Synthesis of Enantiopure trans-3,4-Disubstituted Piperidines. An Enantiodivergent Synthesis of (+)- And (-)-Paroxetine

Article abstract of DOI:10.1021/jo991816p

Reaction of (R)-phenylglycinol with methyl 5-oxopentanoate gave either bicyclic lactam cis-1 (the kinetic product) or its isomer trans-1 (under equilibrating conditions) as the major products, which were converted to the corresponding (cis or trans) unsaturated lactams 4 and 5. On treatment with lithium alkyl (or aryl) cyanocuprates, these chiral building blocks undergo conjugate addition to give enantiopure trans-3,4-substituted 2-piperidone derivatives in high yield and stereoselectivity. The synthetic potential of this transformation is illustrated by the synthesis of (+)-femoxetine and the two enantiomers of the known antidepressant paroxetine.

Full text of DOI:10.1021/jo991816p

3074
J . Org. Chem. 2000, 65, 3074-3084
Syn th esis of En a n tiop u r e tr a n s-3,4-Disu bstitu ted P ip er id in es. An
En a n tiod iver gen t Syn th esis of (+)- a n d (-)-P a r oxetin e
Mercedes Amat,*,† J oan Bosch,† J ose´ Hidalgo,† Margalida Canto´,† Maria Pe´rez,† Nu´ria Llor,†
Elies Molins,‡ Carles Miravitlles,‡ Modesto Orozco,§ and J avier Luque|
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona,
08028-Barcelona, Spain; Institut de Cie`ncia de Materials (CSIC), Campus UAB,
08193-Cerdanyola, Spain; Department of Biochemistry and Molecular Biology,
Faculty of Chemistry, University of Barcelona, 08028-Barcelona, Spain; and Department of
Physical Chemistry, Faculty of Pharmacy, University of Barcelona, 08028-Barcelona, Spain
Received November 23, 1999
Reaction of (R)-phenylglycinol with methyl 5-oxopentanoate gave either bicyclic lactam cis-1 (the
kinetic product) or its isomer trans-1 (under equilibrating conditions) as the major products, which
were converted to the corresponding (cis or trans) unsaturated lactams 4 and 5. On treatment
with lithium alkyl (or aryl) cyanocuprates, these chiral building blocks undergo conjugate addition
to give enantiopure trans-3,4-substituted 2-piperidone derivatives in high yield and stereoselectivity.
The synthetic potential of this transformation is illustrated by the synthesis of (+)-femoxetine and
the two enantiomers of the known antidepressant paroxetine.
Sch em e 1
The piperidine nucleus can be frequently recognized
in the structure of numerous naturally occurring alka-
loids and synthetic compounds with interesting biological
and pharmacological properties. As a consequence, the
development of general methods for the enantioselective
synthesis of piperidine derivatives has been the subject
of considerable synthetic efforts.1 In previous reports from
this laboratory we have described our studies in the
enantioselective preparation of diversely substituted
piperidines from a common synthetic intermediate, the
bicyclic lactam trans-1, which have resulted in the
synthesis of 2-alkyl [(R)-coniine],2 cis-2,6-dialkyl [(2R,6S)-
dihydropinidine],3 trans-2,6-dialkyl [lupetidine, solenop-
sin A],4 and 3-alkyl [(R)-decarbomethoxytetrahydrosec-
odine]5 substituted piperidine alkaloids. In this paper we
describe the enantioselective preparation of trans-3,4-
disubstituted piperidines by conjugate addition of cyano-
cuprates to R,â-unsaturated lactams derived from both
the bicyclic lactam trans-1 and its C-8a epimer cis-1, and
the application of this methodology to the enantioselec-
tive synthesis of the antidepressive drugs (+)-femoxetine
and the two enantiomers of paroxetine.6
Chiral, nonracemic bicyclic lactams have been exten-
sively employed by Meyers for the synthesis of enan-
tiopure carbocycles and carboxylic acids containing qua-
ternary stereocenters7 and, more recently, nitrogen-
containing heterocycles.8 Although cyclodehydration of
γ- or δ-keto acids and amino alcohols constitutes an
excellent procedure for the synthesis of angular-substi-
tuted bicyclic lactams,7a,9 the use of aldehyde acids under
the same conditions is less satisfactory, and alternative
methods for the preparation of angular hydrogen lactams
have been described.9 Nevertheless, in our hands, heating
a toluene solution of (R)-phenylglycinol and methyl
5-oxopentanoate at reflux temperature for 36 h under
neutral conditions, with azeotropic removal of water,
afforded a 85:15 mixture of bicyclic lactams cis-1 and
trans-1, respectively, in 86% overall yield (Scheme 1).
These lactams were efficiently separated by column
chromatography. On the other hand, when a solution of
lactam cis-1 and TFA in dichloromethane was stirred for
64 h at 25 °C, a 14:86 mixture of cis-1 and trans-1 was
recovered quantitatively. Thus, pure lactam cis-1 can be
directly obtained by cyclodehydration whereas lactam
trans-1 is accessible by cyclodehydration followed by
* E-mail: amat@farmacia.far.ub.es.
† Laboratory of Organic Chemistry.
‡ Institut de Cie`ncia de Materials.
§ Department of Biochemistry and Molecular Biology.
| Department of Physical Chemistry.
(1) (a) J ones, T. H.; Blum, M. S. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1983;
Vol. 1, Chapter 2, pp 33-84. (b) 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. (c) Strunz, G. M.;
Findlay, J . A. In The Alkaloids; Brossi, A., Ed.; Academic Press:
London, 1985; Vol. 26, Chapter 3, pp 89-183. (d) Angle, R. S.;
Breitenbucher, J . G. In Studies in Natural Products Chemistry.
Stereoselective Synthesis (Part J ); Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, 1995; Vol. 16, pp 453-502. (e) Schneider, M. J . In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1996; Vol. 10, Chapter 3, pp 155-355.
(2) Amat, M.; Llor, N.; Bosch, J . Tetrahedron Lett. 1994, 35, 2223.
(3) Amat, M.; Llor, N.; Hidalgo, J .; Herna´ndez, A.; Bosch, J .
Tetrahedron: Asymmetry 1996, 7, 977.
(6) For a preliminary account of a part of this work, see: Amat, M.;
Hidalgo, J .; Bosch, J . Tetrahedron: Asymmetry 1996, 7, 1845.
(7) For reviews, see: a) Romo, D.; Meyers, A. I. Tetrahedron 1991,
47, 9503. (b) Meyers, A. I. In Stereocontrolled Organic Synthesis; Trost,
B. M., Ed.; Blackwell Scientific Publications: Oxford, 1994; pp 145-
161.
(4) Amat, M.; Hidalgo, J .; Llor, N.; Bosch, J . Tetrahedron: Asym-
metry 1998, 9, 2419.
(5) Amat, M.; Pshenichnyi, G.; Bosch, J .; Molins, E.; Miravitlles, C.
Tetrahedron: Asymmetry 1996, 7, 3091.
(8) For a review, see: Meyers, A. I.; Brengel, G. P. Chem. Commun.
1997, 1.
(9) Meyers, A. I.; Lefker, B. A.; Sowin, T. J .; Westrum, L. J . J . Org.
Chem. 1989, 54, 4243.
10.1021/jo991816p CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/20/2000

Enantiopure trans-3,4-Disubstituted Piperidines
J . Org. Chem., Vol. 65, No. 10, 2000 3075
Sch em e 2a
dition products 8 and 9 were obtained in 65% and 63%
yield, respectively, as approximately 3:1 mixtures of 6,7-
trans (series a ) and 6,7-cis (series b) C-6 epimers. In some
runs, small amounts (<5%) of pyridone 6 were isolated.
Similarly, addition of arylcyanocuprates (lithium phenyl-
or p-fluorophenylcyanocuprate) to the unsaturated lac-
tam trans-4 afforded the corresponding conjugate addi-
tion products 10 and 11, although in higher yield (70-
75%) and stereoselectivity (ratio a :b 97:3, determined by
1
300-MHz H NMR). Even slightly better chemical yields
(>80%) were obtained when the reaction with arylcy-
anocuprates was carried out from the R-methoxycarbonyl
unsaturated lactam trans-5. To confirm that compounds
8a -13a and 8b-13b, obtained in the above conjugate
addition reactions, were isomers at the epimerizable C-6
carbon, the mixtures of R-benzyloxycarbonyl compounds
8a b, 9a b, and 11a b were subjected to hydrogenolysis
with subsequent decarboxylation of the resulting â-keto
acid. Compounds 14, 15, and 16 were obtained as single
isomers detectable by NMR, making evident the high
stereoselectivity in the diastereofacial addition of the
cuprates on the Si face of the electrophilic carbon of the
double bond. On the other hand, the absolute stereo-
chemical outcome of the cuprate additions was unam-
biguously proven by X-ray diffraction techniques from a
crystal of 12a .14 Thus, compounds 8a -13a are 6R,7S
whereas the isomers 8b-13b are 6S,7S.
a
Reagents and conditions: (i) LHMDS, ClCO2R, PhSeBr, THF,
-78 °C, 77% (trans-2), 96% (trans-3); (ii) O3, CH2Cl2, -78 °C, then
O2, 25 °C; (iii) R′Cu(CN)Li, THF, -78 °C, 65% (8), 63% (9), 72%
(10), 70% (11), 86% (12), 80% (13); (iv) HCO2NH4, Pd-C, MeOH,
25 °C, then toluene, reflux, 73% (14), 74% (15), 98% (16).
Next we decided to study the addition of organocu-
prates to the C-8a epimeric R,â-unsaturated lactams cis-4
and cis-5, which were prepared from the bicyclic lactam
cis-1, via the seleno derivatives cis-2 and cis-3, following
the same procedure described above for the corresponding
trans isomers (Scheme 3). Addition of lithium methylcy-
anocuprate to cis-4 afforded a 3:1 mixture of isomers 17a
(trans) and 17b (cis) in 64% overall yield, which, by
hydrogenolysis followed by decarboxylation in refluxing
toluene, were converted to the methyl derivative 21 as a
single stereoisomer. This result again makes evident the
high stereoselectivity in the cuprate addition to the R,â-
unsaturated dicarbonyl moiety of cis-4. Similarly, com-
pounds 18-20 were obtained as 97:3 mixtures of isomers
by addition of arylcyanocuprates to the unsaturated
lactams cis-4 or cis-5.
equilibration under acidic conditions of the initially
formed reaction mixture.10
Since simple R,â-unsaturated lactams are known to be
poor Michael acceptors,11 we decided to use the unsatur-
ated lactams trans-4 and trans-5, in which the presence
of an additional electron-withdrawing substituent on the
R position would enhance the reactivity of the conjugated
system,12 thus allowing the efficient addition of organo-
cuprates. These lactams were prepared in excellent
overall yield by sequential treatment of trans-1 with
LHMDS (2.2 equiv), benzyl or methyl chloroformate (1.0
equiv), respectively, and phenylselanyl bromide (1.4
equiv), followed by ozonolysis of the resulting selenides
trans-2 and trans-3 under neutral conditions (Scheme 2).
Interestingly, when oxidation of these intermediate
selenides was effected with m-CPBA, the corresponding
6,7-epoxides were formed instead.13 Lactams trans-4 and
trans-5 proved to be sensitive to both mild acid and basic
conditions, affording the corresponding pyridones 6 and
7, respectively. For this reason, they were prepared
immediately before the next reaction and used without
further purification. In this manner, when trans-4 was
treated with alkylcyanocuprates (lithium methyl- or
n-butylcyanocuprate), the corresponding conjugate ad-
To compare the stereochemical outcome of the conju-
gate addition to the trans and cis isomers of unsaturated
lactams 4 and 5, compounds 12a and 18a were treated
with alane (LiAlH4/AlCl3), which caused the cleavage of
the C-O bond of the oxazolidine ring and the simulta-
(14) The experiment was done on a 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) corrections. Full-matrix least
squares refinement (SHELXL-93) using anisotropic thermal param-
eters for non-H atoms and a global isotropic thermal parameters for
H-atoms (positioned at calculated positions) converged to a R factor of
0.075 (for 12a ) and 0.057 (for 22) (calculated for the reflections with I
> 2σ(I)). Complete data have been deposited at the Cambridge
Crystallographic Data Centre. 12a : Crystal data: C21H21NO4, mono-
clinic, space group P212121, a ) 5.947(2) Å, b ) 7.876(2) Å, c ) 38.968-
(7) Å, V ) 1825.2 Å3, µ (Mo KR) ) 0.089 mm-1, Dc ) 1.279 g/cm3.
Approximate dimensions: 0.29 × 0.16 × 0.15 mm. Data collection was
up to a resolution of 2θ ) 50° producing 1902 reflections. Maximum
and minimum heights at the final difference Fourier synthesis were
0.301 and -0.324 eÅ-3. 22: Crystal data: C20H25NO2, monoclinic, space
group C2, a ) 21.889(3) Å, b ) 5.876(1) Å, c ) 13.842(2) Å, V ) 1780.2-
(5) Å3, µ (Mo KR) ) 0.074 mm-1, Dc ) 1.162 g/cm3. Approximate
dimensions: 0.35 × 0.10 × 0.10 mm. Data collection was up to a
resolution of 2θ ) 50° producing 1569 reflections. Maximum and
minimum heights at the final difference Fourier synthesis were 0.249
(10) Bicyclic lactams trans-1 and cis-1 have also been prepared by
alternative multistep sequences: (a) Royer, J .; Husson, H.-P. Hetero-
cycles 1993, 36, 1493. (b) Micouin, L.; Quirion, J .-C.; Husson, H.-P.
Synth. Commun. 1996, 26, 1605.
(11) (a) Nagashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K. Tetra-
hedron Lett. 1985, 26, 657. (b) Hagen, T. J . Synlett 1990, 63.
(12) The presence of an alkoxycarbonyl group facilitates the conju-
gate addition of organocuprates to unsaturated five-12a,b and six-
membered12c lactams: (a) Meyers, A. I.; Snyder, L. J . Org. Chem. 1992,
57, 3814. (b) Meyers, A. I.; Snyder, L. J . Org. Chem. 1993, 58, 36. (c)
Overman, L. E.; Robichaud, A. J . J . Am. Chem. Soc. 1989, 111, 300.
See also: Amat, M.; Llor, N.; Bosch, J .; Solans, X. Tetrahedron 1997,
53, 719.
(13) Amat, M.; Llor, N.; Hidalgo, J .; Bosch, J .; Molins, E.; Miravitlles,
C. Tetrahedron: Asymmetry 1996, 7, 2501.
and -0.168 eÅ-3
.

3076 J . Org. Chem., Vol. 65, No. 10, 2000
Amat et al.
Sch em e 3a
Sch em e 5a
a
Reagents and conditions: (i) LHMDS, ClCO2R, PhSeBr, THF,
-78 °C, 77% (cis-2), 81% (cis-3); (ii) O3, CH2Cl2, -78 °C; then O2,
25 °C; (iii) R′Cu(CN)Li, THF, -78 °C, 64% (17), 75% (18), 64% (19),
67% (20); (iv) HCO2NH4, Pd-C, MeOH, 25 °C, then toluene, reflux,
85%.
a
Reagents and conditions: (i) AlCl3, LiAlH4, THF, -78 °C to
25 °C, 50% (30), 75% (31); (ii) H2, (t-BuOCO)2O, 20% Pd(OH)2-C,
AcOEt, 25 °C, 57%; (iii) MsCl, pyr, 10 °C, then NaH, Ar-OH, THF,
reflux, 66%; (iv) TFA, CH2Cl2, rt, 72%.
Sch em e 4a
F igu r e 1.
shielding the corresponding signal in the 13C NMR
spectra by about 7 ppm (see Figure 1). Moreover, due to
the anisotropic affect of the phenyl group, the axial H-2
proton in 22 and H-6 proton in 30 are shielded by about
1
0.6 ppm in the H NMR spectra as compared with the
axial proton on the alternative position R to the nitrogen.
The diastereomeric nature of the trans-3,4-substituted
piperidines 22 and 30 confirms that the conjugate addi-
tion of cyanocuprates to the above trans and cis R,â-
unsaturated lactams takes place stereoselectively on
different faces (Si and Re, respectively) of the double
bond. These results deserve attention because lactams 4
and 5 are derived from the same chiral inductor, (R)-
phenylglycinol; removal of the chiral substituent on the
piperidine nitrogen from the above diastereomeric trans-
3,4-substituted piperidines would provide the two enan-
tiomers in an enantiodivergent process.
To understand the origin of the stereoselectivity in the
conjugate addition of cyanocuprates to the carbon-carbon
double bond in the cis and trans isomers of lactams 4
and 5, we examined the reactivity pattern of the cis and
trans isomers of the model unsaturated bicyclic lactam
A from GMIPp15,16 calculations (see Computational Meth-
ods). To this end, we determined the GMIPp interaction
energy profile for the approach of a negatively charged
classical point particle along the line perpendicular to
the six-membered ring passing through carbon atoms 6
and 7. The GMIPp values and their components are given
in Table 1.
a
Reagents and conditions: (i) AlCl3, LiAlH4, THF, -78 °C to
25 °C, 86% (22), 74% (24); (ii) H2, (t-BuOCO)2O, 20% Pd(OH)2-C,
AcOEt, 25 °C, 88% (23), 73% (25); (iii) MsCl, pyr, 10 °C, then NaH,
Ar-OH, THF, reflux, 50% (26), 56% (28); (iv) LiAlH4, Et2O, 0 °C,
74%; (v) TFA, CH2Cl2, rt, 77%.
neous reduction of the ester and amide carbonyl groups
to give the alcohols 22 (Scheme 4) and 30 (Scheme 5),
respectively, as the only stereoisomers detectable by
NMR. The trans relative stereochemistry of the hy-
droxymethyl and phenyl substituents of piperidines 22
and 30 was inferred by NMR, and for compound 22 it
was confirmed by X-ray crystallography.14 In these pi-
peridines the formation of a hydrogen bond between the
nitrogen atom and the hydroxy group of the (R)-1-phenyl-
2-hydroxyethyl substituent situates the phenyl group
near one of the R carbons of the piperidine ring, thus
Inspection of the total interaction energies clearly
shows the different susceptibility of the two faces of the
(15) Orozco, M.; Luque, F. J . In Molecular Electrostatic Potentials:
Concepts and Applications; Murray, J . S.; Sen, K., Eds.; Elsevier:
Amsterdam, 1996; pp 181-218.
(16) Luque, F. J .; Orozco, M. J . Comput. Chem. 1998, 19, 866.

Enantiopure trans-3,4-Disubstituted Piperidines
J . Org. Chem., Vol. 65, No. 10, 2000 3077
Ta ble 1. Electr osta tic (Eele), P ola r iza tion (Ep ol), va n d er Wa a ls (EvW), a n d Tota l In ter a ction En er gy (Etota l) Deter m in ed
fr om GMIP p Ca lcu la tion s for th e Atta ck of a Nega tively Ch a r ged Cla ssica l P oin t Ch a r ge to th e Si a n d Re F a ces of th e
Ca r bon -Ca r bon Dou ble Bon d in cis-A a n d tr a n s-Aa
face Re
face Si
Eele
Epol
EvW
Etotal
Eele
Epol
EvW
Etotal
Attack on C-7
-14.5
cis-A
-4.9
-0.7
-1.8
-12.2
-10.7
-10.7
+2.5
+3.0
+2.6
+1.0
-4.9
-3.3
-11.6
-12.4
-12.3
+2.3
+1.7
+2.2
-8.3
-15.6
-13.3
trans-Ab
trans-Ac
-8.5
-9.9
Attack on C-6
-10.7
cis-A
-0.7
+6.2
+4.4
-11.3
-10.7
-10.7
+1.3
+1.4
+1.3
+8.0
-0.7
+1.8
-11.5
-12.3
-11.5
+1.1
+1.0
+1.1
-2.4
-12.0
-8.7
trans-Ab
trans-Ac
-3.1
-4.9
a
b
All values are in kcal/mol. Conformation with C-2 down. c Conformation with C-2 up.
double bond to the attack of a nucleophilic reagent. Thus,
in cis-A the attack on the Re face is energetically more
favorable than on the Si face. Conversely, a nucleophilic
attack on the Si face is preferred in trans-A. Comparison
of the GMIPp energetic contributions for the attack on
each face shows that the origin of such a preference lies
mainly in the electrostatic term, which favors the ap-
proach of the nucleophile by the Re face in cis-A, whereas
the reverse trend is found for trans-A. As it could be
expected, the results in Table 1 also show that for a given
isomer the attack on C-7 is energetically preferred to the
attack on C-6.
The synthetic potential of this transformation is il-
lustrated by the synthesis of (+)-femoxetine and the two
enantiomers of the known antidepressant paroxetine.
Femoxetine (27) and paroxetine (29)17 are closely related
serotonin (5-hydroxytryptamine) reuptake inhibitors,
which have been used clinically for the treatment of
depression.18 For the eutomer of paroxetine, the configu-
rations at the C-3 and C-4 stereocenters are 3S,4R,
whereas for femoxetine they are 3R,4S.19 The method for
obtaining the requisite configuration of these compounds
in enantiopure form employs the chemical or enzymatic
resolution of a racemic intermediate, although very
recently an enantioselective synthesis of femoxetine and
paroxetine involving the stereoselective conjugate addi-
tion to a 1,2,5,6-tetrahydro-3-pyridyl ester derived from
a chiral alcohol has been reported.20
subsequent nucleophilic substitution with the sodium salt
of p-methoxyphenol, and finally LiAlH4 reduction of the
protecting N-tert-butoxycarbonyl group in the resulting
aryl ether 26 (Scheme 4).
On the other hand, alane reduction of the p-fluoro-
phenyl derivative 13a afforded the trans piperidine 24,
which was converted into alcohol 25 by hydrogenolysis
in the presence of di-tert-butyl dicarbonate. Mesylation
of this alcohol, followed by reaction with the sodium salt
of sesamol gave 28, which, on treatment with TFA,
afforded the secondary amine 29. The spectroscopic data
of 29 were coincident with those found for a sample of
paroxetine obtained from commercial Seroxat except for
the sign of the specific rotation.
Finally, the synthesis of the eutomer of paroxetine was
accomplished from esters 19a and 20a . As in the above
series, alane reduction brought about the cleavage of the
oxazolidine ring and the reduction of the ester and lactam
carbonyl groups to give the enantiopure trans piperidine
31, which was converted to (-)-paroxetine (ent-29) fol-
lowing a synthetic sequence parallel to that previously
performed in the opposite enantiomeric series (Scheme
5).
In summary, we have developed an enantiodivergent
synthesis of trans-3,4-substituted piperidines. Starting
from a single enantiomer of phenylglycinol it is possible
to gain access to the two enantiomeric series of these
piperidine derivatives. It is simply a matter of using
either the kinetic bicyclic lactam cis-1 formed in the
cyclodehydration of (R)-phenylglycinol with methyl
5-oxopentanoate or the most stable isomer trans-1 (Scheme
6). Conjugate addition of appropriate organocopper re-
The synthesis of (+)-femoxetine (27) from piperidine
22 simply required the exchange of the chiral inductor
on the piperidine nitrogen by a methyl group and the
etherification of the hydroxymethyl substituent with an
appropriate aryl group. This was accomplished by hy-
drogenolysis of the benzylic N-substituent in the presence
of di-tert-butyl dicarbonate, followed by conversion of the
resulting alcohol 23 into the corresponding mesylate,
Sch em e 6
(17) (a) Christensen, J . A.; Squires, R. F. Ger. Patent 2,404,113,
1974. U.S. Patent 3,912,743, 1975. U.S. Patent 4,007,196, 1977; Chem.
Abstr. 1974, 81, 152011q. (b) Barnes, R. D.; Wood-Kaczmar, M. W.;
Richardson, J . E.; Lynch, I. R.; Buxton, P. C.; Curzons, A. D., Eur.
Patent 0223403, 1986; Chem. Abstr. 1987, 107, 141102z.
(18) (a) Femoxetine: Drugs Fut. 1977, 2, 309. (b) Paroxetine: Drugs
Fut. 1986, 11, 112. (c) For a review, see: Dechant, K. L.; Clissold, S.
P. Drugs 1991, 41, 225.
(19) J ones, P. G.; Kennard, O.; Horn, A. S. Acta Crystallogr. 1979,
B35, 1732.
(20) Murthy, K. S. K.; Rey, A. W. WO Patent 9907680, 1999; Chem.
Abstr. 1999, 130, 182361.

3078 J . Org. Chem., Vol. 65, No. 10, 2000
Amat et al.
Ep im er iza tion of cis-1. A solution of pure lactam cis-1 (25
g, 0.11 mol) in anhydrous CH2Cl2 (80 mL) was added to a
solution of TFA (80 mL, 1.04 mol) in anhydrous CH2Cl2 (1.8
L) cooled with an ice-water bath. After 10 min the bath was
removed, and the solution was stirred at 25 °C for 64 h. The
resulting acidic solution was neutralized with a 2 M aqueous
NaHCO3 (530 mL). The organic phase was separated, and the
aqueous layer was extracted with CH2Cl2. The combined
organic solutions were dried and concentrated, and the residue
was chromatographed (97:3 AcOEt-EtOH) to give pure trans-1
(21.5 g, 86%) and cis-1 (3.5 g, 14%).
agents to R,â-unsaturated lactams derived from either
cis-1 or trans-1 provides enantiopure diastereomeric
trans-3,4-substituted piperidines, which are ultimately
converted to the corresponding separate enantiomers.
The above results significantly expand the potential
of bicyclic lactams cis-1 and trans-1, derived from (R)-
phenylglycinol, as chiral building blocks for the synthesis
of diversely substituted enantiopure piperidine deriva-
tives.
(3R ,8a S )-6-(Be n zyloxyca r b on yl)-5-oxo-3-p h e n yl-6-
(ph en ylselan yl)-2,3,6,7,8,8a-h exah ydr o-5H-oxazolo[3,2-a ]-
p yr id in e (tr a n s-2). Lithium bis(trimethylsilyl)amide (10.1
mL of a 1 M solution in THF) was slowly added at -78 °C to
a solution of lactam trans-1 (1.0 g, 4.6 mmol) in anhydrous
THF (65 mL), and the resulting mixture was stirred for 45
min. Then, benzyl chloroformate (0.65 mL, 4.6 mmol) and, after
20 min of continuous stirring at -78 °C, PhSeBr (1.52 g, 6.4
mmol) were sequentially added to the solution. The resulting
mixture was stirred for 50 min and poured into 5% aqueous
NH4Cl. The aqueous layer was extracted with AcOEt (4 × 10
mL), and the combined organic extracts were dried and
concentrated. Flash chromatography (2:3 AcOEt-hexane) of
the resulting oil afforded compound trans-2 (1.8 g, 77% overall
yield) as a mixture of C-6 epimers. trans-2 (higher Rf epimer):
IR (film) 1734, 1655 cm-1; 1H NMR (CDCl3) δ 1.85-2.20 (m, 4
H), 3.72 (t, J ) 8.5 Hz, 1 H), 4.47 (t, J ) 8.5 Hz, 1 H), 4.90 (br
s, 1 H), 5.13 (d, J ) 12.3 Hz, 1 H), 5.28 (d, J ) 12.3 Hz, 1 H),
5.34 (t, J ) 8.5 Hz, 1 H), 7.00-7.60 (m, 15 H); 13C NMR (CDCl3)
δ 24.8 (CH2), 27.4 (CH2), 55.0 (C), 58.6 (CH), 67.7 (CH2), 72.1
(CH2), 87.5 (CH), 135.2 (C), 138.4 (CH), 138.8 (C), 165.1 (C),
170.2 (C). trans-2 (lower Rf epimer): 1H NMR (CDCl3) δ 1.50-
2.50 (m, 4 H), 3.80 (dd, J ) 9.0, 7.4 Hz, 1 H), 4.42 (dd, J ) 9.0,
7.8 Hz, 1 H), 4.73 (dd, J ) 9.1, 4.5 Hz, 1 H), 5.24 (s, 2 H), 5.30
(t, J ) 7.4 Hz, 1 H), 7.10-7.70 (m, 15 H); 13C NMR (CDCl3) δ
26.9 (CH2), 29.7 (CH2), 54.0 (C), 58.9 (CH), 68.0 (CH2), 72.4
(CH2), 88.1 (CH), 135.3 (C), 138.2 (CH), 138.4 (CH), 138.8 (C),
165.1 (C), 170.2 (C).
(3R ,8a S )-6-(Me t h o x y c a r b o n y l)-5-o x o -3-p h e n y l-6-
(ph en ylselan yl)-2,3,6,7,8,8a-h exah ydr o-5H-oxazolo[3,2-a ]-
p yr id in e (tr a n s-3). Operating as in the above preparation
of trans-2, from lactam trans-1 (1.0 g, 4.6 mmol), methyl
chloroformate (0.35 mL, 4.6 mmol), and PhSeBr (1.52 g, 6.4
mmol) was obtained selenide trans-3 as a mixture of C-6
epimers (1.9 g, 96% overall yield) after column chromatography
(2:3 AcOEt-hexane). Both epimers could be purified by
crystallization (THF-hexane). trans-3 (higher Rf epimer): 1H
NMR (CDCl3) δ 1.95-2.20 (m, 4 H), 3.77 (t, J ) 8.0 Hz, 1 H),
3.78 (s, 3 H), 4.48 (t, J ) 8.0 Hz, 1 H), 4.97 (t, J ) 6.0 Hz, 1
H), 5.34 (t, J ) 8.0 Hz, 1 H), 7.18-7.45 (m, 8 H), 7.70 (dm, J
) 6.8 Hz, 2 H); 13C NMR (CDCl3) δ 24.9 (CH2), 27.3 (CH2),
53.2 (CH3), 54,8 (C), 58.6 (CH), 72,2 (CH2), 87.6 (CH), 125.7
(CH), 126.8 (C), 127.6 (CH), 128.7 (CH), 128.9 (CH), 129.7
(CH), 138,2 (CH), 138.8 (C), 165.1 (C), 170.9 (C). trans-3 (lower
Rf epimer): 1H NMR (CDCl3) δ 1.75 (m, 1 H), 2.00-2.23 (m, 2
H), 2.41 (m, 1 H), 3.80 (masked, 1 H), 3.80 (s, 3 H), 4.44 (t, J
) 7.9 Hz, 1 H), 4.72 (dd, J ) 9.3, 4.4 Hz, 1 H), 5.3 (t, J ) 7.7
Hz, 1 H), 7.10-7.40 (m, 8H), 7.50 (dm, J ) 7.0 Hz, 2 H); 13C
NMR (CDCl3) δ 26.8 (CH2), 29.6 (CH2), 53.4 (CH3), 53.9 (C),
58.8 (CH), 72.4 (CH2), 88.0 (CH), 126.1 (C), 126.8 (CH), 127.7
(CH), 128.6 (CH), 128.8 (CH), 129.4 (CH), 138.1 (CH), 138.6
(C), 165.1 (C), 170.7 (C).
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, Merck),
and the spots were located with aqueous potassium perman-
ganate solution or with iodoplatinate reagent. Column chro-
matography was carried out on SiO2 (silica gel 60, SDS, 70-
200 µm). Flash chromatography was carried out on SiO2 (silica
gel 60, SDS, 35-70 µm). All reagents were purchased from
Aldrich or Fluka and were used without further purification.
Solvents for chromatography were distilled at atmospheric
pressure prior to use and dried using standard procedures.
Drying of the organic extracts during the workup of reactions
was performed over Na2SO4. Evaporation of solvents was
accomplished with a rotatory evaporator. Microanalyses and
HRMS were performed by Centre d’Investigacio´ i Desenvolu-
pament (CSIC), Barcelona.
(3R,8a R)- a n d (3R,8a S)-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 (cis-1 a n d tr a n s-
1). Methyl 5-hydroxypentanoate (23.7 g, 0.18 mol), prepared
in 90% yield by methanolysis of δ-valerolactone, was slowly
added to a suspension of PCC (59.2 g, 0.27 mol) and Celite
(59.2 g) in anhydrous CH2Cl2 (370 mL), and the resulting
mixture was stirred at 25 °C for 1.5 h. The solution was
decanted, and the solids were washed with Et2O (3 × 100 mL).
The combined organic solutions were filtered through an
alumina column to afford methyl 5-oxopentanoate (19.1 g,
82%). A stirred solution of (-)-(R)-phenylglycinol (18.3 g, 133
mmol) and methyl 5-oxopentanoate (20.8 g, 160 mmol) in
toluene (380 mL), containing molecular sieves (4 Å, 15 g), was
heated at reflux for 36 h, with azeotropic elimination of water
produced. The resulting solution was concentrated, and the
residue was taken up with Et2O. The organic solution was
washed with saturated aqueous NH4Cl (3 × 50 mL), dried,
and concentrated to give an orange oil (30 g). Column chro-
matography (97:3 AcOEt-EtOH) afforded a mixture of cis-1
(21.2 g, 73%) and its C-8a epimer trans-1 (3.8 g, 13%). cis-1:
1
IR (KBr) 1653 cm-1; H NMR (CDCl3, 500 MHz) δ 1.77 (m, 2
H), 2.05 (m, 1 H), 2.26 (ddd, J ) 18.5, 11.0, 7.0 Hz, 1 H), 2.33-
2.40 (m, 2 H), 4.00 (dd, J ) 9.0, 1.5 Hz, 1 H), 4.15 (dd, J ) 9.0,
7.0 Hz, 1 H), 4.85 (dd, J ) 9.5, 3.4 Hz, 1 H), 4.92 (dd, J ) 7.0,
1.5 Hz, 1 H), 7.30 (m, 5 H); 13C NMR (CDCl3) δ 17.6 (CH2),
28.0 (CH2), 30.8 (CH2), 58.7 (CH), 73.7 (CH2), 88.9 (CH), 126.4
(CH), 127.6 (CH), 128.6 (CH), 141.6 (C), 167.6 (C); mp 65-67
°C; [R]22D -66.3 (c 1.0, EtOH); [R]22D -45.8 (c 2.2, CH2Cl2), {lit.:
[R]22 -51.0 (c 2.2, CH2Cl2)}. Anal. Calcd for C13H15NO2:
10a
D
C, 71.87; H, 6.96; N, 6.45. Found: C, 71.78; H, 6.93; N, 6.48.
trans-1: IR (film) 1646 cm-1
;
1H NMR (CDCl3, 500 MHz) δ
[3R,6R(a n d 6S),7S,8a S]-6-(Ben zyloxyca r bon yl)-7-m eth -
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 a n d 8b). A stream of ozone gas was bubbled
through a cooled (-78 °C) solution of the selenide trans-2 (500
mg, 0.99 mmol) in anhydrous CH2Cl2 (40 mL) until it turned
pale blue. The solution was purged with O2, and the temper-
ature was slowly raised to 25 °C. After 30 min of stirring, the
mixture was poured into brine (20 mL), and the aqueous layer
was extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were dried and concentrated under reduced pressure
(external temperature 25 °C) to give (3R,8a S)-6-(ben zyloxy-
car bon yl)-5-oxo-3-ph en yl-2,3,8,8a-tetr ah ydr o-5H-oxazolo-
1.53 (dddd, J ) 13.5, 12.5, 9.0, 3.5 Hz, 1 H), 1.75 (m, 1 H),
1.98 (m, 1 H), 2.34 (ddd, J ) 18.0, 11.5, 6.5 Hz, 1 H), 2.36 (m,
1 H), 2.51 (ddm, J ) 18.0, 6.0 Hz, 1 H), 3.76 (dd, J ) 9.0, 8.0
Hz, 1 H), 4.50 (dd, J ) 9.0, 8.0 Hz, 1 H), 5.02 (dd, J ) 9.0, 5.0
Hz, 1 H), 5.28 (t, J ) 8.0 Hz, 1 H), 7.20-7.45 (m, 5 H); 13C
NMR (CDCl3) δ 16.7 (CH2), 28.1 (CH2), 31.0 (CH2), 57.8 (CH),
72.2 (CH2), 88.5 (CH), 126.0 (CH), 127.5 (CH), 128.7 (CH),
139.6 (C), 169.0 (C); mp 88-90 °C (C6H6-hexane); [R]22
D
-122.0 (c 1.0, EtOH); [R]22D -90.8 (c 0.6, CH2Cl2), {lit.:10a [R]22
D
-88.0 (c 0.6, CH2Cl2)}. Anal. Calcd for C13H15NO2: C, 71.87;
H, 6.96; N, 6.45. Found: C, 71.92; H, 6.96; N, 6.56.

Enantiopure trans-3,4-Disubstituted Piperidines
J . Org. Chem., Vol. 65, No. 10, 2000 3079
[3,2-a ]p yr id in e (tr a n s-4) as an oil, which was used in the
trans-2 (500 mg, 0.99 mmol) and PhCu(CN)Li (2.5 equiv)
[prepared from 1.6 M PhLi in cyclohexanes-Et2O (1.55 mL)
and CuCN (245 mg, 2.74 mmol)] was obtained a 97:3 mixture
of C-6 epimers 10a and 10b, respectively, (304 mg, 72% from
trans-2) after column chromatography (2:3 AcOEt-hexane).
Crystallization from acetone-Et2O-hexane afforded pure
10a : IR (film) 1740, 1668 cm-1; 1H NMR (CDCl3) δ 2.38 (ddd,
J ) 14.3, 8.7, 4.7 Hz, 1 H), 2.47 (dt, J ) 14.3, 4.7 Hz, 1 H),
3.67 (td, J ) 8.7, 4.7 Hz, 1 H), 3.80 (dd, J ) 8.3, 7.6 Hz, 1 H),
3.85 (d, J ) 8.7 Hz, 1 H), 4.53 (t, J ) 8.3 Hz, 1 H), 4.90 (t, J
) 4.7 Hz, 1 H), 5.09 (d, J ) 12.4 Hz, 1 H), 5.12 (d, J ) 12.4
Hz, 1 H), 5.47 (dd, J ) 8.3, 7.6 Hz, 1 H), 7.10-7.40 (m, 15 H);
13C NMR (CDCl3) δ 33.3 (CH2), 38.1 (CH), 54.0 (CH), 58.6 (CH),
67.0 (CH2), 71.7 (CH2), 85.9 (CH), 135.3 (C), 139.3 (C), 140.4
next reaction without further purification: IR (film) 1735, 1669
1
cm-1; H NMR (CDCl3) δ 2.56 (ddd, J ) 18.0, 10.2, 2.4 Hz, 1
H), 2.92 (ddd, J ) 18.0, 6.8, 5.5 Hz, 1 H), 3.93 (dd, J ) 9.0, 6.5
Hz, 1H), 4.47 (dd, J ) 9.0, 7.0 Hz, 1 H), 5.26 (s, 2 H), 5.31 (t,
J ) 6.5 Hz, 1 H), 5.43 (dd, J ) 10.2, 5.5 Hz, 1 H), 7.30 (m, 1
H), 7.35 (m, 10 H); 13C NMR (CDCl3) δ 29.8 (CH2), 58.0 (CH),
66.3 (CH2), 72.8 (CH2), 85.9 (CH), 135.3 (C), 138.5 (C), 142.6
(CH), 157.0 (C), 162.6 (C). A solution of the above crude
unsaturated lactam trans-4 in anhydrous THF (2 mL) was
added dropwise at -78 °C to a solution of CH3Cu(CN)Li (2.5
equiv) [prepared from 1.6 M CH3Li in Et2O (1.55 mL) and
CuCN (245 mg, 2.74 mmol)] in anhydrous THF (22 mL), and
the resulting solution was stirred for 90 min. The mixture was
allowed to reach 25 °C and poured into saturated aqueous
NaHCO3. The aqueous layer was extracted with AcOEt (3 ×
10 mL), and the combined organic extracts were dried and
concentrated. The residue was chromatographed (2:3 AcOEt-
hexane) to give (234 mg, 65% from trans-2) a 3:1 mixture of
C-6 epimers 8a and 8b, respectively. 8a : IR (film) 1739, 1662
cm-1; 1H NMR (CDCl3) δ 1.13 (d, J ) 6.8 Hz, 1 H), 1.98 (ddd,
J ) 14.0, 8.3, 5.0 Hz, 1 H), 2.22 (ddd, J ) 14.0, 5.0, 5.0 Hz, 1
H), 2.52 (m, 1 H), 3.21 (d, J ) 7.2 Hz, 1 H), 3.80 (dd, J ) 8.5,
8.0 Hz, 1 H), 4.50 (dd, J ) 8.5, 8.0 Hz, 1 H), 5.02 (t, J ) 5.0
Hz, 1 H), 5.23 (s, 2 H), 5.40 (t, J ) 8.0 Hz, 1 H), 7.15-7.40 (m,
10 H); 13C NMR (CDCl3) δ 19.6 (CH3), 27.8 (CH), 32.3 (CH2),
55.7 (CH), 58.5 (CH), 67.0 (CH2), 71.8 (CH2), 85.9 (CH), 135.5
(C), 139.4 (C), 165.8 (C), 169.6 (C). 8b: 1H NMR (CDCl3,
selected resonances) δ 1.12 (d, J ) 6.6 Hz, 3 H), 3.56 (d, J )
5.0 Hz, 1 H), 3.69 (dd, J ) 8.5, 8.0 Hz, 1 H), 4.51 (dd, J ) 8.5,
8.0 Hz, 1H); 13C NMR (CDCl3) δ 17.3 (CH3), 27.7 (CH), 32.0
(CH2), 54.2 (CH), 57.9 (CH), 67.0 (CH2), 72.0 (CH2), 86.3 (CH),
(C), 166.0 (C), 169.0 (C); mp 121-123 °C; [R]22 -30.2 (c 0.5,
D
CH2Cl2). Anal. Calcd for C27H25NO4: C, 75.86; H, 5.89; N, 3.28.
Found: C, 75.86; H, 5.81; N, 3.29.
(3R ,6R ,7S ,8a S )-6-(Be n zyloxyca r b on yl)-7-(p -flu or o-
ph en yl)-5-oxo-3-ph en yl-2,3,6,7,8,8a-h exah ydr o-5H-oxazolo-
[3,2-a ]p yr id in e (11a ). Operating as in the preparation of 8,
from selenide trans-2 (800 mg, 1.58 mmol) and lithium
(p-fluorophenyl)cyanocuprate (1.6 equiv) [prepared from 0.13
M (p-fluorophenyl)lithium21 in THF (20 mL) and CuCN (252
mg, 2.8 mmol)] was obtained a 97:3 mixture of C-6 epimers
11a and 11b, respectively, (490 mg, 70% from trans-2) after
purification by column chromatography (2:3 AcOEt-hexane).
Crystallization from acetone-Et2O-hexane afforded pure
11a : IR (film) 1743, 1663 cm-1; 1H NMR (CDCl3) δ 2.31 (ddd,
J ) 14.5, 9.5, 5.0 Hz, 1 H), 2.44 (dt, J ) 14.5, 4.3 Hz, 1 H),
3.62 (td, J ) 9.5, 4.3 Hz, 1 H), 3.75 (d, J ) 9.5 Hz, 1 H), 3.81
(dd, J ) 8.8, 7.5 Hz, 1 H), 4.51 (t, J ) 8.8 Hz, 1 H), 4.91 (t, J
) 4.8 Hz, 1 H), 5.06 (d, J ) 12.0 Hz, 1 H), 5.10 (d, J ) 12.0
Hz, 1 H), 5.47 (t, J ) 7.8 Hz, 1 H), 6.97 (t, J ) 8.5 Hz, 1 H),
7.05-7.40 (m, 14 H); 13C NMR (CDCl3) δ 33.4 (CH2), 37.3 (CH),
54.6 (CH), 58.6 (CH), 67.0 (CH2), 71.5 (CH2), 85.7 (CH), 115.6
(d, J ) 21.0 Hz, CH), 126.1 (CH), 135.2 (C), 136.0 (d, J ) 3.6
Hz, C), 139.3 (C), 161.2 (d, J ) 244.8 Hz, C), 166.1 (C), 168.6
134.5 (C), 139.4 (C), 164.5 (C), 168.3 (C). Anal. Caldc for C22H23
-
NO4‚1/4H2O (mixture of epimers): C, 71.43; H, 6.40; N, 3.78.
Found: C, 71.79; H, 6.42; N, 3.79. In some runs, small amounts
(<5%) of pyridone 6 were isolated: IR (film) 3430, 1727, 1650
cm-1; 1H NMR (CDCl3) δ 4.20 (dd, J ) 12.2, 6.5 Hz, 1 H), 4.30
(dd, J ) 12.2, 5.2 Hz, 1 H), 5.27 (s, 2 H), 6.10 (t, J ) 7.0 Hz,
1 H), 6.47 (dd, J ) 6.5, 5.2 Hz, 1 H), 7.20-7.45 (m, 10 H), 7.55
(dd, J ) 7.0, 2.2 Hz, 1 H), 8.06 (dd, J ) 7.0, 2.2 Hz, 1 H); 13C
NMR (CDCl3) δ 59.5 (CH), 62.2 (CH2), 66.4 (CH2), 104.6 (CH),
119.2 (C), 135.7 (C), 136.7 (C), 141.3 (CH), 144.3 (CH), 160.0
(C); mp 132 °C; [R]22 -52.2 (c 0.5, CH2Cl2). Anal. Calcd for
D
C
27H24FNO4: C, 72.80; H, 5.43; N, 3.14. Found: C, 72.63; H,
5.42; N, 3.10.
(3R,6R,7S,8a S)-6-(Meth oxyca r bon yl)-5-oxo-3,7-d ip h en -
yl-2,3,6,7,8,8a-h exah ydr o-5H-oxazolo[3,2-a ]pyr idin e (12a).
Operating as in the preparation of the unsaturated lactam
trans-4, the selenide trans-3 (500 mg, 1.16 mmol) was con-
verted to (3R,8a S)-6-(m eth oxyca r bon yl)-5-oxo-3-p h en yl-
2,3,8,8a -tetr a h yd r o-5H-oxa zolo[3,2-a ]p yr id in e (tr a n s-5),
which was used without further purification: IR (film) 1736,
(C), 164.3 (C); mp 115-116 °C (Et2O-acetone); [R]22 -274.8
D
(c 1.0, EtOH). Anal. Calcd for C21H19NO4: C, 72.19; H, 5.48;
N, 4.01. Found: C, 72.24; H, 5.46; N, 3.95.
[3R,6R(a n d 6S),7S,8a S]-6-(Ben zyloxyca r bon yl)-7-bu -
tyl-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 (9a a n d 9b). Operating as in the above prepara-
tion of 8, from selenide trans-2 (500 mg, 0.99 mmol) and
n-BuCu(CN)Li (2.5 equiv) [prepared from 1.6 M n-BuLi in
hexane (1.55 mL) and CuCN (245 mg, 2.74 mmol)] was
obtained a 72:28 mixture of C-6 epimers 9a and 9b, respec-
tively, (253 mg, 63% from trans-2) after purification by column
chromatography (2:3 AcOEt-hexane). 9a : IR (film) 1739, 1666
1
1669 cm-1; H NMR (CDCl3) δ 2.58 (ddd, J ) 17.8, 10.0, 2.4
Hz, 1 H), 2.94 (ddd J ) 17.8, 6.7, 5.3 Hz, 1 H), 3.80 (s, 3 H),
3.94 (dd, J ) 8.9, 6.3 Hz, 1 H), 4.48 (dd, J ) 8.9, 7.0 Hz, 1 H),
5.29 (dd, J ) 7.0, 6.3 Hz, 1 H), 5.45 (dd, J ) 10.0, 5.3 Hz, 1
H), 7.6 (m, 1 H), 7.10-7.50 (m, 6 H); 13C NMR (CDCl3) δ 30.1
(CH2), 52.2 (CH3), 58.3 (CH), 73.1 (CH2), 86.3 (CH), 126.1 (CH),
127.6 (CH), 128.6 (CH), 129.4 (C), 138.7 (C), 142.6 (CH), 157.2
(C), 164.2 (C). A solution of the above crude lactam trans-5 in
anhydrous THF (2 mL) was allowed to react with PhCu(CN)-
Li (2.5 equiv) [prepared from 1.7 M PhLi in THF (1.7 mL, 2.9
mmol) and CuCN (293 mg, 3.2 mmol)] as in the above
preparation of 10. The resulting crude oil (598 mg) was
chromatographed (4:1 to 2:1 AcOEt-hexane) to afford (352 mg,
86% from trans-3) a 97:3 mixture of C-6 epimers 12a and 12b,
respectively. Crystallization from THF-hexane rendered pure
12a : IR (film) 1745, 1665 cm-1; 1H NMR (CDCl3) δ 2.37 (ddd,
J ) 14.0, 8.3, 5.0 Hz, 1 H), 2.45 (dt, J ) 14.0, 5.0 Hz, 1 H),
3.65 (s, 3 H), 3.66 (td, J ) 8.3, 5.0 Hz, 1 H), 3.78 (dd, J ) 9.0,
7.7 Hz, 1 H), 3.79 (d, J ) 8.3 Hz, 1 H), 4.51 (dd, J ) 9.0, 7.7
Hz, 1 H), 4.87 (t, J ) 5.0 Hz, 1 H), 5.41 (t, J ) 7.7 Hz, 1 H),
7.20-7.40 (m, 10 H); 13C NMR (CDCl3) δ 33.2 (CH2), 37.9 (CH),
52.3 (CH3), 53.6 (CH), 58.6 (CH), 71.6 (CH2), 85.8 (CH), 126.1
(CH), 126.7 (CH), 127.2 (CH), 127.6 (CH), 128.6 (CH), 128.7
(CH), 139.3 (C), 140.5 (C), 165.8 (C), 169.50 (C); mp 112-114
°C; [R]22D -45.2 (c 1.0, MeOH). Anal. Calcd for C21H21NO4: C,
1
cm-1; H NMR (CDCl3) δ 0.89 (t, J ) 7.0 Hz, 3 H), 1.20-1.50
(m, 6 H), 2.08 (m, 1 H), 2.17 (ddd, J ) 14.0, 6.5, 4.4 Hz, 1 H),
2.34 (m, 1 H), 3.30 (d, J ) 5.7 Hz, 1 H), 3.78 (dd, J ) 9.0, 8.0
Hz, 1 H), 4.50 (t, J ) 8.6 Hz, 1 H), 5.03 (dd, J ) 6.5, 5.2 Hz,
1 H), 5.17 (d, J ) 12.6 Hz, 2 H), 5.23 (d, J ) 12.6 Hz, 2 H),
5.36 (t, J ) 8.0 Hz, 1 H), 7.15-7.40 (m, 10 H); 13C NMR (CDCl3)
δ 13.9 (CH3), 22.4 (CH2), 28.9 (CH2), 29.8 (CH2), 33.1 (CH),
33.5 (CH2), 54.0 (CH), 58.5 (CH), 67.0 (CH2), 72.0 (CH2), 86.1
(CH), 135.5 (C), 139.4 (C), 165.5 (C), 170.0 (C); MS m/e (relative
intensity): 407 (M+, 3), 316 (61), 298 (12), 120 (23), 111 (18),
104 (64), 77 (16), 65 (15), 55 (32). 9b: 1H NMR (CDCl3, selected
resonances) δ 3.62 (d, J ) 4.1 Hz, 1 H), 3.67 (dd, J ) 9.0, 8.0
Hz, 1 H), 4.48 (t, J ) 8.6 Hz, 1 H); 13C NMR (CDCl3) δ 13.9
(CH3), 22.4 (CH2), 29.6 (CH2), 31.7 (CH2), 32.7 (CH), 52.9 (CH),
57.9 (CH), 67.1 (CH2), 71.8 (CH2), 86.4 (CH), 135.6 (C), 139.5
(C), 165.2 (C), 168.5 (C). Anal. Calcd for C25H29NO4 (mixture
of epimers): C, 73.68; H, 7.17; N, 3.44. Found: C, 73.44; H,
7.13; N, 3.40.
(3R ,6R ,7S ,8a S )-6-(Be n zyloxyca r b on yl)-5-oxo-3,7-d i-
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
(10a ). Operating as in the preparation of 8, from selenide
(21) Brandsma, L.; Verkruijsse, H. Preparative Polar Organometallic
Chemistry 1; Springer-Verlag: Heidelberg, 1987; p 189.

3080 J . Org. Chem., Vol. 65, No. 10, 2000
Amat et al.
71.77; H, 6.02; N, 3.98. Found: C, 71.64; H, 6.01; N, 3.94. In
Pd-C (110 mg) was obtained compound 16 (84 mg, 98%) as
1
some runs small amounts (<5%) of pyridone 7 were isolated:
white solid: IR (film) 1659 cm-1; H NMR (CDCl3, 500 MHz)
1
IR (film) 1729, 1650 cm-1; H NMR (CDCl3) δ 3.86 (s, 3 H),
δ 2.09 (ddd, J ) 13.5, 6.0, 4.0 Hz, 1 H), 2.34 (ddd, J ) 13.5,
7.0, 4.5 Hz, 1 H), 2.66 (d, J ) 5.0 Hz, 2 H), 3.35 (m, 1 H), 3.61
(dd, J ) 8.5, 7.0 Hz, 1 H), 4.40 (t, J ) 9.0 Hz, 1 H), 4.68 (t, J
) 5.5 Hz, 1 H), 5.30 (t, J ) 8.0 Hz, 1 H), 6.97 (m, 1 H), 7.10-
7.22 (m, 7 H), 7.27 (m, 1 H); 13C NMR (CDCl3) δ 33.7 (CH),
34.6 (CH2), 37.3 (CH2), 58.2 (CH), 72.0 (CH2), 86.1 (CH), 115.5
(d, J ) 21.0 Hz, CH), 125.8 (CH), 127.6 (CH), 128.2 (d, J )
8.1 Hz, CH), 128.8 (CH), 137.5 (d, J ) 3.0 Hz, C), 139.6 (C),
4.25 (dd, J ) 12.0, 6.7 Hz, 1 H), 4.33 (dd, J ) 12.0, 5.0 Hz, 1
H), 6.23 (t, J ) 6.9 Hz, 1 H), 6.49 (dd, J ) 6.7, 5.0 Hz, 1 H),
7.35 (m, 5 H), 7.60 (dd, J ) 6.9, 2.1 Hz, 1 H), 8.13 (dd, J ) 6.9,
2.1 Hz, 1 H); 13C NMR (CDCl3, 75.4 MHz) δ 51.9 (CH3), 59.7
(CH), 61.9 (CH2), 104.7 (CH), 119.1 (C), 127.8 (CH), 128.0 (CH),
128.7 (CH), 136.8 (C), 141.4 (CH), 144.5 (CH), 159.9 (C), 165.3
(C). [R]22 -280.9 (c 1.1, MeOH). Anal. Calcd for C15H15NO4‚
D
1/4H2O: C, 64.86; H, 5.62; N, 5.04. Found: C, 65.09; H, 5.95;
N, 5.23.
161.6 (d, J ) 244.8 Hz, C), 168.8 (C); [R]22 +15.1 (c 0.5, CH2-
D
Cl2). Anal. Calcd for C19H18FNO2: C, 73.29; H, 5.83; N, 4.50.
Found: C, 73.01; H, 5.86; N, 4.43.
(3R,6R,7S,8a S)-7-(p -F lu or op h en yl)-6-(m et h oxyca r b o-
n 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 (13a ). Operating as in the above preparation
of 12, from selenide trans-3 (644 mg, 1.5 mmol) and lithium
(p-fluorophenyl)cyanocuprate (2.5 equiv) [prepared from 0.16
M (p-fluorophenyl)lithium21 in THF (24 mL) and CuCN (374
mg, 4.18 mmol)] was obtained a 97:3 mixture of C-6 epimers
13a and 13b, respectively, (429 mg, 80% from trans-3) after
purification by column chromatography (2:3 AcOEt-hexane).
Crystallization from THF-hexane afforded pure 13a : IR (film)
1746, 1665 cm-1; 1H NMR (CDCl3, 500 MHz) δ 2.24 (ddd, J )
14.5, 9.0, 5.0 Hz, 1 H), 2.34 (dt, J ) 14.5, 4.5 Hz, 1 H), 3.54
(td, J ) 9.0, 4.5 Hz, 1 H), 3.55 (s, 3 H), 3.62 (d, J ) 9.0 Hz, 1
H), 3.71 (dd, J ) 8.5, 7.0 Hz, 1 H), 4.41 (t, J ) 8.5 Hz, 1 H),
4.80 (t, J ) 4.5 Hz, 1 H), 5.34 (t, J ) 8.0 Hz, 1 H), 6.94 (t, J )
8.5 Hz, 1 H), 7.11 (dd, J ) 8.5, 5.0 Hz, 1 H), 7.16-7.22 (m, 3
H), 7.26 (m, 2 H); 13C NMR (CDCl3) δ 33.1 (CH2), 37.2 (CH),
52.2 (CH3), 54.1 (CH), 58.5 (CH), 71.5 (CH2), 85.6 (CH), 115.5
(d, J ) 21.0 Hz, CH), 126.0 (CH), 127.6 (CH), 128.3 (d, J )
8.2 Hz, CH), 128.6 (CH), 136.2 (d, J ) 2.7 Hz, C), 139.2 (C),
161.5 (d, J ) 244.8 Hz, C), 165.8 (C), 169.2 (C); mp 127 °C;
(3R ,8a R )-6-(Be n zylox-yca r b on yl)-5-oxo-3-p h e n yl-6-
(ph en ylselan yl)-2,3,6,7,8,8a-h exah ydr o-5H-oxazolo[3,2-a ]-
p yr id in e (cis-2). Operating as in the preparation of trans-2,
from lactam cis-1 (1.0 g, 4.6 mmol), benzyl chloroformate (0.65
mL, 4.6 mmol), and PhSeBr (1.5 g, 6.4 mmol) was obtained
compound cis-2 as a mixture of C-6 epimers (1.8 g, 77%) after
column chromatography (1:1 AcOEt-hexane). cis-2 (higher Rf
epimer): 1H NMR (CDCl3) δ 1.82 (m, 1 H), 2.12 (m, 2 H), 2.37
(m, 1 H), 3.95 (dd, J ) 9.0, 1.7 Hz, 1 H), 4.03 (dd, J ) 9.0, 6.9
Hz, 1 H), 4.38 (dd, J ) 10.0, 3.2 Hz, 1 H), 4.84 (dd, J ) 6.9,
1.7 Hz, 1 H), 5.06 (s, 2 H), 7.10-7.40 (m, 13 H), 7.60 (d, J )
6.8 Hz, 2 H); 13C NMR (CDCl3) δ 27.1 (CH2), 31.0 (CH2), 54.0
(C), 59.3 (CH), 67.8 (CH2), 74.0 (CH2), 88.6 (CH), 135.1 (C),
138.2 (CH), 140.4 (C), 163.3 (C), 170.1 (C). cis-2 (lower Rf
epimer): 1H NMR (CDCl3) 2.00-2.30 (m, 4 H), 4.00-4.10 (m,
2 H), 4.71 (dd, J ) 8.5, 4.5 Hz, 1 H), 4.92 (dd, J ) 6.0, 2.0 Hz,
1 H), 5.14 (d, J ) 12.2 Hz, 1 H), 5.23 (d, J ) 12.2 Hz, 1 H),
7.17-7.40 (m, 15 H); 13C NMR (CDCl3) δ 25.7 (CH2), 28.0
(CH2), 55.2 (C), 59.0 (CH), 67.6 (CH2), 74.0 (CH2), 87.4 (CH),
135.3 (C), 138.2 (CH), 140.6 (C), 163.0 (C), 169.7 (C).
(3R ,8a R )-6-(Me t h o x y c a r b o n y l)-5-o x o -3-p h e n y l-6-
(ph en ylselan yl)-2,3,6,7,8,8a-h exah ydr o-5H-oxazolo[3,2-a ]-
p yr id in e (cis-3). Operating as in the preparation of trans-2,
from lactam cis-1 (755 mg, 3.5 mmol), methyl chloroformate
(0.27 mL, 3.5 mmol), and PhSeCl (932 mg, 4.9 mmol) was
obtained compound cis-3 as a mixture of C-6 epimers (1.21 g,
81%) after column chromatography (1:1 AcOEt-hexane); IR
(film) 1727, 1663 cm-1. cis-3 (higher Rf epimer): 1H NMR
(CDCl3) δ 1.80 (dddd, J ) 12.5, 12.5, 10.2, 3.5 Hz, 1 H), 2.08
(td, J ) 14.2, 3.5 Hz, 1 H), 2.18 (dq, J ) 12.5, 3.5 Hz, 1 H),
2.34 (td, J ) 14.2, 3.5 Hz, 1 H), 3.60 (s, 3 H), 4.00 (dd, J ) 9.5,
1.8 Hz, 1 H), 4.10 (dd, J ) 9.5, 7.0 Hz, 1 H), 4.54 (dd, J )
10.2, 3.5 Hz, 1 H), 4.87 (dd, J ) 7.0, 1.8 Hz, 1 H), 7.20-7.45
(m, 8 H), 7.66 (d, J ) 6.8 Hz, 2 H); 13C NMR (CDCl3) δ 27.0
(CH2), 30.8 (CH2), 52.8 (CH3), 52.9 (C), 59.0 (CH), 73.9 (CH2),
88.6 (CH), 126.6 (CH), 126.7 (CH), 127.4 (CH), 128.1 (CH),
128.7 (CH), 138.1 (CH), 140.4 (C), 163.3 (C), 170.8 (C). cis-3
(lower Rf epimer): 1H NMR (CDCl3) δ 2.05-2.35 (m, 4 H), 3.73
(s, 3 H), 4.08 (dd, J ) 9.0, 1.4 Hz, 1 H), 4.19 (dd, J ) 9.0, 6.7
Hz, 1 H), 4.90 (dd, J ) 8.8, 4.2 Hz, 1 H), 4.94 (dd, J ) 6.7, 1.4
Hz, 1 H), 7.20-7.42 (m, 8 H), 7.47 (d, J ) 6.8 Hz, 2 H); 13C
NMR (CDCl3) δ 25.6 (CH2), 28.1 (CH2), 53.1 (CH3), 55.2 (C),
59.0 (CH), 74.0 (CH2), 87.7 (CH), 126.8 (CH), 127.6 (CH), 128.4
(CH), 128.7 (CH), 129.5 (CH), 138.1 (CH), 140.5 (C), 163.0 (C),
170.5 (C).
[R]22 -37.1 (c 0.5, CH2Cl2). Anal. Calcd for C21H20FNO4: C,
D
68.28; H, 5.46; N, 3.79. Found: C, 68.26; H, 5.46; N, 3.77.
(3R,7S,8aS)-7-Meth yl-5-oxo-3-ph en yl-2,3,6,7,8,8a-h exah y-
d r o-5H-oxa zolo[3,2-a ]p yr id in e (14). Ammonium formate
(110 mg, 1.75 mmol) and 10% Pd-C (47 mg) were added to a
solution of 8 (80 mg, 0.22 mmol) in anhydrous MeOH (3 mL).
The resulting suspension was stirred at 25 °C for 20 h, filtered,
and concentrated to give an oil, which was dissolved in toluene
(17 mL). The solution was heated to reflux for 2 h, cooled, and
poured into brine. The aqueous layer was extracted with
AcOEt (2 × 15 mL), and the combined organic layers were
dried and concentrated. The residue was chromatographed (1:1
AcOEt-hexane) to afford pure lactam 14 (37 mg, 73%) as a
1
white solid: IR (film) 1668 cm-1; H NMR (CDCl3) δ 1.15 (d,
J ) 6.8 Hz, 3 H), 1.92 (ddd, J ) 13.6, 6.0, 4.0 Hz, 1 H), 2.05
(m, 1 H), 2.15-2.35 (m, 2 H), 2.52 (dd, J ) 16.7, 4.0 Hz, 1 H),
3.74 (dd, J ) 8.8, 7.6 Hz, 1 H), 4.50 (t, J ) 8.6 Hz, 1 H), 5.04
(t, J ) 5.8 Hz, 1 H), 5.37 (t, J ) 7.8 Hz, 1 H), 7.20-7.40 (m, 5
H); 13C NMR (CDCl3) δ 20.0 (CH3), 24.3 (CH), 34.0 (CH2), 39.4
(CH2), 57.9 (CH), 71.9 (CH2), 86.4 (CH), 125.8 (CH), 127.5 (CH),
128.8 (CH), 139.9 (C), 169.4 (C); [R]22 -168.2 (c 0.5, MeOH).
D
Anal. Calcd for C14H17NO2‚1/4H2O: C, 71.32; H, 7.48; N, 5.94.
Found: C, 71.32; H, 7.38; N, 5.82.
(3R,7S,8a S)-7-Bu tyl-5-oxo-3-p h en yl-2,3,6,7,8,8a -h exa h y-
d r o-5H-oxa zolo[3,2-a ]p yr id in e (15). Operating as above,
from lactam 9 (350 mg, 0.86 mmol), ammonium formate (432
mg, 6.88 mmol), and 10% Pd-C (183 mg) was obtained
compound 15 (176 mg, 74%) as an oil: IR (film) 1662 cm-1; 1H
NMR (CDCl3) δ 0.91 (t, J ) 7.0 Hz, 3 H), 1.25-1.55 (m, 6 H),
1.91 (m, 1 H), 2.10-2.15 (m, 2 H), 2.24 (dd, J ) 17.0, 7.0 Hz,
1 H), 2.52 (dd, J ) 17.0, 5.0 Hz, 1 H), 3.73 (dd, J ) 8.8, 7.6
Hz, 1 H), 4.48 (t, J ) 8.5 Hz, 1 H), 5.00 (t, J ) 5.0 Hz, 1 H),
5.36 (t, J ) 8.0 Hz, 1 H), 7.20-7.40 (m, 5 H); 13C NMR (CDCl3)
δ 13.8 (CH3), 22.4 (CH2), 29.0 (CH), 29.1 (CH2), 32.1 (CH2),
33.7 (CH2), 37.7 (CH2), 57.8 (CH), 71.7 (CH2), 86.2 (CH), 125.6
(CH), 127.3 (CH), 128.6 (CH), 139.7 (C), 169.4 (C); [R]22D -114,9
(c 1.6, MeOH). Anal. Calcd for C17H23NO2‚1/4H2O: C, 73.50;
H, 8.46; N, 5.05. Found: C, 73.53; H, 8.56; N, 5.03.
[3R,6S(an d 6R),7R,8aR]-6-(Ben zyloxycar bon yl)-7-m eth -
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 (17a a n d 17b). Operating as in the preparation
of the unsaturated lactam trans-4, the selenide cis-2 (530 mg,
1.05 mmol) was converted to (3R,8a R)-6-(ben zyloxyca r bo-
n yl)-5-oxo-3-p h en yl-2,3,8,8a -tetr a h yd r o-5H-oxa zolo[3,2-
a ]p yr id in e (cis-4), which was used without further purifica-
tion: IR (film) 1733, 1669 cm -1; 1H NMR (CDCl3) δ 2.70 (ddd,
J ) 17.5, 11.5, 2.2 Hz, 1 H), 2.96 (ddd, J ) 17.5, 6.8, 4.5 Hz,
1 H), 4.18 (dd, J ) 9.0, 1.8 Hz, 1 H), 4.23 (dd, J ) 9.0, 6.3 Hz,
1 H), 5.05 (dd, J ) 6.3, 1.8 Hz, 1 H), 5.14 (dd, J ) 11.5, 4.5
Hz, 1 H), 5.20 (d, J ) 12.4 Hz, 1 H), 5.22 (d, J ) 12.4 Hz, 1 H),
7.25-7.63 (m, 11 H); 13C NMR (CDCl3) δ 30.0 (CH2), 58.0 (CH),
66.9 (CH2), 74.5 (CH2), 86.1 (CH), 126.6 (CH), 128.1 (CH), 128.4
(CH), 127.6 (C), 130.3 (C), 135.4 (C), 140.3 (C), 143.3 (CH),
157.7 (C), 163.4 (C). A solution of crude lactam cis-4 was
allowed to react with CH3Cu(CN)Li (2.5 equiv) [prepared from
(3R,7S,8aS)-7-(p-Flu or oph en yl)-5-oxo-3-ph 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 (16). Operating
as in the preparation of 14, from lactam 11 (120 mg, 0.26
mmol), ammonium formate (131 mg, 2.08 mmol), and 5%

Enantiopure trans-3,4-Disubstituted Piperidines
J . Org. Chem., Vol. 65, No. 10, 2000 3081
1.7 M CH3Li in Et2O (1.54 mL) and CuCN (258 mg, 2.88
mmol)] as in the above preparation of 8 to give (245 mg, 64%
from cis-2) a 3:1 mixture of C-6 epimers 17a and 17b,
respectively, after purification by column chromatography (3:7
(m, 6 H); 13C NMR (CDCl3) δ 30.5 (CH2), 52.2 (CH3), 58.0 (CH),
74.4 (CH2), 86.1 (CH), 126.7 (CH), 127.6 (CH), 128.4 (CH),
130.0 (C), 140.2 (C), 143.4 (CH), 157.3 (C), 164.2 (C). A solution
of crude lactam cis-5 in anhydrous THF (5 mL) was allowed
to react with p-FC6H4Cu(CN)Li (2.5 equiv) [prepared from 0.13
M (p-fluorophenyl)lithium21 in THF (30 mL) and CuCN (372
mg, 4.2 mmol)] as in the above preparation of 19. The resulting
crude oil (705 mg) was chromatographed (1:4 to 1:1 AcOEt-
hexane) to give a 97:3 mixture of C-6 epimers 20a and 20b
AcOEt-hexane). 17a : IR (film) 1739, 1666 cm-1 1H NMR
;
(CDCl3) δ 1.17 (d, J ) 7.2 Hz, 3 H), 2.10 (m, 1 H), 2.32 (ddd,
J ) 13.1, 9.3, 6.6 Hz, 1 H), 2.59 (m, 1 H), 3.13 (d, J ) 5.4 Hz,
1 H), 4.04 (dd, J ) 9.0, 1.2 Hz, 1 H), 4.19 (dd, J ) 9.0, 6.8 Hz,
1 H), 4.94 (dd, J ) 6.8, 1.2 Hz, 1 H), 4.99 (dd, J ) 9.4, 4.7 Hz,
1 H), 5.08 (d, J ) 12.4 Hz, 1 H), 5.13 (d, J ) 12.4 Hz, 1 H),
7,22-7,35 (m, 10 H); 13C NMR (CDCl3) δ 20.5 (CH3), 28.5 (CH),
32.5 (CH2), 54.9 (CH), 58.7 (CH), 66.9 (CH2), 74.1 (CH2), 85.8
(CH2), 126.3 (CH), 127.5 (CH), 128.3 (CH), 128.4 (CH), 135.4
(C), 140.5 (C), 163.2 (C), 169.5 (C). 17b: 1H NMR (CDCl3,
selected resonances) δ 1.08 (d, J ) 6.7 Hz, 3 H), 3.40 (d, J )
5.0 Hz, 1 H), 4.03 (dd, J ) 9.0, 1.2 Hz, 1 H), 4.17 (dd, J ) 9.0,
7.0 Hz, 1 H), 4,88 (dd, J ) 7.0, 1.2 Hz, 1 H), 5.15 (masked, 1
H), 5.15 (s, 2 H), 7.22-7.35 (m, 10 H); 13C NMR (CDCl3,
selected resonances) δ 17.6 (CH3), 28.4 (CH), 33.1 (CH2), 54.4
(CH), 58.3 (CH), 66.8 (CH2), 73.8 (CH2), 86.1 (CH), 135.3 (C),
141.1 (C), 163.4 (C), 168.6 (C).
(388 mg, 67%), respectively. 20a : IR (film) 1744, 1681 cm-1
;
1H NMR (CDCl3) δ 2.39 (dt, J ) 13.2, 4.7 Hz, 1 H), 2.55 (ddd,
J ) 13.2, 9.3, 7.0 Hz, 1 H), 3.59 (s, 3 H), 3.63 (d, J ) 6.0 Hz,
1 H), 3.72 (m, 1 H), 4.04 (dd, J ) 9.0, 1.3 Hz, 1 H), 4.14 (dd, J
) 9.0, 6.8 Hz, 1 H), 4.81 (dd, J ) 9.3, 4.7 Hz, 1 H), 4.96 (dd, J
) 6.8, 1.3 Hz, 1 H), 7.03 (t, J ) 8.5 Hz, 2 H), 7.18 (dd, J ) 8.5,
5.0 Hz, 2 H), 7.20-7.40 (m, 5 H); 13C NMR (CDCl3) δ 33.8
(CH2), 38.4 (CH), 52.4 (CH3), 53.3 (CH), 58.9 (CH), 74.2 (CH2),
85.9 (CH), 115.7 (d, J ) 21.2 Hz, CH), 126.5 (CH), 127.7 (CH),
128.3 (d, J ) 8.2 Hz, CH), 128.5 (CH), 137.6 (d, J ) 2.6 Hz,
C), 140.4 (C), 161.7 (d, J ) 244.7 Hz, C), 163.0 (C), 169.6 (C);
mp 116-118 °C (Et2O); [R]22 -99.2 (c 1.0, MeOH), [R]22
D
D
(3R,6S,7R,8a R)-6-(Be n zyloxyca r b on yl)-5-oxo-3,7-d i-
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 (18a ). Operating as above, from the selenide cis-2 (377
mg, 0.74 mmol) and PhCu(CN)Li (2.5 equiv) [prepared from
1.7 M C6H5Li in cyclohexane (1.1 mL) and CuCN (186 mg, 2.1
mmol)] was obtained a 97:3 mixture of C-6 epimers 18a and
18b, respectively, (240 mg, 75% from cis-2) after purification
by column chromatography (3:7 AcOEt-hexane). Crystalliza-
tion from Et2O-hexane afforded pure 18a : IR (film) 1737,
-120.8 (c 0.2, CH2Cl2). Anal. Calcd for C21H20FNO4: C, 68.28;
H, 5.46; N, 3.79. Found: C, 68.19; H, 5.49; N, 3.77.
(3R ,7R ,8a R )-7-Me t h y l-5-o x o -3-p h e n y l-2,3,6,7,8,8a -
h exa h yd r o-5H-oxa zolo[3,2-a ]p yr id in e (21). Operating as
in the preparation of 14, from lactam 17 (200 mg, 0.55 mmol),
ammonium formate (275 mg, 4.38 mmol), and 10% Pd-C (116
mg) was obtained compound 21 (107 mg, 85%) as a solid: IR
(film) 1662 cm-1; 1H NMR (CDCl3) δ 1.13 (d, J ) 7.1 Hz, 1 H),
2.02 (ddd, J ) 13.0, 8.8, 6.3 Hz, 1 H), 2.07 (dd, J ) 16.5, 5.1
Hz, 1 H), 2.13 (td, J ) 13.0, 5.0 Hz, 1 H), 2.34 (dd, J ) 6.3,
12.1 Hz, 1 H), 2.43 (dd, J ) 16.5, 5.7 Hz, 1 H), 4.03 (dd, J )
9.0, 1.3 Hz, 1 H), 4.18 (dd, J ) 9.0, 6.8 Hz, 1 H), 4.93 (d, J )
6.8 Hz, 1 H), 5.00 (dd, J ) 8.8, 5.0 Hz, 1 H), 7.13-7.31 (m, 5
H); 13C NMR (CDCl3) δ 20.8 (CH3), 24.5 (CH), 34.3 (CH2), 39.0
(CH2), 58.2 (CH), 73.8 (CH2), 85.9 (CH), 126.1 (CH), 128.3 (CH),
127.2 (C), 141.2 (C), 167.4 (C); mp 61-64 °C (i-Pr2O-hexane);
1
1676 cm-1; H NMR (CDCl3) δ 2,42 (m, 1 H), 2.57 (ddd, J )
13.2, 6.7, 2.9 Hz, 1 H), 3.73 (m, 2 H), 4.03 (dd, J ) 9.0, 1.5 Hz,
1 H), 4.13 (dd, J ) 9.0, 6.8 Hz, 1 H), 4.81 (dd, J ) 9.2, 4.5 Hz,
1 H), 4.97 (dd, J ) 6.8, 1.5 Hz, 1 H), 5.03 (d, J ) 12.4 Hz, 1
H), 5.07 (d, J ) 12.4 Hz, 1 H), 7.13-7.40 (m, 15 H); 13C NMR
(CDCl3) δ 33.7 (CH2), 39.0 (CH), 53.1 (CH), 58.9 (CH), 67.1
(CH2), 74.1 (CH2), 86.0 (CH), 126.4 (CH), 126.9 (CH), 128.0
(CH), 128.4 (CH), 128.5 (CH), 129.0 (CH), 127.2 (CH), 127.7
(CH), 128.1 (CH), 135.2 (C), 140.4 (C), 141.8 (C), 163.1 (C),
[R]22 -46.3 (c 1.0, MeOH). Anal. Calcd for C14H17NO2: C,
D
72.70; H, 7.41; N, 6.06. Found: C, 72.78; H, 7.44; N, 6.06.
(3R,4S)-1-[(1R)-2-Hyd r oxy-1-p h en yleth yl]-4-p h en yl-3-
p ip er id in em eth a n ol (22). To a suspension of AlCl3 (163 mg,
1.2 mmol) in anhydrous THF (9.5 mL) at 0 °C was slowly
added LiAlH4 (142 mg, 3.7 mmol). After the mixture was
stirred at 25 °C for 30 min and cooled to -78 °C, lactam 12a
(200 mg, 0.56 mmol) was slowly added. The stirring was
continued for 90 min at -78 °C and for 2 h at 25 °C. Then,
the mixture was cooled to 0 °C, and the reaction was quenched
with H2O. The aqueous layer was extracted with CH2Cl2 (3 ×
10 mL), and the combined organic extracts were dried and
concentrated to give a foam. Column chromatography (98:2
AcOEt-DEA) afforded pure 22 (152 mg, 86%): IR (film) 3383
cm-1; 1H NMR (CDCl3) δ 1.68 (t, J ) 11.0 Hz, 1 H), 1.78-2.40
(m, 3 H), 2.17 (td, J ) 11.5, 4.5 Hz, 1 H), 2.41 (td, J ) 11.5,
2.8 Hz, 1 H), 3.01 (dm, J ) 11.5 Hz, 1 H), 3.14 (dd, J ) 11.0,
7.1 Hz, 1 H), 3.20 (dm, J ) 11.0 Hz, 1 H), 3.35 (dd, J ) 11.0,
3.3 Hz, 1 H), 3.67 (dd, J ) 10.2, 4.8 Hz, 1 H), 3.80 (dd, J )
10.2, 4.8 Hz, 1 H), 4.08 (t, J ) 10.2 Hz, 1 H), 7.10-7.40 (m, 10
H); 13C NMR (CDCl3) δ 34.8 (CH2), 44.4 (CH), 45.1 (CH), 49.4
(CH2), 53.2 (CH2), 60.0 (CH2), 63.7 (CH2), 70.1 (CH), 126.4
(CH), 127.3 (CH), 127.7 (CH), 128.1 (CH), 128.3 (CH), 128.7
(CH), 135.1 (C), 144,08 (C); mp 124-126 °C (AcOEt-hexane);
169.3 (C); mp 93-96 °C; [R]22 -93.5 (c 1.0, MeOH). Anal.
D
Calcd for C27H25NO4: C, 75.86; H, 5.89; N, 3.28. Found: C,
75.90; H, 5.90; N, 3.29.
(3R ,6S ,7R ,8a R )-6-(Be n zyloxyca r b on yl)-7-(p -flu or o-
ph en yl)-5-oxo-3-ph en yl-2,3,6,7,8,8a-h exah ydr o-5H-oxazolo-
[3,2-a ]p yr id in e (19a ). Operating as above, from the selenide
cis-2 (664 mg, 1.3 mmol) and p-FC6H4Cu(CN)Li (2.6 equiv)
[prepared from 0.13 M (p-fluorophenyl)lithium21 in THF (25
mL) and CuCN (319 mg, 3.6 mmol)] was obtained a 97:3
mixture of C-6 epimers 19a and 19b, respectively, (383 mg,
64% from cis-2) after purification by column chromatography
(1:4 to 1:1 AcOEt-hexane). 19a : IR (film) 1741, 1680 cm-1
;
1H NMR (CDCl3) δ 2.38 (dt, J ) 13.5, 5.0 Hz, 1 H), 2.56 (ddd,
J ) 13.5, 9.0, 7.0 Hz, 1 H), 3.68 (m, 2 H), 4.06 (dd, J ) 9.0, 1.5
Hz, 1 H), 4.16 (dd, J ) 9.0, 6.8 Hz, 1 H), 4.85 (dd, J ) 9.5, 5.0
Hz, 1 H), 4.98 (dd, J ) 6.8, 1.5 Hz, 1 H), 7.11 (t, J ) 8.5 Hz,
2 H), 7.14 (m, 4 H), 7.20-7.40 (m, 8 H); 13C NMR (CDCl3) δ
34.1 (CH2), 38.3 (CH), 53.7 (CH), 58.7 (CH), 67.0 (CH2), 74.2
(CH2), 85.9 (CH), 115.6 (d, J ) 21.5 Hz, CH), 126.3 (CH), 127.6
(CH), 127.9 (CH), 128.1 (CH), 128.3 (d, J ) 8.1 Hz, CH), 128.5
(CH), 128.6 (CH), 135.2 (C), 137.5 (d, J ) 3.0 Hz, C), 140.3
(C), 161.5 (d, J ) 244.7 Hz, C), 163.0 (C), 168.8 (C); mp 76-78
°C (Et2O); [R]22D -72.4 (c 1.0, MeOH), [R]22D -66.0 (c 0.2, CH2-
Cl2). Anal. Calcd for C27H24FNO4: C, 72.79; H, 5.43; N, 3.14.
Found: C, 72.71; H, 5.46; N, 3.12.
[R]22 +28.6 (c 0.5, MeOH). Anal. Calcd for C20H25NO2‚1/
D
4H2O: C, 76.04; H, 8.14; N, 4.43. Found: C, 75.86; H, 7.86; N,
4.49.
(3R,6S,7R,8a R)-7-(p-F lu or op h en yl)-6-(m eth oxyca r bo-
n 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 (20a ). Operating as in the preparation of the
unsaturated lactam trans-4, the selenide cis-3 (675 mg, 1.57
mmol) was converted to (3R,8a R)-6-(m eth oxyca r bon yl)-5-
oxo-3-p h en yl-2,3,8,8a -tetr a h yd r o-5H-oxa zolo[3,2-a ]p yr i-
d in e (cis-5), which was used without further purification: 1H
NMR (CDCl3) δ 2.71(ddd, J ) 17.5, 11.6, 2.2 Hz, 1 H), 3.00
(ddd, J ) 17.5, 6.8, 4.5 Hz, 1 H), 3.79 (s, 3 H), 4.20 (dd, J )
9.0, 1.9 Hz, 1 H), 4.26 (dd, J ) 9.0, 6.3 Hz, 1 H), 5.03 (dd, J )
6.3, 1.9 Hz, 1 H), 5.15 (dd, J ) 11.6, 4.5 Hz, 1 H), 7.20-7.40
(3R ,4S )-1-(t er t -Bu t oxyca r b on yl)-4-p h e n yl-3-p ip e r i-
d in em eth a n ol (23). A solution of piperidine 22 (191 mg, 0.61
mmol) and di-tert-butyl dicarbonate (267 mg, 1.22 mmol) in
AcOEt (20 mL) containing 20% Pd(OH)2-C (48 mg) was
hydrogenated at 25 °C for 15 h. The catalyst was removed by
filtration, and the solvent was evaporated. The resulting oil
was chromatographed (3:7 AcOEt-hexane with 4% DEA) to
give a mixture (214 mg) of compound 23 and phenylethanol.
Crystallization (THF-hexane) afforded pure carbamate 23
(150 mg, 88%): IR (film) 3400, 1692, 1670 cm-1
;
1H NMR
(CDCl3) δ 1.48 (s, 9 H), 1.60-1.74 (m, 3 H), 2.51 (td, J ) 11.3,

3082 J . Org. Chem., Vol. 65, No. 10, 2000
Amat et al.
4.1 Hz, 1 H), 2.69 (dd, J ) 13.2, 11.5 Hz, 1 H), 2.78 (tm, J )
12.7 Hz, 1 H), 3.25 (dd, J ) 11.0, 6.5 Hz, 1 H), 3.42 (dd, J )
11.0, 3.3 Hz, 1 H), 4.20 (dm, J ) 12.7 Hz, 1 H), 4.36 (dm, J )
13.2 Hz, 1 H), 7.15-7.35 (m, 5 H); 13C NMR (CDCl3) δ 28.5
(CH3), 33.9 (CH2), 43.7 (CH), 44.5 (CH2), 44.9 (CH), 46.9 (CH2),
63.1 (CH2), 79.6 (C), 126.6 (CH), 127.4 (CH), 128.6 (CH), 143.8
(C), 154.9 (C); mp 132-133 °C; [R]22D +6.4 (c 0.4, MeOH). Anal.
Calcd for C17H25NO3‚1/4H2O: C, 69.01; H, 8.69; N, 4.73.
Found: C, 69.10; H, 8.51; N, 4.64.
(dd, J ) 9.6, 6.9 Hz, 1 H), 3.63 (dd, J ) 9.6, 3.0 Hz, 1 H), 3.71
(s, 3 H), 4.25 (dm, J ) 12.3 Hz, 1 H), 4.47 (dm, J ) 11.4 Hz,
1 H), 6.34 (d, J ) 9.0 Hz, 2 H), 6.72 (d, J ) 9.0 Hz, 2 H), 7.11-
7.29 (m, 5 H); 13C NMR (CDCl3) δ 28.4 (CH3), 33.8 (CH2), 41.6
(CH), 44.3 (CH2), 44.8 (CH), 47.4 (CH2), 55.6 (CH3), 68.6 (CH2),
79.5 (C), 114.5 (CH), 115.4 (CH), 126.6 (CH), 127.3 (CH), 128.6
(CH), 143.5 (C), 152.9 (C), 153.7 (C), 154.7 (C); [R]22 +22.9 (c
D
0.26, MeOH). Anal. Calcd for C24H31O4N‚H2O: C, 69.59; H,
7.99; N, 3.38. Found: C, 69.59; H, 7.52; N, 3.28.
(3R,4S)-4-(p-F lu or op h en yl)-1-[(1R)-2-h yd r oxy-1-p h en -
yleth yl]-3-p ip er id in em eth a n ol (24). Operating as in the
preparation of 22, from lactam 13a (595 mg, 1.61 mmol), AlCl3
(462 mg, 3.47 mmol), and LiAlH4 (396 mg, 10.45 mmol) was
obtained compound 24 (370 mg, 74%) after column chroma-
(3R,4S)-3-(p-Meth oxyph en oxym eth yl)-1-m eth yl-4-ph en -
ylp ip er id in e (F em oxetin e, 27). A solution of carbamate 26
(188 mg, 0.45 mmol) in anhydrous Et2O (1.7 mL) was added
to a suspension of LiAlH4 (78 mg, 2.05 mmol) in anhydrous
Et2O (1.0 mL) at 0 °C, and the mixture was stirred at room
temperature for 2 h. The reaction was quenched by addition
of 2 N aqueous NaOH, and the aqueous layer was extracted
with Et2O. The combined ethereal extracts were dried and
concentrated, and the resulting residue was chromatographed
(98:2 Et2O-DEA) to give femoxetine (27, 135 mg, 74%) as an
oil: IR (film) 1509, 1230 cm-1; 1H NMR (CDCl3) δ 1.84 (dm, J
) 12.7 Hz, 1 H), 1.92 (m, 1 H), 2.04 (m, 2 H), 2.32 (m, 1 H),
2.38 (s, 3 H), 2.44 (td, J ) 11.3, 4.4 Hz, 1 H), 2.99 (dm, J )
10.3 Hz, 1 H), 3.25 (dm, J ) 11.2 Hz, 1 H), 3.48 (dd, J ) 9.4,
7.1 Hz, 1 H), 3.61 (dd, J ) 9.4, 2.9 Hz, 1 H), 3.72 (s, 3 H), 6.66
(d, J ) 9.0 Hz, 2 H), 6.74 (d, J ) 9.0 Hz, 2 H), 7.10-7.35 (m,
5 H). 13C NMR (CDCl3) δ 34.1 (CH2), 41.7 (CH), 44.1 (CH),
46.3 (CH3), 55.5 (CH3), 56.1 (CH2), 59.5 (C-2), 69.2 (CH2), 114.3
(CH), 115.2 (CH), 126.4 (CH), 127.4 (CH), 128.5 (CH), 143.8
1
tography (97:3 AcOEt-DEA): IR (film) 3416 cm-1; H NMR
(CDCl3) δ 1.65 (t, J ) 11.0 Hz, 1 H), 1.70-1.95 (m, 3 H), 2.14
(td, J ) 11.3, 4.6 Hz, 1 H), 2.37 (td, J ) 11.5, 3. 3 Hz, 1 H),
2.39 (br s, 2 H), 2.95 (dm, J ) 11.5 Hz, 1 H), 3.09 (dd, J )
11.0, 7.3 Hz, 1 H), 3.18 (dm, J ) 11.0 Hz, 1 H), 3.30 (dd, J )
11.0, 3.2 Hz, 1 H), 3.63 (dd, J ) 10.4, 5.0 Hz, 1 H), 3.77 (dd, J
) 10.4, 5.0 Hz, 1 H), 4.04 (t, J ) 10.4 Hz, 1 H), 6.92 (t, J ) 8.8
Hz, 2 H), 7.06 (dd, J ) 8.8, 5.6 Hz, 2 H), 7.19 (m, 2 H), 7.32
(m, 2 H); 13C NMR (CDCl3) δ 35.0 (CH2), 44.2 (CH), 44.6 (CH),
49.3 (CH2), 53.2 (CH2), 60.0 (CH2), 63.6 (CH2), 70.1 (CH), 115.2
(d, J ) 21.0 Hz, CH), 127.9 (CH), 128.2 (CH), 128.6 (d, J )
7.5 Hz, CH), 128.9 (CH), 135.1 (C), 139.7 (d, J ) 3.0 Hz, C),
161.0 (d, J ) 243.2 Hz, C); mp 138-139 °C (Et2O); [R]22D +31.4
(c 0.5, MeOH). Anal. Calcd for C20H24FNO2: C, 72.92; H, 7.34;
N, 4.25. Found: C, 73.06; H, 7.49; N, 4.26.
(C), 152.9 (C), 153.5 (C); [R]22 +75.7 (c 0.6, MeOH). Femox-
D
(3R,4S)-1-(ter t-Bu toxyca r bon yl)-4-(p-flu or op h en yl)-3-
p ip er id in em eth a n ol (25). Operating as in the preparation
of 23, from compound 24 (495 mg, 1.60 mmol), di-tert-butyl
dicarbonate (625 mg, 2.87 mmol), and 20% Pd(OH)2-C (150
mg) was obtained carbamate 25 (363 mg, 73%) after column
etine hydrochloride: mp 179-180 °C (acetone-Et2O); [R]22
D
+78.7 (c 0.2, MeOH). Anal. Calcd for C20H26NO2Cl: C, 69.05;
H, 7.53; N, 4.03. Found: C, 69.12; H, 7.58; N, 4.03.
(3R,4S)-1-(ter t-Bu toxyca r bon yl)-4-(p-flu or op h en yl)-3-
[3,4-(m eth ylen edioxy)ph en oxym eth yl]piper idin e (28). Op-
erating as in the preparation of 26, from alcohol 25 (260 mg,
0.84 mmol) and methanesulfonyl chloride (73 mL, 0.94 mmol)
was obtained a crude mesylate (238 mg): 1H NMR (CDCl3) δ
1.49 (s, 9 H), 1.67 (qd, J ) 12.8, 4.3 Hz, 1 H), 1.80 (dm, J )
12.8 Hz, 1 H), 2.05 (m, 1 H), 2.56 (td, J ) 11.7, 3.8 Hz, 1 H),
2.76 (m, 2 H), 2.89 (s, 3 H), 3.81 (dd, J ) 10.0, 6.6 Hz, 1 H),
3.97 (dd, J ) 10.0, 3.0 Hz, 1 H), 4.23 (m, 1 H), 4.38 (m, 1 H),
7.02 (t, J ) 8.6 Hz, 2 H), 7.15 (dd, J ) 8.6, 5.4 Hz, 2 H); 13C
NMR (CDCl3) δ 28.2 (CH3), 33.8 (CH2), 36.8 (CH3), 40.8 (CH),
43.6 (CH), 43.9 (CH2), 46.1 (CH2), 68.3 (CH2), 79.6 (C), 115.4
(CH), 128.4 (CH), 137.9 (C), 157.0 (C), 163.1 (C). To a solution
of sodium methoxide, prepared from sodium (80 mg) and
MeOH (0.6 mL), was added 3,4-(methylenedioxy)phenol (464
mg, 3.4 mmol), and the mixture was stirred at room temper-
ature for 20 min. Then, a solution of the above crude mesylate
in MeOH (1 mL) was added, and the resulting mixture was
heated at reflux for 90 min, cooled, and concentrated. The
residue was taken up with Et2O, washed with 0.5 N aqueous
NaOH, dried, and concentrated. The residue was chromato-
graphed (97:3 CH2Cl2-Et2O), affording pure compound 28 (200
chromatography (1:1 CH2Cl2-Et2O): IR (film) 3515, 1666 cm-1
;
1H NMR (CDCl3) δ 1.30 (m, 1 H), 1.48 (s, 9H), 1.55-1.90 (m,
3 H), 2.53 (td, J ) 11.5, 4.1 Hz, 1 H), 2.70 (dd, J ) 13.3, 11.2
Hz, 1 H), 2.77 (td, J ) 12.4, 2.8 Hz, 1 H), 3.25 (dt, J ) 11.0,
6.1 Hz, 1 H), 3.43 (ddd, J ) 11.0, 4.6, 3.4 Hz, 1 H), 4.18 (dm,
J ) 13.0 Hz, 1 H), 4.35 (ddd, J ) 13.2, 4.1, 1.7 Hz, 1 H), 6.98
(m, 2 H), 7.13 (m, 2 H); 13C NMR (CDCl3) δ 28.5 (CH3), 34.4
(CH2), 43.9 (CH), 44.2 (CH), 44.4 (CH2), 47.0 (CH2), 63.0 (CH2),
79.6 (C), 115.4 (d, J ) 20.5 Hz, CH), 128.7 (d, J ) 7.6 Hz,
CH), 139.6 (d, J ) 3.3 Hz, C), 154.8 (C), 161.3 (d, J ) 243.1
Hz, C); [R]22 +5.8 (c 1.75, MeOH). Anal. Calcd for C17H24
-
D
FNO3: C, 65.99; H, 7.82; N, 4.53. Found: C, 65.78; H, 7.89;
N, 4.37.
(3R,4S)-1-(ter t-Bu t oxyca r b on yl)-3-(p -m et h oxyp h en -
oxym eth yl)-4-p h en ylp ip er id in e (26). Methanesulfonyl chlo-
ride (141 mL, 1.82 mmol) was slowly added to a solution of
alcohol 23 (391 mg, 1.40 mmol) in pyridine (2 mL) at 10 °C,
and the mixture was stirred at this temperature for 1 h. The
resulting suspension was poured into 10% aqueous NaHCO3
and extracted with Et2O (3 × 10 mL). The combined organic
extracts were dried and concentrated to give a crude mesylate
1
mg, 56%) as an oil: IR (film) 1693 cm-1; H NMR (CDCl3) δ
(670 mg) as an oil: IR (film) 1690 cm-1
;
1H NMR (CDCl3) δ
1.50 (s, 9 H), 1.60-1.90 (m, 2 H), 2.02 (m, 1 H), 2.67 (td, J )
11.6, 4.0 Hz, 1 H), 2.80 (m, 2 H), 3.44 (dd, J ) 9.3, 6.6 Hz, 1
H), 3.58 (dd, J ) 9.6, 2.8 Hz, 1 H), 4.24 (dm, J ) 13.3 Hz, 1
H), 4.44 (dm, J ) 13.5 Hz, 1 H), 5.88 (s, 2 H), 6.13 (dd, J )
8.5, 2.5 Hz, 1 H), 6.36 (d, J ) 2.5 Hz, 1 H), 6.63 (d, J ) 8.5 Hz,
1 H), 6.98 (t, J ) 8.6 Hz, 2 H), 7.13 (m, 2 H); 13C NMR (CDCl3)
δ 28.4 (CH3), 33.8 (CH2), 41.8 (CH), 44.0 (CH), 44.2 (CH2), 47.1
(CH2), 68.7 (CH2), 79.6 (C), 97.9 (CH), 101.0 (CH2), 105.4 (CH),
107.8 (CH), 115.4 (d, J ) 21.1 Hz, CH), 128.7 (d, J ) 7.7 Hz,
CH), 139.0 (C), 141.8 (C), 148.0 (C), 154.2 (C), 154.8 (C), 161.5
1.50 (s, 9 H), 1.62-1.90 (m, 2 H), 2.10 (m, 1 H), 2.56 (td, J )
11.7, 4.1 Hz, 1 H), 2.66-2.88 (m, 2 H), 2.86 (s, 3 H), 3.83 (dd,
J ) 9.9, 6.6 Hz, 1 H), 3.97 (dd, J ) 9.9, 3.0 Hz, 1 H), 4.23 (m,
1 H), 4.40 (m, 1 H), 7.15-7.38 (m, 5 H); 13C NMR (CDCl3) δ
28.4 (CH3), 33.8 (CH2), 36.9 (CH3), 40.8 (CH), 44.5 (CH2), 44.7
(CH), 46.9 (CH2), 69.7 (CH2), 79.9 (C), 127.2 (CH), 127.4 (CH),
128.9 (CH), 142.3 (C), 154.6 (C). To a suspension of NaH (122
mg, 2.8 mmol, 55-65% dispersion in mineral oil) in anhydrous
THF (3.5 mL) at 0 °C was added p-methoxyphenol (347 mg,
2.8 mmol), and the mixture was stirred for 45 min. Then, a
solution of the above crude mesylate in anhydrous THF (2 mL)
was slowly added, and the resulting mixture was heated at
reflux for 3 h, cooled, and poured into 2 N aqueous NaOH.
The aqueous layer was extracted with Et2O, and the combined
organic extracts were dried and concentrated to give an oil.
Column chromatography (CH2Cl2) afforded compound 26 (261
(d, J ) 243.0 Hz, C); [R]22 +24.8 (c 1.0, MeOH). Anal. Calcd
D
for C24H28FNO5: C, 67.11; H, 6.57; N, 3.26. Found: C, 66.96;
H, 6.58; N, 3.22.
(3R,4S)-4-(p -F lu or op h en yl)-3-[(3,4-(m et h ylen ed ioxy)-
p h en oxym eth yl]p ip er id in e [(+)-P a r oxetin e, 29]. TFA (2.4
mL, 31 mmol) was slowly added to a solution of carbamate 28
(180 mg, 0.42 mmol) in anhydrous CH2Cl2 (2.5 mL), and the
resulting solution was stirred at room temperature for 15 min.
The mixture was poured into saturated aqueous NaHCO3, and
the aqueous layer was extracted with CH2Cl2 (3 × 10 mL).
1
mg, 50%): IR (film) 1693 cm-1; H NMR (CDCl3) δ 1.50 (s, 9
H), 1.65-1.90 (m, 2 H), 2.09 (m, 1 H), 2.65 (td, J ) 11.4, 4.5
Hz, 1 H), 2.80 (t, J ) 11.4 Hz, 1 H), 2.83 (masked, 1 H), 3.48

Enantiopure trans-3,4-Disubstituted Piperidines
J . Org. Chem., Vol. 65, No. 10, 2000 3083
The combined organic extracts were dried and concentrated,
and the resulting residue was chromatographed (95:5 AcOEt-
DEA) to afford pure 29 (110 mg, 77%) as a colorless oil: IR
(film) 2919 cm-1; 1H NMR (CDCl3) δ 1.66-1.90 (m, 2 H), 2.10
(m, 1 H), 2.60 (td, J ) 12.0, 5.0 Hz, 1 H), 2.71 (t, J ) 12.0 Hz,
1 H), 2.76 (td, J ) 12.0, 3.0 Hz, 1 H), 3.21 (dm, J ) 12.0 Hz,
1 H), 3.44 (dd, J ) 9.5, 7.0 Hz, 1 H), 3.44 (masked, 1 H), 3.56
(dd, J ) 9.5, 3.0 Hz, 1 H), 5.88 (s, 2 H), 6.12 (dd, J ) 8.5, 2.5
Hz, 1 H), 6.34 (d, J ) 2.5 Hz, 1 H), 6.62 (d, J ) 8.5 Hz, 1 H),
6.98 (t, J ) 8.8 Hz, 2 H), 7.13 (dd, J ) 8.8, 5.5 Hz, 2 H); 13C
NMR (CDCl3) δ 32.9 (CH2), 41.3 (CH), 43.2 (CH), 45.8 (CH2),
48.6 (CH2), 68.5 (CH2), 97.8 (CH), 101.1 (CH2), 105.4 (CH),
107.8 (CH), 115.6 (d, J ) 20.7 Hz, CH), 128.7 (d, J ) 7.3 Hz,
CH), 138.6 (d, J ) 3.0 Hz, C), 141.7 (C), 148.1 (C), 154.0 (C),
161.0 (d, J ) 243.3 Hz, C); [R]22D +81.7 (c 1.3, MeOH). Sample
(3S,4R)-1-(ter t-Bu toxyca r bon yl)-4-(p-flu or op h en yl)-3-
[3,4-(m et h ylen ed ioxy)p h en oxym et h yl]p ip er id in e (ent-
28). Operating as in the opposite enantiomeric series, alcohol
ent-25 (83 mg, 0.26 mmol) was converted to a crude mesylate
(100 mg). Operating as in the preparation of 26, from this
crude mesylate, NaH (35 mg, 0.8 mmol, 55-65% dispersion
in mineral oil), and 3,4-(methylenedioxy)phenol (111 mg, 0.8
mmol) was obtained compound ent-28 (76 mg, 66%) after
column chromatography (gradient of eluents hexanes-Et2O):
[R]22 -25.1 (c 1.0, MeOH). Anal. Calcd for C24H28FNO5: C,
D
67.12; H, 6.57; N, 3.26. Found: C, 67.06; H, 6.74; N, 3.20.
(3S,4R)-4-(p -flu or op h en yl)-3-[(3,4-(m et h ylen ed ioxy)-
p h en oxym eth yl]p ip er id in e [(-)-P a r oxetin e, en t-29]. Op-
erating as in the opposite enantiomeric series, from carbamate
ent-28 (119 mg, 0.27 mmol) and TFA (1.55 mL, 20.3 mmol)
was obtained pure ent-29 [(-)-paroxetine] (65 mg, 72%) after
from Seroxat: [R]22 -89.4 (c 0.75, MeOH).
D
column chromatography (95:5 AcOEt-DEA): [R]22 -80.8 (c
(3S,4R)-1-[(1R)-2-Hyd r oxy-1-p h en yleth yl]-4-p h en yl-3-
p ip er id in em eth a n ol (30). Operating as in the preparation
of 22, from lactam 18a (265 mg, 0.62 mmol), AlCl3 (165 mg,
1.2 mmol), and LiAlH4 (165 mg, 4.3 mmol) was obtained
compound 30 (96 mg, 50%) after column chromatography (98:2
D
1.25, MeOH), sample from Seroxat: [R]22 -89.4 (c 0.75,
D
MeOH). An HPLC analysis showed that the sample was not
contaminated by defluoroparoxetine (a common impurity in
paroxetine samples). Anal. Calcd for C19H18FNO3‚1/4H2O C,
68.35; H, 6.18; N, 4.19. Found: C, 68.38; H, 6.25; N, 4.21.
1
AcOEt-DEA): IR (film) 3393 cm-1; H NMR (CDCl3) δ 1.78
(m, 3 H), 2.05-2.16 (m, 2 H), 2.25 (t, J ) 10.5 Hz, 1 H), 2.96
(dm, J ) 7.0 Hz, 1 H), 3.18 (dd, J ) 11.0, 7.0 Hz, 1 H), 3.24
(ddd, J ) 10.5, 3.2, 2.0 Hz, 1 H), 3.37 (dd, J ) 11.0, 3.0 Hz, 1
H), 3.66 (dd, J ) 10.2, 5.2 Hz, 1 H), 3.80 (dd, J ) 10.2, 5.2 Hz,
1 H), 4.03 (t, J ) 10.2 Hz, 1 H), 7.13-7.36 (m, 10 H); 13C NMR
(CDCl3) δ 34.5 (CH2), 44.8 (CH), 45.1 (CH), 46.4 (CH2), 56.6
(CH2), 60.1 (CH2), 63.8 (CH2), 70.1 (CH), 126.4 (CH), 127.9
(CH), 127.3 (CH), 128.1 (CH), 128.6 (CH), 129.0 (CH), 135.0
Com p u ta tion a l Meth od s. The generalized molecular in-
teraction potential with polarization (GMIPp)15,16 has been
used to investigate the reactivity pattern of the model unsat-
urated bicyclic lactams cis-A and trans-A. The GMIPp com-
putes the interaction energy between the molecule, which is
treated at the quantum mechanical (QM) level, and a classical
probe entity. Such an interaction energy is determined from
the addition of three terms (see eq 1): (i) an electrostatic
contribution that is computed from the electrostatic potential
computed at the QM level; (ii) a classical dispersion-repulsion
term; and (iii) a polarization contribution derived from per-
turbational theory. In eq 1 RA and RB stand for the positions
of the nuclei (ZA) in the QM molecule and of the atoms in the
classical particle, c denotes the coefficient of atomic orbitals
in the molecular orbital-linear combination of atomic orbitals
(MO-LCAO) approximation, Pµν is the first-order density
matrix, φ is the set of atomic orbitals, ꢀAB and R*AB are the
van der Waals parameters, and ê denotes the energy of
molecular orbitals. Let us note that the perturbational esti-
mates of the polarization contribution are very similar to the
self-consistent field values.16 The QM molecule was described
by using the wave function and geometry determined at the
restricted Hartree-Fock level with a 6-31G(d) basis set,22 and
the van der Waals parameters were taken from an in-house
quantum mechanical-molecular mechanical parametriza-
tion.23 The classical particle was defined by a point charge of
-1 units of electrons and van der Waals parameters of a
carbon atom. The parameters ꢀAB and R*AB were computed
(C), 144.0 (C); [R]22 -36,2 (c 1.0, MeOH); 30 hydrochloride:
D
mp 227-230 °C (acetone-EtOH-hexane). Anal. Calcd for
C
20H26NO2Cl‚H2O: C, 65.65; H, 7.71; N, 3.82. Found: C, 65.61;
H, 7.48; N, 3.82.
(3S,4R)-4-p-F lu or op h en yl-1-[(1R)-2-h yd r oxy-1-p h en yl-
eth yl]-3-p ip er id in em eth a n ol (31). From lactam 19a : Op-
erating as in the preparation of 22, from lactam 19a (145 mg,
0.32 mmol), AlCl3 (93 mg, 0.7 mmol), and LiAlH4 (81 mg, 2.15
mmol; stirring at 25 °C for 4 h) was obtained compound 31
(80 mg, 75%) after column chromatography (92:8 AcOEt-
1
DEA). IR (film) 3381 cm-1; H NMR (CDCl3) δ 1.65-1.86 (m,
3 H), 2.05 (m, 1 H), 2.17 (td, J ) 10.7, 4.2 Hz, 1 H), 2.26 (t, J
) 11.0 Hz, 1 H), 2.96 (dm, J ) 10.7 Hz, 1 H), 3.19 (dd, J )
10.8, 7.2 Hz, 1 H), 3.23 (ddd, J ) 11.0, 3.6, 1.8 Hz, 1 H), 3.38
(dd, J ) 10.8, 3.0 Hz, 1 H), 3.66 (dd, J ) 10.0, 5.0 Hz, 1 H),
3.80 (dd, J ) 10.0, 5.0 Hz, 1 H), 4.03 (t, J ) 10.0 Hz, 1 H);
6.97 (t, J ) 8.7 Hz, 2 H), 7.11 (m, 2 H), 7.23 (m, 2 H), 7.34 (m,
3 H); 13C NMR (CDCl3) δ 34.6 (CH2), 44.2 (CH), 44.9 (CH),
46.4 (CH2), 56.5 (CH2), 60.2 (CH2), 63.5 (CH2), 70.1 (CH), 115.3
(d, J ) 20.8 Hz, CH), 127.9 (CH), 128.2 (CH), 128.6 (d, J )
7.7 Hz, CH), 128.9 (CH), 135.3 (C), 139.7 (d, J ) 3.0 Hz, C),
from the atomic parameters using the relationships ꢀAB
)
161.5 (d, J ) 242.8 Hz, C); [R]22 -40.1 (c 0.5, MeOH); 31
D
(ꢀAꢀB)0.5 and R*AB ) R*A + R*B.
hydrochloride: 191-193 °C (THF-hexane). Anal. Calcd for
.
C
20H25ClFNO2 1/4H2O: C, 64.85; H, 6.94; N, 3.78. Found: C,
occ
ZA
|RB - RA|
64.89; H, 7.01; N, 3.86.
1
GMIPp )
-
Pµν φµ
φν +
From lactam 20a : Operating as in the preparation of 22,
from lactam 20a (78 mg, 0.21 mmol), AlCl3 (61 mg, 0.45 mmol),
and LiAlH4 (1.4 mL of a 1 M THF solution, 1.4 mmol; stirring
at 25 °C for 5 h) was obtained compound 31 (80 mg, 75%) after
column chromatography (92:8 AcOEt-DEA).
∑
∑ ∑ ∑
|
|
|RB - r|
A
i
µ
ν
12
6
R*AB
R*AB
ꢀAB
- 2
+
(3S,4R)-1-(ter t-Bu toxyca r bon yl)-4-(p-flu or op h en yl)-3-
p ip er id in em eth a n ol (ent-25). Operating as in the prepara-
tion of 23, from diol 31 (473 mg, 1.33 mmol), di-tert-butyl
dicarbonate (521 mg, 2.39 mmol), and 20% Pd(OH)2-C (133
mg) was obtained carbamate ent-25 (232 mg, 57%) after
∑
(
[
)
(
)
]
|RB - RA|
|RB - RA|
A
occ vir
2
1
1
cµicνj φµ
φν
(1)
∑ ∑
∑ ∑
|
|
{
}
êi - êj
RB - r
i
j
µ
ν
column chromatography (9:1 CH2Cl2-Et2O): [R]22 -6.8 (c
D
1.75, MeOH). Anal. Calcd for C17H24FNO‚1/2H2O: C, 64.13;
H, 7.91; N, 4.39. Found: C, 64.46; H, 8.13; N, 4.26).
GMIPp calculations were performed on the most stable
conformations of the cis and trans isomers of A. To this end,
a preliminary exploration was performed at the molecular
mechanical level using the CVFF9124 force field implemented
in the Insight-II25 program, and the geometry of the selected
conformers was subsequently optimized at the RHF/6-31G(d)
level. One and two stationary points were found for cis-A and
trans-A, respectively, and their minimum energy nature was
(22) Hariharan, P. C.; Pople, J . A. Theor. Chim. Acta 1973, 28, 213.
(23) Alhambra, C.; Luque, F. J .; Orozco, M. J . Phys. Chem. 1995,
99, 3084.
(24) Maple, J . R.; Dinur, U.; Hagler, A. T. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 5350.
(25) Insight-II (version 97.0), Molecular Simulations, San Diego,
1997.

3084 J . Org. Chem., Vol. 65, No. 10, 2000
Amat et al.
verified from harmonic frequency calculations. The two con-
formers found for trans-A differ in the position of carbon 2
(down or up) in the five-membered ring. The difference in
stability between the three optimized structures was deter-
mined to be less than 0.5 kcal/mol at this level of theory.
Cultura” for fellowships to J .H. and M. P., and to the
“Generalitat de Catalunya” for a fellowship to M.C.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H- and
13C NMR spectra of compounds cis-2, trans-2, cis-3, trans-3,
cis-4, trans-4, cis-5, trans-5, 17a ,b, and 29, ORTEP diagrams
and X-ray crystallographic data of compounds 12a and 22, and
complete computational results for cis-A and trans-A. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. Financial support from the DGI-
CYT, Spain (project PB94-0214) and to the “Comissionat
per a Universitats i Recerca”, Generalitat de Catalunya,
for Grant 1999-SGR-00079 are gratefully acknowledged.
Thanks are also due to the “Ministerio de Educacio´n y
J O991816P