minor lactams
17a and 17b were converted into the corresponding
piperidines 20, and 20a was elaborated into the cis-
piperidine ent-19a .
substituent at the piperidine 2-position, starting from
appropriate racemic R-aryl ketones instead of alde-
hydes.13 The required aryl ketoesters 15a and 15b, with
a methoxy group at either the para or meta position of
the phenyl ring, were prepared from the corresponding
1-phenyl-2-propanones, by reaction of the respective
enolates with methyl acrylate. Cyclodehydration reaction
of racemic esters 15a and 15b with (R)-phenylglycinol
was most conveniently effected in the presence of cata-
lytic amounts of p-TsOH to provide in each series a 4:1
mixture of bicyclic lactams 16 and 17 in yields higher
than 70%, thus clearly indicating that a dynamic kinetic
resolution had again occurred (Scheme 5). The absolute
configuration of the major lactams was unambiguously
proven by X-ray diffraction techniques from a crystal of
16b,15 whereas the cis relationship of the 8-aryl and 8a-
alkyl substituents in the minor isomers 17 was evident
after 17a was converted to ent-19a (see below). Interest-
ingly, the stereochemical outcome of these reactions
involving keto esters differs from that observed in the
above cyclodehydrations from aldehyde esters, as lactams
with a cis 3-C6H5/8-aryl relationship are now formed as
the major stereoisomers.17 This result can be accounted
for by considering that, when starting from ketones,
lactamization of the diastereomeric oxazolidines in equi-
librium occurs faster from d ′, as this oxazolidine allows
a less hindered approach (anti with respect both the C6H5
and CH3 ring substituents) of the ester group to the
nitrogen, via a chairlike transition state bearing an
equatorial aryl substituent18 (Scheme 6).
In conclusion, cyclodehydration of racemic γ-aryl-δ-
oxoesters with R- or S-phenylglycinol efficiently leads to
enantiopure bicyclic δ-lactams, in a process that involves
a dynamic kinetic resolution of the stereocenter R to the
aldehyde or the ketone carbonyl group. Further elabora-
tion of these substituted lactams provides the first
general entry to enantiopure 3-aryl- and cis-2-alkyl-3-
arylpiperidines.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were determined in
a capillary tube and are uncorrected. Unless otherwise indi-
cated, NMR spectra were recorded at 200 or 300 MHz (1H)
and 50.3 or 75 MHz (13C) and are reported downfield from
TMS. Only noteworthy IR absorptions are listed. Thin-layer
chromatography was done on SiO2 (silica gel 60 F254), and the
spots were located with aqueous potassium permanganate
solution or with iodoplatinate reagent. All nonaqueous reac-
tions were performed under an inert atmosphere. Solvents for
chromatography were distilled at atmospheric pressure prior
to use and dried following standard procedures. Drying of the
organic extracts during the workup of reactions was performed
over anhydrous Na2SO4 or MgSO4. Evaporation of solvents was
accomplished with a rotatory evaporator. Microanalyses and
HRMS were performed by Centre d’Investigacio´ i Desenvolu-
pament (CSIC), Barcelona.
Meth yl 5-Oxo-4-p h en ylp en ta n oa te (1). Phenylacetalde-
hyde (7.0 g, 58 mmol) was added over a 1-h period with a
syringe pump to a cooled (0 °C) mixture of piperidine (14.3
mL, 145 mmol) and Na2CO3 (2.1 g, 20 mmol), and the mixture
was stirred for 2 h at 0 °C. The solid was filtered through a
Celite pad and the excess of piperidine was removed by
distillation to give 1-styrylpiperidine (8,5 g, 78%). A solution
of methyl acrylate (5.2 mL, 58 mmol) in anhydrous acetonitrile
(15 mL) was slowly added to a stirred solution of the above
(17) Similar differences in stereoselectivity between unsubstituted
aldehyde10c and keto acid derivatives17a-c have been observed in related
cyclodehydrations: (a) Bahajaj, A. A.; Bailey, P. D.; Moore, M. H.;
Morgan, K. M.; Vernon, J . M. J . Chem. Soc., Chem. Commun. 1994,
2511-2512. (b) Munchhof, M. J .; Meyers, A. I. J . Org. Chem. 1995,
60, 7084-7085. (c) Yamazaki, N.; Ito, T.; Kibayashi, C. Tetrahedron
Lett. 1999, 40, 739-742.
(18) For mechanistic considerations about the stereoselectivity in
related cyclodehydrations from unsubstituted keto acids, see: Meyers,
A. I.; Downing, S. V.; Weiser, M. J . J . Org. Chem. 2001, 66, 1413-
1419.
5346 J . Org. Chem., Vol. 67, No. 15, 2002

Enantioselective Synthesis of 3-Arylpiperidines
enamine in anhydrous acetonitrile (32 mL) at 0 °C. The
mixture was stirred at room temperature for 8 h, and then
heated at reflux for 36 h. Glacial acetic acid (2.7 mL) and water
(20 mL) were added, and the resulting solution was heated at
reflux for 8 h. The mixture was allowed to cool to room
temperature, the aqueous phase was saturated with NaCl, and
the solution was extracted with Et2O. The combined organic
layers were successively washed with 5% aqueous HCl, 5%
aqueous NaHCO3, and brine, then dried, filtered, and concen-
trated to give a crude mixture. Distillation under reduced
pressure (95-105 °C, 0.01 mmHg) afforded pure 1 (4.2 g,
45%): 1H NMR (CDCl3, 300 MHz) δ 2.03 (m, 1H), 2.30 (m,
2H), 2.40 (m, 1H), 3.63 (m, 1H), 3.64 (s, 3H), 7.25-7.50 (m,
5H), 9.68 (d, J ) 1.4 Hz, 1H); 13C NMR (CDCl3, 75.4 MHz) δ
24.8 (CH2), 31.2 (CH2), 51.7 (CH3), 58.0 (CH), 127.9 (CH), 128.9
(2 CH), 129.3 (2 CH), 135.1 (C), 178.8 (C), 199.9 (CH).
MeOH); mp 60-62 °C (Et2O-hexane). Anal. Calcd for
C
19H23NO‚1/3H2O: C, 79.42; H, 8.30; N, 4.87. Found: C, 79.22;
H, 8.21; N, 4.83.
(R)-3-P h en ylp ip er id in e (5). A solution of compound 4 (200
mg, 0.71 mmol) in AcOEt (25 mL) containing 20% Pd(OH)2/C
(80 mg) was hydrogenated at 25 °C for 15 h. Then, more
Pd(OH)2/C (20 mg) was added and the resulting suspension
was stirred under hydrogen for 10 additional hours. The
catalyst was removed by filtration and washed with hot MeOH.
The combined organic solutions were concentrated, and the
resulting oil was purified by flash chromatography (98:2
AcOEt-DEA) to give pure 3-phenylpiperidine 5 (86 mg,
75%): 1H NMR (CDCl3, 300 MHz) δ 1.60 (m, 2H), 1.85 (m,
1H), 1.90 (br, 1H), 2.00 (m, 1H), 2.67 (m, 3H), 3.10 (dm, J )
12.0 Hz, 1H), 3.18 (dm, J ) 11.5 Hz, 1H), 7.15-7.35 (m, 5H);
13C NMR (CDCl3, 75.4 MHz) δ 27.1 (CH2), 32.1 (CH2), 44.3
(CH), 46.6 (CH2), 54.1 (CH2), 126.2 (CH), 127.1 (2 CH), 128.3
(3R,8R,8a R)-3,8-Dip h en yl-5-oxo-2,3,6,7,8,8a -h exa h yd r o-
5H-oxa zolo[3,2-a ]p yr id in e (2). (R)-Phenylglycinol (2.7 g,
19.7 mmol) was added to a solution of oxoester 1 (4.0 g, 19.4
mmol) in anhydrous toluene (60 mL), and the mixture was
heated at reflux for 24 h with azeotropic elimination of water
produced by a Dean-Stark apparatus. The resulting suspen-
sion was filtered through a Celite pad, the solution was
concentrated under reduced pressure, and the residue was
taken up with AcOEt. The organic solution was washed with
5% aqueous Na2CO3, dried, and concentrated to give an oil.
Flash chromatography (SiO2 previously washed with 8:2
Et3N-AcOEt; gradient from 7:3 AcOEt-hexane to AcOEt)
afforded lactam 2 (2.8 g, 49%) and its 3R,8S,8aS diastereomer
(2 CH), 144.9 (C). 5‚hydrochloride: IR (film) 3300 cm-1 1H
;
NMR (CDCl3, 300 MHz) δ 1.66 (qd, J ) 12.5, 4.0 Hz, 1H),
1.95-2.21 (m, 3H), 2.86 (masked, 1H), 2.91 (t, J ) 12.5 Hz,
1H), 3.24 (tm, J ) 12.5 Hz, 1H), 3.54 (m, 2H), 7.20-7.35 (m,
5H); 13C NMR (CDCl3, 75.4 MHz) δ 22.7 (CH2), 30.3 (CH2),
39.6 (CH), 43.9 (CH2), 49.3 (CH2), 126.9 (2 CH), 127.5 (CH),
128.9 (2 CH), 140.7 (C); [R]22 -10.3 (c 0.5, MeOH); mp 179-
D
181 °C {lit.8a (for the (S)-enantiomer) [R]D +12.2 (MeOH); mp
182 °C}. Anal. Calcd for C11H16ClN: C, 66.83; H, 8.16; N, 7.08.
Found: C, 66.89; H, 7.96; N, 6.77.
(3S)-1-[(1R)-2-Hyd r oxy-1-p h en yleth yl]-3-p h en ylp ip er i-
d in e (6). Operating as described for 4, starting from lactam 3
(74 mg, 0.25 mmol) piperidine 6 (50 mg, 70%) was obtained
as a transparent oil after flash chromatography (Et2O): IR
3 (0.5 g, 9%). 2 (lower Rf): IR (film) 1658 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 2.15 (m, 2H), 2.50 (ddd, J ) 18.0, 10.5,
7.1 Hz, 1H), 2.58 (ddd, J ) 18.0, 6.3, 3.3 Hz, 1H), 3.08 (ddd, J
) 11.0, 9.2, 5.5 Hz, 1H), 4.00 (dd, J ) 9.1, 1.2 Hz, 1H), 4.10
(dd, J ) 9.1, 6.7 Hz, 1H), 4.93 (d, J ) 9.2 Hz, 1H), 4.97 (dd, J
) 6.7, 1.2 Hz, 1H), 7.20-7.45 (m, 10H); 13C NMR (CDCl3, 75.4
MHz) δ 26.0 (CH2), 31.7 (CH2), 45.7 (CH), 59.1 (CH), 73.7
(CH2), 92.2 (CH), 126.4 (2 CH), 127.5 (CH), 127.6 (2 CH), 128.5
1
(film) 3400 cm-1; H NMR (CDCl3, 300 MHz) δ 1.32 (m, 1H),
1.76 (t, J ) 11.2 Hz, 1H), 1.70-1.80 (m, 2H), 1.84 (dm, J )
12.8 Hz, 1H), 2.33 (m, 1H), 2.71 (tt, J ) 11.2, 3.6 Hz, 1H),
2.92 (m, 2H), 3.05 (br s, 1H), 3.60 (dd, J ) 10.2, 5.1 Hz, 1H),
3.75 (dd, J ) 10.2, 5.1 Hz, 1H), 3.96 (t, J ) 10.2 Hz, 1H), 7.10-
7.40 (m, 10H); 13C NMR (CDCl3, 75.4 MHz) δ 26.3 (CH2), 31.8
(CH2), 43.5 (CH), 53.0 (CH2), 53.3 (CH2), 60.0 (CH2), 70.2 (CH),
126.3 (CH), 127.2 (2 CH), 127.8 (CH), 128.1 (2 CH), 128.3 (2
(2 CH), 128.7 (2 CH), 139.2 (C), 141.3 (C), 166.8 (C); [R]22
D
CH), 128.9 (2 CH), 135.3 (C), 144.5 (C); [R]22 +11.2 (c 0.6,
+80.5 (c 1.0, MeOH); mp 82-84 °C (Et2O-hexane). Anal. Calcd
D
for C19H19NO2: C, 77.79; H, 6.53; N, 4.77. Found: C, 77.69;
MeOH); HRMS calcd for C19H23NO 281.1775, found 281.1779.
Meth yl 4-(3-Meth oxyp h en yl)-5-oxop en ta n oa te (7a ). A
mixture of (3-methoxyphenyl)acetaldehyde19 (1.8 g, 12 mmol),
anhydrous Na2CO3 (445 mg, 4.2 mmol), and pyrrolidine (2.5
mL, 30 mmol), containing 4 Å molecular sieves, was stirred
at 0 °C for 2 h. The solids were filtered through a Celite pad,
and the excess of pyrrolidine was removed by distillation to
give a crude enamine (2.17 g, 89%). A mixture of this enamine
and methyl acrylate (1.9 mL, 21.4 mmol) in anhydrous EtOH
(3.8 mL) containing 4 Å molecular sieves was heated in a
sealed tube at 80 °C for 14 h. Then, acetic acid (0.6 mL) and
water (5.0 mL) were added, and the resulting mixture was
heated at 80 °C for 3 h and filtered. The solution was
concentrated to give a residue, which was dissolved in Et2O.
The ethereal solution was washed with 2 N aqueous HCl and
brine, dried, and concentrated to give an orange oil. Distillation
of this oil (120-125 °C, 0.5 mmHg) afforded aldehyde ester
1
H, 6.59; N, 4.86. 3 (higher Rf): IR (film) 1636 cm-1; H NMR
(CDCl3, 300 MHz) δ 2.08 (dddd, J ) 13.5, 6.8, 3.4, 1.5 Hz, 1H),
2.19 (dddd, J ) 13.5, 12.6, 11.4, 6.0 Hz, 1H), 2.55 (ddd, J )
18.3, 11.4, 6.8 Hz, 1H), 2.71 (ddd, J ) 18.3, 6.0, 1.5 Hz, 1H),
2.83 (ddd, J ) 12.6, 8.7, 3.4 Hz, 1H), 3.70 (dd, J ) 9.0, 8.0 Hz,
1H), 4.47 (dd, J ) 9.0, 8.0 Hz, 1H), 5.03 (d, J ) 8.7 Hz, 1H),
5.32 (t, J ) 8.0 Hz, 1H), 7.20-7.45 (m, 10H); 13C NMR (CDCl3,
75.4 MHz) δ 24.8 (CH2), 31.8 (CH2), 46.1 (CH), 58.4 (CH), 72.4
(CH2), 92.7 (CH), 126.1 (2 CH), 127.4 (2 CH), 127.5 (CH), 127.6
(2 CH), 128.7 (CH), 128.8 (2 CH), 139.4 (C), 139.5 (C), 168.4
(C); [R]22 -9.64 (c 0.25, MeOH); mp 160-162 °C (Et2O-
D
hexane). Anal. Calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77.
Found: C, 77.54; H, 6.61; N, 4.87.
(3R)-1-[(1R)-2-Hyd r oxy-1-p h en yleth yl]-3-p h en ylp ip er i-
d in e (4). To a solution of lactam 2 (350 mg, 1.19 mmol) in
anhydrous THF (15 mL) was slowly added LiAlH4 (145 mg,
3.8 mmol), and the resulting suspension was stirred at room
temperature for 1 h. The reaction was quenched with 10%
aqueous NaOH, and the mixture was extracted with CH2Cl2
(3 × 15 mL). The organic solution was dried, filtered, and
concentrated to give a yellow oil. Purification by flash chro-
matography (Et2O) afforded pure piperidine 4 (242 mg, 72%)
7a (934 mg, 37%) as a transparent oil: IR (film) 1732 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 2.02 (m, 1H), 2.30 (m, 2H), 2.38
(m, 1H), 3.59 (m, 1H), 3.65 (s, 3H), 3.80 (s, 3H), 6.71 (m, 1H),
6.77 (dm, J ) 8.0 Hz, 1H), 6.84 (ddd, J ) 8.3, 2.6, 0.9 Hz, 1H),
7.27 (t, J ) 8.3 Hz, 1H), 9.67 (d, J ) 1.3 Hz, 1H); 13C NMR
(CDCl3, 75.4 MHz) δ 24.6 (CH2), 31.1 (CH2), 51.6 (CH3), 55.1
(CH3), 57.9 (CH), 113.1 (CH), 114.6 (CH), 121.1 (CH), 130.2
(CH), 136.7 (C), 160.1 (C), 173.3 (C), 199.7 (CH); HRMS calcd
for C13H16O4 236.1048, found 236.1048.
1
as a white solid: IR (film) 3400 cm-1; H NMR (CDCl3, 300
MHz) δ 1.34 (qd, J ) 12.6, 4.0 Hz, 1 H), 1.55-1.80 (m, 3H),
1.87 (dm, J ) 12.6 Hz, 1 H), 2.33 (t, J ) 11.0 Hz, 1 H), 2.80-
3.02 (m, 3 H), 3.18 (br s, 1 H), 3.62 (dd, J ) 10.2, 5.3 Hz, 1 H),
3.71 (dd, J ) 10.2, 5.3 Hz, 1 H), 4.00 (t, J ) 10.2 Hz, 1 H),
7.10-7.40 (m, 10H); 13C NMR (CDCl3, 75.4 MHz) δ 26.0 (CH2),
31.4 (CH2), 43.9 (CH), 46.2 (CH2), 60.1 (CH2), 60.5 (CH2), 70.3
(CH), 126.4 (CH), 127.2 (2 CH), 127.8 (CH), 128.1 (2 CH), 128.4
(19) This aldehyde was prepared in 60% overall yield by epoxidation
of m-methoxybenzaldehyde19a followed by treatment of the resulting
epoxide with LiClO4‚Et2O:19b (a) Alvarez, M.; Granados, R.; Lavilla,
R.; Salas, M. J . Heterocycl. Chem. 1985, 22, 745-750. (b) Sudha, R.;
Narasimhan, K. M.; Saraswathy, V. G.; Sankararaman, S. J . Org.
Chem. 1996, 61, 1877-1879.
(2 CH), 128.9 (2 CH), 135.4 (C), 144.3 (C); [R]22 -70.7 (c 0.6,
D
J . Org. Chem, Vol. 67, No. 15, 2002 5347

Amat et al.
(3S,8S,8a S)-8-(3-Met h oxyp h en yl)-5-oxo-3-p h en yl-2,3,
6,7,8,8a -h exa h yd r o-5H-oxa zolo[3,2-a ]p yr id in e (8a ). Op-
erating as described for 2, starting from pure 7a (317 mg, 1.34
mmol) and (S)-phenylglycinol (184 mg, 1.34 mmol) in toluene
(6.7 mL), lactam 8a (238 mg, 59%) and its 3S,8R,8aR dia-
stereomer 9a (44 mg, 10%) were obtained after flash chroma-
tography (SiO2 previously washed with 8:2 Et3N-AcOEt;
gradient from 7:3 AcOEt-hexane to AcOEt). 8a (lower Rf): IR
(film) 1649 cm-1; 1H NMR (CDCl3, 300 MHz) δ 2.03-2.16 (m,
2H), 2.40-2.56 (m, 2H), 3.04 (ddd, J ) 11.5, 9.1, 4.7 Hz, 1H),
3.82 (s, 3H), 3.98 (dd, J ) 9.1, 1.3 Hz, 1H), 4.02 (dd, J ) 9.1,
6.7 Hz, 1H), 4.88 (d, J ) 9.1 Hz, 1H), 4.93 (dd, J ) 6.7, 1.3 Hz,
1H), 6.84 (ddd, J ) 8.2, 2.4, 0.8 Hz, 1H), 6.90 (m, 1H), 6.95
(dm, J ) 7.7 Hz, 1H), 7.24-7.35 (m, 6H); 13C NMR (CDCl3,
75.4 MHz) δ 26.0 (CH2), 31.6 (CH2), 45.6 (CH), 55.1 (CH3), 59.0
(CH), 73.7 (CH2), 92.0 (CH), 112.4 (CH), 113.6 (CH), 119.7
(CH), 126.3 (2 CH), 127.5 (CH), 128.5 (2 CH), 129.7 (CH), 140.7
(C), 141.2 (C), 159.7 (C), 166.9 (C); [R]22D -91.9 (c 0.82, MeOH).
Anal. Calcd for C20H21NO3‚H2O: C, 70.36; H, 6.79; N, 4.10.
Found: C, 70.74; H, 6.79; N, 4.10. 9a (higher Rf): 1H NMR
(CDCl3, 300 MHz) δ 2.04-2.24 (m, 2H), 2.53 (ddd, J ) 18.4,
11.3, 7.1 Hz, 1H), 2.70 (ddd, J ) 18.4, 6.0, 2.0 Hz, 1H), 2.79
(ddd, J ) 12.4, 8.7, 3.6 Hz, 1H), 3.70 (dd, J ) 9.1, 7.8 Hz, 1H),
3.82 (s, 3H), 4.47 (dd, J ) 9.1, 7.8 Hz, 1H), 5.02 (d, J ) 8.6
Hz, 1H), 5.30 (t, J ) 7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.90 (d,
J ) 7.6 Hz, 1H), 7.21-7.36 (m, 6H); 13C NMR (CDCl3, 75.4
MHz) δ 24.9 (CH2), 31.8 (CH2), 46.2 (CH), 55.2 (CH3), 58.5
(CH), 72.5 (CH2), 92.6 (CH), 112.5 (CH), 113.6 (CH), 119.7
(CH), 126.2 (2 CH), 127.6 (CH), 128.8 (2 CH), 129.8 (CH), 139.4
(C), 141.2 (C), 159.8 (C), 168.4 (C); [R]22D +15.8 (c 0.12, MeOH);
HRMS calcd for C20H21NO3 323.1518, found 323.1521.
) 11.4 Hz, 1H), 2.31 (m, 2H), 2.81 (tt, J ) 11.4, 3.6 Hz, 1H),
2.99 (dm, J ) 11.2 Hz, 1H), 3.03 (dm, J ) 11.4 Hz, 1H), 3.79
(s, 3H), 6.72-6.86 (m, 3H), 7.21 (t, J ) 8.0 Hz, 1H); 13C NMR
(CDCl3, 75.4 MHz) δ 12.0 (CH3), 20.0 (CH2), 25.7 (CH2), 31.6
(CH2), 42.9 (CH), 53.9 (CH2), 55.1 (CH3), 61.1 (CH2), 61.2 (CH2),
111.2 (CH), 113.2 (CH), 119.6 (CH), 129.2 (CH), 146.5 (C),
159.5 (C); [R]22D +7.2 (c 2.3, CHCl3). 11‚hydrochloride: IR (film)
1
3410 cm-1; H NMR (CDCl3, 300 MHz) δ 0.99 (t, J ) 7.3 Hz,
3H), 1.67 (qm, J ) 11.8 Hz, 1H), 1.97 (m, 3H), 2.13 (dm, J )
11.0 Hz, 1H), 2.45-2.78 (m, 3H), 2.93 (m, 2H), 3.59 (m, 3H),
3.79 (s, 3H), 6.78-6.83 (m, 3H), 7.25 (t, J ) 10.0 Hz, 1H), 12.38
(br s); 13C NMR (CDCl3, 75.4 MHz) δ 11.2 (CH3), 17.0 (CH2),
22.6 (CH2), 29.5 (CH2), 39.5 (CH), 52.7 (CH2), 55.3 (CH3), 57.8
(CH2), 59.4 (CH2), 112.8 (CH), 112.9 (CH), 119.0 (CH), 129.9
(CH), 141.9 (C), 159.9 (C); [R]22 -6.9 (c 1.76, MeOH) {lit.7a
D
[R]20D -6.5 (c 2.6, MeOH); lit.9b [R]22D -6.7 (c 2.1, MeOH); lit.9d
(for the hydrobromide) [R]25 -6.7 (c 3.0, MeOH)}; mp 198-
D
200 °C (CH2Cl2-Et2O). Anal. Calcd for C15H24ClNO: C, 66.77;
H, 8.97; N, 5.19. Found: C, 66.49; H, 8.83; N, 5.24.
(S)-3-(3-H yd r oxyp h en yl)-1-p r op ylp ip er id in e [(-)-3-
P P P ]. A solution of piperidine 11 (77 mg, 0.33 mmol) in 48%
HBr was heated at reflux for 90 min. After cooling, the
resulting solution was basified by dropwise addition of satu-
rated aqueous Na2CO3. The mixture was extracted with Et2O,
and the resulting ethereal solution was dried, filtered, and
concentrated to give (-)-3-PPP (58 mg, 72%): 1H NMR (CDCl3,
300 MHz) δ 0.87 (t, J ) 7.3 Hz, 3H), 1.42-1.65 (m, 3H), 1.80
(m, 2H), 1.98 (t, J ) 11.4 Hz, 1H), 1.94-2.05 (m, 2H), 2.37 (m,
2H), 2.93 (tt, J ) 11.4, 3.5 Hz, 1H), 3.07 (dm, J ) 11.2 Hz,
1H), 3.23 (dm, J ) 11.4, 1H), 6.65-6.83 (m, 3H), 7.18 (t, J )
8.0 Hz, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 12.0 (CH3), 19.2
(CH2), 25.2 (CH2), 29.8 (CH2), 41.7 (CH), 54.0 (CH2), 61.2 (CH2),
61.4 (CH2), 114.2 (CH), 114.6 (CH), 117.4 (CH), 129.8 (CH),
(3S)-1-[(1S)-2-Hydroxy-1-phenylethyl]-3-(3-methoxyphen-
yl)p ip er id in e (10). LiAlH4 (752 mg, 20 mmol) was slowly
added to a cooled (0 °C) suspension of AlCl3 (880 mg, 6.6 mmol)
in anhydrous THF (66 mL), and the mixture was stirred at
room temperature for 30 min. The temperature was lowered
to -78 °C, lactam 8a (1.0 g, 3.3 mmol) was added, and the
resulting suspension was stirred at -78 °C for 90 min and at
room temperature for 2 h. The mixture was cooled to 0 °C,
and the reaction was quenched with H2O. The aqueous layer
was extracted with CH2Cl2 (3 × 30 mL), and the combined
organic extracts were dried and concentrated to give a foam.
Flash chromatography (1:1 AcOEt-hexane) afforded pure
145.4 (C), 156.8 (C); [R]22 -8.9 (c 1.2, MeOH). The hydro-
D
chloride was obtained by treatment of the crude reaction
mixture with an ethereal solution of HCl: IR (film) 3470 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.97 (t, J ) 7.3 Hz, 3H), 1.68
(qd, J ) 12.3, 3.0 Hz, 1H), 1.87 (m, 1H), 2.02 (m, 1H), 2.25
(qm, J ) 13.0 Hz, 1H), 2.75 (t, J ) 12.0 Hz, 1H), 2.71-2.83
(m, 1H), 2.96 (m, 2H), 3.35 (tt, J ) 12.0, 3.2 Hz, 1H), 3.51 (dm,
J ) 12.0 Hz, 1H), 3.60 (dm, J ) 11.2, 1H), 6.65-6.79 (m, 3H),
7.14 (dd, J ) 8.7, 7.6 Hz, 1H), 10.83 (br s); 13C NMR (CDCl3,
75.4 MHz) δ 10.9 (CH3), 17.0 (CH2), 22.7 (CH2), 28.9 (CH2),
39.6 (CH), 52.4 (CH2), 57.9 (CH2), 59.1 (CH2), 114.1 (CH), 114.7
1
piperidine 10 (751 mg, 78%): IR (film) 3429 cm-1; H NMR
(CH), 117.5 (CH), 129.8 (CH), 141.4 (C), 157.3 (C); [R]22 -6.8
D
(CDCl3, 300 MHz) δ 1.35 (qd, J ) 12.1, 3.9 Hz, 1H), 1.70-
1.84 (m, 3H), 1.89 (dm, J ) 12.5 Hz, 1H), 2.35 (t, J ) 11.0 Hz,
1H), 2.95-3.06 (m, 3H), 3.67 (dd, J ) 10.4, 4.2 Hz, 1H), 3.78
(masked, 1H), 3.79 (s, 3H), 4.07 (t, J ) 10.4 Hz, 1H), 6.74 (m,
1H), 6.77 (m, 1H), 6.79 (m, 1H), 7.16-7.24 (m, 3H), 7.33-7.35
(m, 3H); 13C NMR (CDCl3, 75.4 MHz) δ 25.9 (CH2), 31.3 (CH2),
43.9 (CH), 45.9 (CH2), 55.1 (CH3), 59.9 (CH2), 60.5 (CH2), 70.2
(CH), 111.4 (CH), 113.2 (CH), 119.6 (CH), 127.8 (CH), 128.1
(2 CH), 128.9 (2 CH), 129.3 (CH), 135.1 (C), 145.9 (C), 159.6
(c 0.68, MeOH) {lit.7a [R]20 -6.8 (c 2.1, MeOH); lit.9a,c [R]20
D
D
-7.4 (c 2.2, MeOH); lit.9b [R]22 -7.1 (c 2.2, MeOH)}.
D
(S)-1-(ter t-Bu t oxyca r bon yl)-3-(3-m et h oxyp h en yl)p ip -
er id in e (12). A solution of piperidine 10 (190 mg, 0.61 mmol)
and di-tert-butyl dicarbonate (278 mg, 1.3 mmol) in anhydrous
AcOEt (21 mL) containing 20% Pd(OH)2/C (47 mg) was
hydrogenated at room temperature for 15 h. The catalyst was
removed by filtration and washed with hot MeOH. The
combined organic solutions were concentrated to give a yellow
oil, which was chromatographed (gradient from hexane to 1:1
hexane-AcOEt) affording pure N-Boc piperidine 12 (127 mg,
(C); [R]22 +83.5 (c 1.9, CHCl3). 10‚Hydrochloride: 1H NMR
D
(CDCl3, 300 MHz) δ 1.50 (qd, J ) 12.7, 3.1 Hz, 1H), 1.96-
2.08 (m, 2H), 2.42-2.64 (m, 3H), 3.71 (m, 2H), 3.79 (s, 3H),
4.11 (dm, J ) 12.8 Hz, 1H), 4.38-4.55 (m, 2H), 5.21 (m, 1H),
6.70-6.80 (m, 3H), 7.26 (m, 1H), 7.39 (m, 2H), 7.46 (m, 3H),
71%) as a transparent oil: IR (film) 1694 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.59 (m, 2H), 1.75 (m, 1H),
2.02 (m, 1H), 2.60-2.76 (m, 2H), 2.74 (t, J ) 11.5 Hz, 1H),
3.80 (s, 3H), 4.17 (m, 2H), 6.78 (m, 3H), 7.23 (dd, J ) 7.1, 8.3
Hz, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 25.4 (CH2), 28.4 (3
CH3), 31.7 (CH2), 42.5 (CH), 44.1 (CH2), 50.5 (CH2), 55.1 (CH3),
79.4 (C), 111.6 (CH), 113.0 (CH), 119.4 (CH), 129.4 (CH), 145.2
11.4 (br s, 1H); [R]22 +86.6 (c 1.16, CHCl3); mp 155-157 °C
D
(CH2Cl2-Et2O). Anal. Calcd for C20H26ClNO2: C, 69.05; H, 7.53;
N, 4.03. Found: C, 68.69; H, 7.58; N, 3.99.
(S)-3-(3-Meth oxyp h en yl)-1-p r op ylp ip er id in e (11). To a
solution of piperidine 10 (297 mg, 0.95 mmol) in AcOEt (10
mL) containing 20% Pd(OH)2/C (119 mg) was added propion-
aldehyde (0.27 mL, 3.8 mmol), and the mixture was hydrogen-
ated at 25 °C for 20 h. The catalyst was removed by filtration
and washed with hot MeOH. The combined organic solutions
were concentrated to give a yellow oil (314 mg). Flash chro-
matography (from 4:1 to 7:3 hexane-DEA) afforded pure
compound 11 (133 mg, 60%): 1H NMR (CDCl3, 300 MHz) δ
0.89 (t, J ) 7.3 Hz, 3H), 1.43 (qd, J ) 12.3, 4.5 Hz, 1H), 1.50-
1.60 (m, 2H), 1.68-1.81 (m, 2H), 1.88-1.97 (m, 2H), 1.95 (t, J
(C), 154.7 (C), 159.6 (C); [R]22 -50.7 (c 0.8, CHCl3).
D
(S)-3-(3-Meth oxyp h en yl)p ip er id in e (13). To a solution
of carbamate 12 (107 mg, 0.36 mmol) in anhydrous CH2Cl2
(2.5 mL) was added TFA (2.0 mL, 26 mmol), and the mixture
was stirred at room temperature for 15 min. The solution was
basified by slow addition of saturated aqueous Na2CO3, and
the mixture was extracted with CH2Cl2. The combined organic
extracts were dried and the solvent was removed under
reduced pressure. The resulting yellow oil was purified by flash
5348 J . Org. Chem., Vol. 67, No. 15, 2002

Enantioselective Synthesis of 3-Arylpiperidines
chromatography (98:2 AcOEt-DEA) to give compound 13 (42
Calcd for C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C,
74.72; H, 6.83; N, 4.25.
1
mg, 60%): IR (film) 3390 cm-1; H NMR (CDCl3, 300 MHz) δ
1.61 (m, 2H), 1.78 (m, 1H), 2.01 (m, 1H), 2.19 (br s, 1H), 2.59-
2.74 (m, 3H), 3.10 (dm, J ) 12.3 Hz, 1H), 3.17 (dm, J ) 7.5
Hz, 1H), 3.79 (s, 3H), 6.74-6.83 (m, 3H), 7.23 (td, J ) 7.6, 1.3
Hz, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 26.8 (CH2), 31.9 (CH2),
44.2 (CH), 46.5 (CH2), 53.7 (CH2), 55.1 (CH3), 111.2 (CH), 113.1
(3R,8S,8a S)-8-(3-Met h oxyp h en yl)-8a -m et h yl-5-oxo-3-
p h e n yl-2,3,6,7,8,8a -h e xa h yd r o-5H -oxa zolo[3,2-a ]p yr i-
d in e (16b). Operating as described for 16a , from methyl 4-(3-
methoxyphenyl)-5-oxohexanoate20 (15b; 672 mg, 1.9 mmol),
lactams 16b (534 mg, 59%) and 17b (130 mg, 14%) were
obtained after flash chromatography (3:1 AcOEt-hexane). 16b
(CH), 119.5 (CH), 129.3 (CH), 146.4 (C), 159.6 (C); [R]22 +6.2
D
1
(higher Rf): IR (KBr) 1651 cm-1; H NMR (CDCl3, 300 MHz)
(c 0.75, MeOH). 13‚hydrochloride: mp 170-172 °C (CH2Cl2-
Et2O); [R]22 +9.3 (c 2.1, MeOH) {lit.9b [R]22 +10.1 (c 2.1,
D
D
δ 1.19 (s, 3H), 2.11 (dddd, J ) 13.5, 7.8, 3.3, 1.5 Hz, 1H), 2.34
(dddd, J ) 13.5, 13.5, 10.5, 7.8 Hz, 1H), 2.59 (ddd, J ) 18.6,
10.5, 7.8 Hz, 1H), 2.82 (ddm, J ) 18.6, 7.8 Hz, 1H), 3.06 (dd,
J ) 13.5, 3.3 Hz, 1H), 3.80 (s, 3H), 3.87 (dd, J ) 9.0, 8.0 Hz,
1H), 4.55 (t, J ) 9.0 Hz, 1H), 5.42 (t, J ) 8.0 Hz, 1H), 6.83
(ddd, J ) 8.4, 3.0, 0.9 Hz, 1H), 6.90-6.95 (m, 2H), 7.19-7.35
(m, 6H); 13C NMR (CDCl3, 75.4 MHz) δ 19.2 (CH3), 22.4 (CH2),
31.3 (CH2), 49.8 (CH), 55.0 (CH3), 58.9 (CH), 69.5 (CH2), 95.6
(C), 111.9 (CH), 115.1 (CH), 120.9 (CH), 125.3 (2 CH), 127.0
(CH), 128.4 (2 CH), 128.9 (CH), 139.6 (C), 140.2 (C), 159.1 (C),
MeOH); lit.9d [R]25 +10.3 (c 1.48, MeOH)}. Anal. Calcd for
D
C
12H18ClNO: C, 63.29; H, 7.97; N, 6.15. Found: C, 62.97; H,
7.88; N, 6.06.
(3R)-1-[(1S)-2-H yd r oxy-1-p h en ylet h yl]-3-(3-m et h oxy-
p h en yl)p ip er id in e (14). Operating as described for the
reduction of 8a to give 10, starting from minor lactam 9a (120
mg, 0.38 mmol) pure piperidine 14 (71 mg, 60%) was obtained
after flash chromatography (1:1 AcOEt-hexane): IR (film)
1
3500 cm-1; H NMR (CDCl3, 300 MHz) δ 1.36 (m, 1H), 1.75-
168.8 (C); [R]22 -60.6 (c 2.0, MeOH); mp 98-100 °C (THF-
1.89 (m, 4H), 2.40 (td, J ) 11.3, 3.6 Hz, 1H), 2.85 (m, 1H),
3.05 (m, 2H), 3.67 (m, 2H), 3.78 (s, 3H), 3.98 (t, J ) 10.4 Hz,
1H), 6.69-7.81 (m, 3H), 7.10-7.40 (m, 6H); 13C NMR (CDCl3,
75.4 MHz) δ 26.2 (CH2), 31.6 (CH2), 43.5 (CH), 53.0 (CH2), 53.1
(CH2), 55.1 (CH3), 59.9 (CH2), 70.2 (CH), 111.4 (CH), 113.3
(CH), 119.6 (CH), 127.6 (CH), 127.9 (CH), 128.4 (2 CH), 129.0
D
Et2O). Anal. Calcd for C21H23NO3: C, 74.75; H, 6.87; N, 4.15.
Found: C, 74.93; H, 6.89; N, 4.13. 17b (lower Rf): IR (film)
1655 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.29 (s, 3H), 2.13 (m,
1H), 2.32 (m, 1H), 2.48 (m, 1H), 2.57 (ddd, J ) 18.0, 8.7, 2.0
Hz, 1H), 3.34 (dd, J ) 13.2, 3.9 Hz, 1H), 2.82 (s, 3H), 3.99 (dd,
J ) 9.0, 2.0 Hz, 1H), 4.40 (dd, J ) 9.0, 7.5 Hz, 1H), 4.99 (dd,
J ) 7.5, 2.0 Hz, 1H), 6.86 (ddd, J ) 8.4, 2.4, 0.6 Hz, 1H), 6.99-
7.03 (m, 2H), 7.24-7.40 (m, 6H); 13C NMR (CDCl3, 75.4 MHz)
δ 18.6 (CH3), 22.8 (CH2), 30.8 (CH2), 49.4 (CH), 55.1 (CH3),
59.2 (CH), 71.2 (CH2), 94.9 (C), 111.9 (CH), 115.3 (CH), 121.1
(CH), 126.2 (2 CH), 127.3 (CH), 128.4 (2 CH), 128.9 (CH), 139.9
(C), 141.4 (C), 159.2 (C), 166.5 (C); [R]22D +122.8 (c 1.0, MeOH).
Anal. Calcd for C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found:
C, 74.58; H, 6.88; N, 4.09.
(2 CH), 135.0 (C), 146.0 (C), 159.5 (C); [R]22 -25.7 (c 0.29,
D
CHCl3).
(3R)-3-(3-Meth oxyp h en yl)-1-p r op ylp ip er id in e (en t-11).
Following the procedure described for the preparation of 11,
starting from piperidine 14 (59 mg, 0.19 mmol) pure compound
ent-11 (20 mg, 45%) was obtained after flash chromatogra-
phy: [R]22 -5.5 (c 1.15, CHCl3). ent-11‚hydrochloride: [R]22
D
D
+6.25 (c 1.28, MeOH) {lit.9b [R]22 +6.4 (c 2.1, MeOH)}.
D
(3R,8S,8a S)-8-(4-Met h oxyp h en yl)-8a -m et h yl-5-oxo-3-
p h e n yl-2,3,6,7,8,8a -h e xa h yd r o-5H -oxa zolo[3,2-a ]p yr i-
d in e (16a ). To a mixture of methyl 4-(4-methoxyphenyl)-5-
oxohexanoate20 (15a ; 1.0 g, 4.0 mmol) and (R)-phenylglycinol
(660 mg, 4.8 mmol) in anhydrous toluene (8 mL) was added a
catalytic amount of p-TsOH. The mixture was heated at reflux
for 14 h, cooled, and concentrated under reduced pressure. The
residue was dissolved in AcOEt, washed with 5% aqueous
NaHCO3, and dried. Removal of the solvent followed by flash
chromatography (95:5 Et2O-DEA) afforded pure lactam 16a
(822 mg, 61%) and its 3R,8R,8aR diastereomer 17a (200 mg,
(2R,3S)-1-[(1R)-2-Hydr oxy-1-ph en yleth yl]-3-(4-m eth oxy-
p h en yl)-2-m eth ylp ip er id in e (18a ). Operating as described
for the reduction of lactam 8a , starting from lactam 16a (763
mg, 2.26 mmol) pure piperidine 18a (610 mg, 83%) was
obtained after flash chromatography (4:1 AcOEt-hexane). A
fraction (79 mg, 11%) of 18a containing trace amounts of the
1
C-2 epimer was also obtained. 18a : IR (film) 3402 cm-1; H
NMR (CDCl3, 300 MHz) δ 0.60 (d, J ) 6.6 Hz, 3H), 1.68 (m,
2H), 1.83 (m, 2H), 2.70 (td, J ) 11.4, 3.3 Hz, 1H), 2.77 (dm, J
) 11.4 Hz, 1H), 2.95-3.08 (m, 2H), 3.69-3.80 (m, 2H), 3.73
(s, 3H), 3.91 (dd, J ) 10.5, 5.0 Hz, 1H), 6.78 (dm, J ) 8.7 Hz,
2H), 7.02 (dm, J ) 8.7 Hz, 2H), 7.24-7.39 (m, 5H); 13C NMR
(CDCl3, 75.4 MHz) δ 6.5 (CH3), 23.8 (CH2), 25.5 (CH2), 42.6
(CH2), 45.4 (CH), 55.1 (CH3), 55.2 (CH), 63.1 (CH2), 66.4 (CH),
113.4 (2 CH), 127.5 (CH), 128.3 (2 CH), 128.4 (2 CH), 128.7 (2
1
15%). 16a (higher Rf): IR (film) 1643 cm-1; H NMR (CDCl3,
300 MHz) δ 1.19 (s, 3H), 2.11 (dddd, J ) 14.0, 8.1, 3.3, 1.5 Hz,
1H), 2.34 (dddd, J ) 14.0, 14.0, 10.2, 7.0 Hz, 1H), 2.61 (ddd, J
) 18.0, 10.2, 8.1 Hz, 1H), 2.80 (ddm, J ) 18.0, 7.0 Hz, 1H),
3.05 (dd, J ) 14.0, 3.3 Hz, 1H), 3.80 (s, 3H), 3.88 (dd, J ) 9.0,
8.1 Hz, 1H), 4.56 (t, J ) 9.0 Hz, 1H), 5.42 (t, J ) 8.1 Hz, 1H),
6.90 (dm, J ) 8.7 Hz, 2H), 7.20-7.35 (m, 7H); 13C NMR (CDCl3,
75.4 MHz) δ 18.9 (CH3), 22.4 (CH2), 31.2 (CH2), 48.9 (CH), 54.9
(CH3), 58.9 (CH), 69.4 (CH2), 95.6 (C), 113.4 (2 CH), 125.2 (2
CH), 126.9 (CH), 128.4 (2 CH), 129.4 (2 CH), 130.6 (C), 139.5
(C), 158.6 (C), 168.8 (C); [R]22D -60.4 (c 1.25, MeOH); mp 115-
117 °C (THF-Et2O). Anal. Calcd for C21H23NO3: C, 74.75; H,
6.87; N, 4.15. Found: C, 75.00; H, 6.87; N, 4.10. 17a (lower
Rf): IR (film) 1653 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.27 (s,
3H), 2.11 (dddd, J ) 13.5, 8.5, 4.8, 2.5 Hz, 1H), 2.31 (m, 1H),
2.50 (ddd, J ) 18.3, 8.5, 8.5 Hz, 1H), 2.56 (ddd, J ) 18.3, 8.5,
2.5 Hz, 1H), 3.33 (dd, J ) 13.5, 4.8 Hz, 1H), 3.81 (s, 3H), 3.99
(dd, J ) 9.3, 2.0 Hz, 1H), 4.40 (dd, J ) 9.3, 7.5 Hz, 1H), 5.00
(dd, J ) 7.5, 2.0 Hz, 1H), 6.93 (dm, J ) 8.7 Hz, 2H), 7.23-
7.39 (m, 7H); 13C NMR (CDCl3, 75.4 MHz) δ 18.4 (CH3), 22.9
(CH2), 30.8 (CH2), 48.6 (CH), 55.1 (CH3), 59.3 (CH), 71.2 (CH2),
95.1 (C), 113.6 (2 CH), 126.3 (2 CH), 127.4 (CH), 128.5 (2 CH),
CH), 136.0 (C), 140.0 (C), 157.7 (C); [R]22 -60.9 (c 1.12,
D
MeOH). 18a ‚hydrochloride: 1H NMR (CDCl3, 200 MHz, broad
signals) δ (most significant signals) 0.87 (d, J ) 6.4 Hz, 3H),
3.00 (tm, J ) 13.0 Hz, 1H), 3.75 (s, 3H), 3.95 (dd, J ) 12.4, 3.2
Hz, 1H), 4.55 (dd, J ) 12.4, 7.2 Hz, 1H), 6.77 (d, J ) 8.4 Hz,
2H), 7.0 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3-CD3OD, 75.4
MHz, broad signals) δ 6.0 (CH3), 21.3 (CH2), 22.5 (CH2), 42.5
(CH2), 46.3 (CH), 55.2 (CH3), 59.0 (CH), 63.5 (CH2), 71.0 (CH),
113.8 (2 CH), 128.5 (CH), 128.7 (2 CH), 129.0 (2 CH), 129.2 (2
CH), 132.9 (C), 144.1 (C), 158.3 (C); [R]22 -75.4 (c 0.65,
D
MeOH); mp 238-240 °C (acetone-MeOH). Anal. Calcd for
C
21H28ClNO2: C, 69.69; H, 7.80; N, 3.87. Found: C, 69.30; H,
7.84; N, 3.88.
(2R,3S)-1-[(1R)-2-Hydr oxy-1-ph en yleth yl]-3-(3-m eth oxy-
p h en yl)-2-m eth ylp ip er id in e (18b). Operating as described
for the reduction of lactam 8a , starting from lactam 16b (348
mg, 1.03 mmol) piperidine 18b (275 mg, 82%) impurified by
trace amounts of the C-2 epimer was obtained after flash
chromatography (9:1 Et2O-hexane). Pure piperidine 18b was
obtained by crystallization of the hydrochloride (acetone-
MeOH). 18b: IR (film) 3410 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.62 (d, J ) 6.6 Hz, 3H), 1.71 (m, 2H), 1.86 (m, 2H), 2.61 (br
s, 1H), 2.71 (td, J ) 11.4, 3.9 Hz, 1H), 2.82 (dm, J ) 11.4 Hz,
129.7 (2 CH), 130.4 (C), 141.6 (C), 158.9 (C), 166.8 (C); [R]22
D
+113.6 (c 1.0, MeOH); mp 95-97 °C (hexanes-Et2O). Anal.
(20) Keto esters 15a and 15b were prepared in 65% yield by reaction
of the corresponding 1-(methoxyphenyl)-2-propanones with methyl
acrylate in the presence of NaH.
J . Org. Chem, Vol. 67, No. 15, 2002 5349

Amat et al.
1H), 3.03 (dt, J ) 11.0, 4.0 Hz, 1H), 3.08 (m, 1H), 3.74 (s, 3H),
3.71-3.80 (m, 2H), 3.91 (dd, J ) 10.5, 5.0 Hz, 1H), 6.65-6.70
(m, 2H), 7.14 (t, J ) 7.8 Hz, 1H), 7.24-7.40 (m, 6H); 13C NMR
(CDCl3, 75.4 MHz) δ 6.5 (CH3), 23.5 (CH2), 25.4 (CH2), 42.6
(CH2), 46.1 (CH), 54.9 (CH), 55.1 (CH3), 63.2 (CH2), 66.5 (CH),
110.6 (CH), 113.9 (CH), 120.2 (CH), 127.5 (CH), 128.2 (2 CH),
converted into piperidine 19b in 91% yield (50 mg): IR (film)
1
3255 cm-1; H NMR (CDCl3, 300 MHz) δ 0.73 (d, J ) 6.9 Hz,
3H), 0.88 (t, J ) 7.2 Hz, 3H), 1.58 (m, 2H), 1.76-1.84 (m, 4H),
2.48 (m, 3H), 2.77 (dm, J ) 11.7 Hz, 1H), 3.28 (m, 1H), 3.60
(m, 1H), 6.65 (d, J ) 7.8 Hz, 1H), 6.74 (dd, J ) 7.8, 2.1 Hz,
1H), 6.84 (s, 1H), 7.18 (t, J ) 7.8 Hz, 1H); 13C NMR (CDCl3,
75.4 MHz) δ 2.9 (CH3), 12.1 (CH3), 18.9 (CH2), 21.5 (CH2), 24.9
(CH2), 41.4 (CH), 46.7 (CH2), 56.4 (CH), 56.7 (CH2), 114.3 (CH),
128.3 (2 CH), 128.8 (CH), 139.8 (C), 145.5 (C), 159.2 (C); [R]22
D
-55.1 (c 0.8, MeOH). 18b‚hydrochloride: 1H-RMN (CDCl3, 300
MHz, broad signals) δ 0.85 (d, J ) 6.9 Hz, 3H), 1.82-2.00 (m,
4H), 2.80 (m, 1H), 3.06 (m, 1H), 3.53 (m, 1H), 3.72 (s, 3H),
3.95 (dm, J ) 12.3 Hz, 1H), 4.06 (s, 1H), 4.16 (dm, J ) 13.0
Hz, 1H), 4.36 (dm, J ) 13.0 Hz, 1H), 4.57 (m, 1H), 4.78 (br s,
1H), 6.59 (s, 1H), 6.66 (d, J ) 8.0 Hz, 1H), 6.72 (dd, J ) 8.0,
2.1 Hz, 1H), 7.15 (t, J ) 8.0 Hz, 1H), 7.42 (m, 3H), 7.77 (d, J
) 6.0 Hz, 2H); 13C NMR (CDCl3, 75.4 MHz) δ 5.4 (CH3), 20.7
(CH2), 22.3 (CH2), 42.6 (CH2), 47.0 (CH), 55.2 (CH3), 59.1 (CH),
63.2 (CH2), 71.7 (CH), 112.2 (CH), 113.7 (CH), 119.9 (CH),
129.3 (2 CH), 129.4 (CH), 129.6 (2 CH), 132.5 (C), 142.0 (C),
114.5 (CH), 117.0 (CH), 129.7 (CH), 144.2 (C), 157.1 (C); [R]22
D
+4.8 (c 0.28, MeOH). 19b‚hydrochloride: 1H NMR (CDCl3, 300
MHz) δ (most significant signals) 0.97 (br, 3H), 6.62 (d, J )
7.8 Hz, 1H), 6.85 (d, J ) 7.8 Hz, 1H), 7.00 (br, 1H), 7.14 (t, J
) 7.8 Hz, 1H); 13C NMR (CDCl3-CD3OD, 75.4 MHz) δ 5.0
(CH3), 11.2 (CH3), 17.4 (CH2), 20.5 (CH2), 22.8 (CH2), 42.7 (CH),
46.5 (CH2), 56.4 (CH2), 59.6 (CH), 114.7 (CH), 114.9 (CH), 117.6
(CH), 129.6 (CH), 140.7 (C), 157.2 (C); mp 170-172 °C (EtOH-
Et2O). Anal. Calcd for C15H24ClNO‚1/3H2O: C, 65.33; H, 9.01;
N, 5.08. Found: C, 65.02; H, 9.33; N, 5.10.
160.1 (C); [R]22 -18.5 (c 0.5, MeOH); mp 168-170 °C. Anal.
D
(2S,3R)-1-[(1R)-2-Hydr oxy-1-ph en yleth yl]-3-(4-m eth oxy-
p h en yl)-2-m eth ylp ip er id in e (20a ). Operating as described
in the preparation of 18, starting from 17a (224 mg, 0.66
mmol) piperidine 20a (188 mg, 87%) impurified with trace
amounts of its C-2 epimer was obtained after flash chroma-
tography (Et2O). Pure piperidine 20a was obtained by crystal-
lization of the hydrochloride (acetone-MeOH). 20a : IR (film)
Calcd for C21H28ClNO2: C, 69.69; H, 7.80; N, 3.87. Found: C,
69.29; H, 7.79; N, 3.77.
(2R,3S)-3-(4-Hyd r oxyp h en yl)-2-m eth yl-1-p r op ylp ip er i-
d in e (19a ). Operating as described in the preparation of 11,
piperidine 18a (200 mg, 0.62 mmol) was converted to the
corresponding N-propylpiperidine, which was obtained in 79%
yield (120 mg) after flash chromatography (95:5 Et2O-DEA):
1H NMR (CDCl3, 300 MHz) δ 0.69 (d, J ) 6.6 Hz, 3H), 0.96 (t,
J ) 7.2 Hz, 3H), 1.60 (m, 2H), 1.70-1.90 (m, 4H), 2.40-2.54
(m, 3H), 2.67 (dt, J ) 11.7, 4.2 Hz, 1H), 3.11-3.24 (m, 2H),
3.83 (s, 3H), 6.89 (dm, J ) 8.4 Hz, 2H), 7.19 (dm, J ) 8.4 Hz,
2H); 13C NMR (CDCl3, 75.4 MHz) δ 3.8 (CH3), 12.0 (CH3), 20.7
(CH2), 23.2 (CH2), 25.5 (CH2), 45.0 (CH), 45.7 (CH2), 55.2 (CH3),
57.1 (CH2), 58.0 (CH), 113.5 (2 CH), 128.6 (2 CH), 136.3 (C),
1
3410 cm-1; H NMR (CDCl3, 300 MHz) δ 0.64 (d, J ) 7.0 Hz,
3H), 1.59-1.92 (m, 4H), 2.48 (td, J ) 11.4, 2.8 Hz, 1H), 2.66
(dm, J ) 11.4 Hz, 1H), 3.13 (dt, J ) 12.4, 3.6 Hz, 1H), 3.34
(m, 1H), 3.69 (dd, J ) 8.7, 3.3 Hz, 1H), 3.72-3.84 (m, 2H),
3.78 (s, 3H), 6.85 (dm, J ) 8.7 Hz, 2H), 7.09 (dm, J ) 8.7 Hz,
2H), 7.27-7.37 (m, 5H); 13C NMR (CDCl3, 75.4 MHz) δ 6.4
(CH3), 22.7 (CH2), 26.0 (CH2), 40.8 (CH2), 45.5 (CH), 55.2 (CH3),
58.8 (CH), 62.1 (CH2), 68.7 (CH), 113.5 (2 CH), 127.7 (CH),
128.4 (2 CH), 128.5 (2 CH), 128.7 (2 CH), 135.7 (C), 139.8 (C),
157.7 (C); [R]22 +5.3 (c 0.89, MeOH); HRMS calcd for
D
C
16H25NO 247.1936, found 247.1941. Operating as described
157.8 (C); [R]22 -29.1 (c 1.3, MeOH). 20a ‚hydrochloride: IR
D
1
in the preparation of (-)-3-PPP, the above N-propylpiperidine
(90 mg, 0.36 mmol) was converted into piperidine 19a in 94%
yield (80 mg): IR (film) 3220 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.72 (d, J ) 6.9 Hz, 3H), 0.89 (t, J ) 7.2 Hz, 3H), 1.64 (m,
3H), 1.79 (m, 3H), 2.48 (m, 3H), 2.75 (dm, J ) 11.1 Hz, 1H),
3.17 (m, 1H), 3.38 (m, 1H), 6.83 (d, J ) 8.4 Hz, 2H), 7.19 (d, J
) 8.4 Hz, 2H), 7.75 (br s, 1H); 13C NMR (CDCl3, 75.4 MHz) δ
3.3 (CH3), 11.9 (CH3), 19.4 (CH2), 22.1 (CH2), 24.7 (CH2), 43.8
(CH), 45.9 (CH2), 56.9 (CH2), 57.5 (CH), 115.6 (2 CH), 128.5
(film) 3412 cm-1; H NMR (CDCl3, 300 MHz; two epimers at
the nitrogen atom were observed) δ (most significant signals
for the major epimer)1.21 (d, J ) 7.0 Hz, 3H), 2.78 (tm, J )
12.5 Hz, 1H), 2.90 (dm, J ) 12.5 Hz, 1H), 3.82 (s, 3H), 6.90 (d,
J ) 9.0 Hz, 2H), 7.24 (d, J ) 9.0 Hz, 2H); δ (most significant
signals for the minor epimer)1.14 (d, J ) 7.0 Hz, 3H), 3.75 (s,
3H), 6.70 (d, J ) 9.0 Hz, 2H), 6.76 (d, J ) 9.0 Hz, 2H); 13C
NMR (CDCl3, 75.4 MHz; two epimers at the nitrogen atom
were also observed) δ (major epimer) 5.3 (CH3), 20.3 (CH2),
22.7 (CH2), 41.7 (CH), 45.4 (CH2), 54.9 (CH3), 60.6 (CH), 61.4
(CH2), 69.4 (CH), 113.7 (2 CH), 127.6 (CH), 128.3 (2 CH), 129.3
(2 CH), 129.6 (2 CH), 131.6 (C), 132.7 (C), 158.3 (C); δ (minor
epimer) 10.0 (CH3), 18.2 (CH2), 20.2 (CH2), 36.0 (CH), 43.5
(CH2), 54.8 (CH3), 58.5 (CH), 63.0 (CH2), 66.5 (CH), 113.8 (2
CH), 127.8 (CH), 128.6 (2 CH), 129.6 (2 CH), 129.8 (2 CH),
130.1 (C), 132.7 (C), 158.3 (C); mp 247-250 °C (acetone-
MeOH). Anal. Calcd for C21H28ClNO2: C, 69.69; H, 7.80; N,
3.87. Found: C, 69.39; H, 7.85; N, 3.93.
(2 CH), 133.8 (C), 155.4 (C); [R]22 +3.7 (c 1.0, MeOH). 19a ‚
D
hydrochloride: 1H NMR (CDCl3, 300 MHz) δ 1.0 (d, J ) 7.0
Hz, 3H), 1.01 (t, J ) 7.0 Hz, 3H), 1.81-2.05 (m, 6H), 2.20 (m,
1H), 2.85-3.00 (m, 3H), 3.32 (dm, J ) 10.5 Hz, 1H), 3.67 (m,
1H), 3.90 (br s, 1H), 6.82 (d, J ) 8.4 Hz, 2H), 7.05 (d, J ) 8.4
Hz, 2H); 13C NMR (CDCl3, 75.4 MHz) δ 5.0 (CH3), 10.9 (CH3),
17.4 (CH2), 20.7 (CH2), 22.5 (CH2), 41.7 (CH), 46.1 (CH2), 55.8
(CH2), 59.3 (CH), 115.3 (2 CH), 128.3 (2 CH), 130.2 (C), 155.8
(C); mp 270-272 °C (EtOH-hexane). Anal. Calcd for C15H24
-
ClNO: C, 66.77; H, 8.97; N, 5.19. Found: C, 66.83; H, 9.08;
N, 5.04.
(2S,3R)-1-[(1R)-2-Hydr oxy-1-ph en yleth yl]-3-(3-m eth oxy-
p h en yl)-2-m eth ylp ip er id in e (20b). Operating as described
in the preparation of 18, starting from 17b (93 mg, 0.27 mmol)
piperidine 20b (57 mg, 64%) impurified with trace amounts
of its C-2 epimer was obtained after flash chromatography (7:3
Et2O-hexane). Pure piperidine 20b was obtained by crystal-
lization of the hydrochloride (acetone-MeOH). 20b: IR (KBr)
(2R,3S)-3-(3-Hyd r oxyp h en yl)-2-m eth yl-1-p r op ylp ip er i-
d in e (19b). Operating as described in the preparation of 11,
piperidine 18b (144 mg, 0.44 mmol) was converted to the
corresponding N-propylpiperidine, which was obtained in 74%
yield (81 mg) after flash chromatography (4:1 Et2O-hexane):
1H NMR (CDCl3, 300 MHz) δ 0.65 (d, J ) 6.6 Hz, 3H), 0.91 (t,
J ) 7.8 Hz, 3H), 1.53 (m, 2H), 1.65-1.91 (m, 4H), 2.39 (t, J )
7.8 Hz, 2H), 2.46 (td, J ) 11.7, 3.6 Hz, 1H), 2.60 (dt, J ) 11.7,
2.7 Hz, 1H), 3.11 (dt, J ) 12.0, 3.6 Hz, 1H), 3.19 (m, 1H), 3.79
(s, 3H), 6.74 (ddd, J ) 7.8, 2.4, 0.6 Hz, 1H), 6.79-6.83 (m, 2H),
7.23 (t, J ) 7.8 Hz, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 3.9
(CH3), 12.1 (CH3), 20.9 (CH2), 23.1 (CH2), 25.6 (CH2), 45.7
(CH2), 45.9 (CH), 55.1 (CH3), 57.2 (CH2), 57.9 (CH), 110.7 (CH),
1
3232 cm-1; H NMR (CDCl3, 300 MHz) δ 0.65 (d, J ) 6.6 Hz,
3H), 1.59-1.91 (m, 4H), 2.50 (td, J ) 12.0, 2.7 Hz, 1H), 2.70
(dm, J ) 12.0 Hz, 1H), 3.15 (dt, J ) 13.0, 3.6 Hz, 1H), 3.39
(m, 1H), 3.67 (dd, J ) 10.0, 5.4 Hz, 1H), 3.72-3.70 (m, 2H),
3.79 (s, 3H), 6.70-6.75 (m, 3H), 7.18-7.35 (m, 6H); 13C NMR
(CDCl3, 75.4 MHz) δ 6.7 (CH3), 22.7 (CH2), 26.2 (CH2), 40.7
(CH2), 46.5 (CH), 55.1 (CH3), 58.7 (CH), 62.2 (CH2), 68.7 (CH),
110.9 (CH), 113.6 (CH), 120.0 (CH), 127.6 (CH), 128.3 (2 CH),
113.9 (CH), 120.2 (CH), 128.9 (CH), 146.1 (C), 159.3 (C); [R]22
128.7 (2 CH), 129.0 (CH), 140.1 (C), 145.4 (C), 159.4 (C); [R]22
D
D
+4.2 (c 1.2, MeOH); HRMS calcd for C16H25NO 247.1936, found
247.1930. Operating as described in the preparation of (-)-3-
PPP, the above N-propylpiperidine (58 mg, 0.23 mmol) was
-18.1 (c 1.4, MeOH); mp 216-218 °C (THF-hexane). Anal.
Calcd for C21H27NO2: C, 77.50; H, 8.36; N, 4.30. Found: C,
77.67; H, 8.42; N, 4.60. 20b‚hydrochloride: 1H NMR (CDCl3,
5350 J . Org. Chem., Vol. 67, No. 15, 2002

Enantioselective Synthesis of 3-Arylpiperidines
300 MHz; two epimers at the nitrogen atom were observed) δ
(most significant signals for the major epimer) 1.16 (d, J )
6.9 Hz, 3H), 3.80 (s, 3H); δ (most significant signals for the
minor epimer) 1.25 (d, J ) 7.2 Hz, 3H), 3.64 (s, 3H); 13C NMR
(CDCl3, 75.4 MHz; two epimers at the nitrogen atom were also
observed) δ (major epimer) 6.08 (CH3), 20.4 (CH2), 22.9 (CH2),
42.3 (CH), 45.5 (CH2), 55.3 (CH3), 61.9 (CH), 62.1 (CH2), 70.7
(CH), 112.2 (CH), 113.8 (CH), 120.1 (CH), 129.5 (2 CH), 129.8
(2 CH), 130.0 (CH), 131.9 (C), 141.7 (C), 159.8 (C); δ (minor
epimer) 10.0 (CH3), 18.2 (CH2), 20.2 (CH2), 37.1 (CH), 44.2
(CH2), 55.3 (CH3), 58.5 (CH), 63.7 (CH2), 67.4 (CH), 112.6 (CH),
113.8 (CH), 119.1 (CH), 129.6 (2 CH), 129.8 (2 CH), 130.0 (CH),
132.0 (CH), 141.5 (C), 159.8 (C).
(2S,3R)-3-(4-Hyd r oxyp h en yl)-2-m eth yl-1-p r op ylp ip er i-
d in e (en t-19a ). Following the procedure described above from
18, starting from 20a (86 mg, 0.26 mmol) (2S,3R)-3-(4-
methoxyxyphenyl)-2-methyl-1-propylpiperidine (52 mg, 80%)
was obtained after flash chromatography: [R]22D -5.7 (c 0.75,
MeOH). This compound (45 mg, 0.2 mmol) was O-demeth-
ylated as described for the preparation of 19a to give pure ent-
19a (27 mg, 66%) after flash chromatography: [R]22 -4.1 (c
D
1.31, MeOH).
Ack n ow led gm en t. This work was supported by the
DGICYT, Spain (BQU2000-0651). Thanks are also due
to the DURSI, Generalitat de Catalunya, for Grant
2001SGR-0084 and a fellowship to M.C. We thank DSM
Deretil (Almer´ıa, Spain) for the generous gift of (R)-
phenylglycine.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 2-6, 8a , 9a , 10-14, (-)-3-P P P , 16a -
20a , 16b-19b, and (2R,3S)-3-[4-(and 3-)methoxyphenyl]-2-
methyl-1-propylpiperidine, and ORTEP diagrams and X-ray
crystallographic data of compounds 10 and 16b. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O025894F
J . Org. Chem, Vol. 67, No. 15, 2002 5351