Stereocontrolled reduction of chiral pyrrolidine and piperidine β-enamino esters: Formal enantioselective synthesis of (+)-calvine

Article abstract of DOI:10.1016/j.tet.2005.05.079

The results of a study dealing with the chemio- and diastereoselective reduction of chiral pyrrolidine and piperidine β-enamino esters 1, 2 and 3, 4 into β-amino esters are reported. This approach was successfully applied to a formal synthesis of (+)-calvine.

Full text of DOI:10.1016/j.tet.2005.05.079

Tetrahedron 61 (2005) 7774–7782
Stereocontrolled reduction of chiral pyrrolidine and piperidine
b-enamino esters: formal enantioselective synthesis of (C)-calvine
´
Sandrine Calvet-Vitale, Corinne Vanucci-Bacque, Marie-Claude Fargeau-Bellassoued
*
´
and Gerard Lhommet
´ ´ ´
Laboratoire de Chimie Organique, UMR 7611, Equipe de Chimie des Heterocycles, Universite P. et M. Curie,
4 Place Jussieu, 75252 Paris cedex 05, France
Received 15 March 2005; revised 24 May 2005; accepted 25 May 2005
Available online 15 June 2005
Abstract—The results of a study dealing with the chemio- and diastereoselective reduction of chiral pyrrolidine and piperidine b-enamino
esters 1, 2 and 3, 4 into b-amino esters are reported. This approach was successfully applied to a formal synthesis of (C)-calvine.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Diastereoselective synthesis of chiral a,a0-disubstituted
pyrrolidines and piperidines, which are sub-structures
present in many naturally occurring and biologically
important compounds, is of considerable current interest.1
In a previous report, we described the diastereoselective
preparation of chiral pyrrolidine and piperidine bicyclic
b-enamino esters 1, 2 and 3, 4 (Fig. 1) by condensation of
(S)-phenylglycinol on u-oxo alkynoates or u-oxo b-keto
esters.2 We now wish to report the results of a study aimed
at diastereoselectively reducing the double bond of the
b-enamino ester moiety of 1–4 in order to obtain the
corresponding b-amino esters. Related heterocycles have
been indeed already described as useful intermediates in the
total synthesis of alkaloids.1d,3 Finally, as an illustration of
the interest of our approach, we will describe a formal
synthesis of enantiopure (C)-calvine (5).
In order to assess the influence of the reducing agent on
the chemio- and diastereoselectivity of the reaction, the
reductions of b-enamino esters were carried out either by
catalytic hydrogenation or using an hydride. Catalytic
hydrogenations were performed under atmospheric pressure
using PtO2 and Pd(OH)2 as catalysts, whereas hydride
reductions were carried out with sodium triacetoxyboro-
hydride in acetic acid.4
We first investigated the reduction of the pyrrolidine and
piperidine bicyclic compounds 1 (Scheme 1) and 3 (Scheme
2), which both contain an angular hydrogen atom.
Treatment with sodium triacetoxyborohydride of 1 and 3
led to the reduction of the C–C double bond along with the
cleavage of the oxazolidine ring to give compounds 6 and 7,
respectively. Pyrrolidine 6 was obtained in high yield (95%)
Figure 1.
Keywords: Reduction; b-Amino esters; Pyrrolidine; Piperidine; Calvine.
*
Corresponding author. Tel.: C33 1 44 27 31 78; fax: C33 1 44 27 30 56;
e-mail: lhommet@ccr.jussieu.fr
Scheme 1. Reduction of 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.079

S. Calvet-Vitale et al. / Tetrahedron 61 (2005) 7774–7782
7775
Scheme 2. Reduction of 3.
and excellent diastereoselectivity (95% de) (Scheme 1). The
stereochemistry of the major isomer 6a was assigned as (2S)
by comparison of spectroscopic data with that described in
the literature.5 Concerning the piperidine derivative 3
(Scheme 2), the reaction proceeded with poor diastereo-
selectivity (deZ20%) and afforded 7 as an inseparable
mixture of diastereomers. The major isomer 7a was
identified as the (2S) isomer, since spectroscopic data
were found identical to that previously reported for this
compound.5 Acetylation of the crude mixture (Ac2O,
pyridine) resulted in a mixture of two compounds (2S)-8a
and (2R)-8b that were isolated in 52 and 34% yield,
respectively.
obtained transiently and in situ transformed into tert-butyl
carbamates 9 and 10, respectively, in 71 and 70% isolated
yield. Analysis by chiral GC and optical rotation measure-
ments showed that both compounds were obtained with
poor stereoselectivity (ee for 9: 30% and for 10: 40%) and
that the (2R) isomers ent-9a6 and ent-10a 3c were the major
enantiomers.
Hydrogenation of compound 1 in the presence of PtO2 as the
catalyst was surprisingly ineffective.7 In contrast, under the
same reaction conditions, compound 3 was chemioselec-
tively reduced into bicyclic piperidines 11 as a mixture of
four isomers (Scheme 2). Column chromatography allowed
the isolation of inseparable piperidines 11a, 11c (ratio
65:35) on the one hand and of inseparable piperidines 11b,
11d (ratio 82:18) on the other hand in, respectively, 67 and
14% yields. In order to secure stereochemistry, each mixture
Catalytic hydrogenation in the presence of Pd(OH)2 and
Boc2O of compounds 1 and 3 was then performed (Schemes
1 and 2). In both cases, N-debenzylated b-amino esters were
Scheme 3. Reduction of 2.

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was submitted to hydrogenolysis in the presence of Pd(OH)2
and Boc2O to yield N-tert-butoxycarbonyl derivatives 10 in
a one-pot procedure. Analysis of the crude mixtures by
chiral GC showed in each case the presence of only one
isomer, respectively, piperidines 10a (eeO98%) and ent-
10a (eeO98%) (Scheme 2). This result demonstrated that
the initial mixtures were composed of epimers at C-8a. NOE
experiments conducted on each mixture showed a transfer
of saturation from one species to the other, which confirmed
that both mixtures of oxazolidines consisted of equilibrated
C-8a epimers, as previously observed on related compounds
by others.8 The stereochemistry of the C-8a center is of little
importance, since alkylation at C-8a of similar oxazolidines
by organometallic or silyl enol ether reagents is known to
give selectively cis disubstituted piperidines, whatever the
initial configuration of the angular carbon.9 Moreover,
comparison of the spectroscopic data of tert-butyl carba-
mate 10a and ent-10a with that reported in the literature3c
demonstrated that absolute configuration at C-5 for 11a and
11c was (5S) and that for 11b and 11d was (5R).
Concerning the angularly substituted bicyclic b-enamino
ester 2 (Scheme 3), reduction by sodium triacetoxyboro-
hydride diastereoselectively afforded monocyclic disubsti-
tuted pyrrolidine 12, with an excellent diastereomeric
excess (deZ90%), as previously observed for the pyrro-
lidine analogue 1. From the crude mixture, compound 12a
was isolated in 84% yield.
Since we were unable to prepare a crystalline salt from 12a
and hence to determine its absolute configuration, we had to
rely upon chemical correlation (Scheme 4). With this aim in
mind (S)-pyroglutamic acid was transformed into the chiral
lactim ether 14 according to a previously described
procedure.10 The latter was condensed with Meldrum’s
acid in the presence of a catalytic amount of Ni(acac)2 to
give in 88% yield b-enamino diester 15, which in turn
underwent successive transesterification and decarboxyl-
ation upon heating in a solution of sodium methoxide.11
Though catalytic hydrogenation of the resulting b-enamino
ester 16 had been reported to give stereoselectively the cis
isomer,12 in our hands, hydrogenation of 16 in the presence
of PtO2 and Boc2O gave the cis (2R, 5R) isomer ent-13a
along with the trans (2S, 5R) isomer 13c as a 85:15 mixture,
in 60% overall yield. On the other hand, crude 12 resulting
from the reduction of 2 by NaBH(OAc)3 was hydrogeno-
lyzed in the presence of Pd(OH)2 and Boc2O to yield a
mixture of 13a and 13c (Scheme 3). Comparison by chiral
GC of the two reaction mixtures allowed us to assign the cis
stereochemistry and a (2S, 5S) absolute configuration to the
major isomer 12a, whereas a trans (2S, 5R) configuration
was assigned to the minor isomer 12c.
Compound 2 was then hydrogenated in the presence of
Pd(OH)2 and Boc2O. Under these conditions, we obtained,
in 66% yield, a disappointing mixture of three isomers, as
determined by chiral GC analysis, consisting of a 67:33
mixture of the cis isomers ((2S,5S)-13a and (2R,5R)-ent-
13a; (ratio 61:39)) and of the trans isomer (2S,5R)-13c
(Scheme 3). Finally, as for compound 1, hydrogenation of 2
in the presence of PtO2 left the product unchanged.7
Scheme 4.
Scheme 5. Reduction of 4.

S. Calvet-Vitale et al. / Tetrahedron 61 (2005) 7774–7782
7777
Finally, we turned out our attention to the reductions of the
angularly substituted piperidine 4 (Scheme 5). Catalytic
hydrogenation of this compound in the presence of catalytic
Pd(OH)2 (3 atm, 12 h) followed by reaction with methyl-
chloroformate had previously been reported by Meyers3b to
afford stereoselectively the cis (2S, 6S) isomer 19a. We
repeated this two-step procedure13 in order to obtain 19a as
a reference compound of established absolute configur-
ation3b (Scheme 5).
us to assign the (5S, 8aR) configuration to the oxazolidine
20a.
Our study clearly showed that bicylic pyrrolidine and
piperidine b-enamino esters displayed different behaviours
depending on reduction conditions. Considering that these
substrates possess three bonds that may be affected under
reductive conditions, diastereoselectivity depends on the
timing of the different processes. Efficient reduction of
pyrrolidines 1 (Scheme 1) and 2 (Scheme 3) in terms of
yield and diastereoselectivity required the use of sodium
triacetoxyborohydride under acidic conditions. In contrast,
reductions of piperidines 3 (Scheme 2) and 4 (Scheme 5)
under similar conditions proceeded with lower
diastereoselectivities.
On the other hand, the chemical reduction of 4 by
NaBH(OAc)3 afforded monocyclic b-amino ester 17 as a
80:20 mixture of two isomers in 89% overall yield. In order
to assign the stereochemistry of these compounds, the
mixture was hydrogenolyzed and then reacted with
methylchloroformate. Analysis by chiral and achiral GC
led us to attribute to the major isomer 17a the cis (2S, 6S)
configuration and the trans (2R, 6S) configuration to the
minor isomer 17d. Finally, PtO2 catalyzed hydrogenation
gave bicyclic piperidine 20a as a single isomer, in 87%
yield. In contrast to what was observed for the hydrogen-
ation of 3, no epimerization at the quaternary angular carbon
had occurred. Hydrogenolysis of 20a and subsequent
methoxycarbonylation led to compound 19a, which allowed
In the case of compounds 1 and 3, we suppose that the
double bond was reduced before the cleavage of the
oxazolidine ring, which would explain the observed
stereoselectivies (respectively, 95 and 20% diastereomeric
excess). Indeed, the presence of the oxazolidine moieties is
clearly key in these reductions as substantiated by the
comparison with the sodium triacetoxyborohydride-
mediated reduction of monocyclic iminium ions I and II
that we previously reported5 to proceed, respectively, in 70
and 90% diastereomeric excess (Scheme 6).
Concerning angularly-substituted compounds 2 and 4,
preliminary reduction of the double bond is also likely to
be involved. Moreover, the presence of the methyl
substituent instead of an hydrogen atom appeared necessary
to induce a better control of the stereochemistry at the C-2
center. In both cases, one can note the major obtention of cis
a,a0-disubstituted products 12a and 17a from compounds 2
and 4, respectively.14 Initial reduction of the double bond
under acidic conditions would proceed via bicyclic iminium
ions III (Scheme 7), preferentially from the less hindered
endo face, to lead mainly to the (S) stereochemistry at C-2,
with a better control for strained pyrrolidine compounds
than for piperidine ones. The resulting bicyclic oxazolidine
would be in equilibrium with open borohydride-containing
iminium IV12,16 that would evolve toward products through
intramolecular hydride delivery to the iminium bonds.
Scheme 6.
Thus, in the case of piperidine 4, reduction at C-2 would
lead to the formation of two isomeric iminium ions IV(2S)
Scheme 7.
Scheme 8. Proposed mechanism for formation of 17a and 17d from piperidine 4.

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S. Calvet-Vitale et al. / Tetrahedron 61 (2005) 7774–7782
and IV(2R) whose reactive conformations are depicted in
Scheme 8. The observed stereochemistry would result from
an axial delivery of the hydride from the favoured
conformations IV(2S)b and IV(2R)b under stereoelectronic
control. In comparison, conformations IV(2S)a and IV(2R)a
appear disfavoured due to the strong steric interactions
between the phenyl ring of the chiral auxiliary and the C-2
subtituent.17 In the case of conformation IV(2S)a whose
reduction would lead to an unobserved trans (2,6)
piperidine, the destabilization induced by the above steric
constraints would be able to overcome the benefit arising
from the minimization of the A1,2 allylic strain present in
this particular conformation, whereas in conformation
IV(2R)a, steric factors and allylic strain are additive to
disfavour this conformation. Regarding reduction of
pyrrolidine 2, a similar rationale should be considered to
account for the major cis stereochemistry of the isolated
compounds.
As far as catalytic hydrogenations are concerned, these
reduction conditions were efficient and selective only in the
case of angular methyl-containing oxazolopiperidine 4
(Scheme 5). PtO2 catalyzed hydrogenation of 4 afforded
bicyclic piperidine 20a with a complete control of the
stereochemistry at C-5 as the result of hydrogen attacking
anti to the phenyl and methyl substituents. Reduction of 4 in
the presence of Pd(OH)2 yielded piperidine 18a as a single
cis isomer. This result was assumed to result from the initial
reductions of the double and C–O bonds from the endo face
followed by N-debenzylation.3b In all other cases (com-
pounds 1, 2, and 3), the poor selectivities observed under
these conditions might result from early N-debenzylations
and/or oxazolidine cleavages, which prevented any stereo-
chemical control during the subsequent reduction of the
double bonds. Noteworthy was the (R) absolute stereo-
chemistry at C-2 of the major isomers obtained upon
hydrogenation of compounds 1 and 3, a result that contrasts
with what was observed in other cases of this study. We
have no clear explanation for this result.
Scheme 9. Formal synthesis of (C)-calvine.
enantiomer (K)-25 using (R)-phenylglycinol as the chiral
inductor ([a]2D0 K17 (c 1.08, CHCl3)). In order to check the
optical purity of these compounds by chiral GC, both
enantiomers were transformed into their methoxycarbonyl
derivatives 26.18,20 This allowed us to confirm that each
sample consisted of a single enantiomer. This high
diastereoselectivity of the reduction of 24 was consistent
with that previously observed for the angularly methylated
piperidine 4. Compound 25, which is also an alkaloid
isolated from Calvia, is an intermediate previously
described in the total synthesis of (C)-calvine.20
In order to illustrate the synthetic potential of our approach,
we envisioned to carry out a formal synthesis of (C)-
calvine (5), a piperidine alkaloid isolated from ladybird
beetles of the Genus Calvia18 (Scheme 9). The key step of
our strategy relied on the diastereoselective reduction of
bicyclic b-enamino ester 24. The latter was obtained starting
from methyl oxo heptynoate 2119 in three steps. Addition of
n-pentylmagnesium bromide to 21 gave alcohol 22, which
was subsequently oxidized to the corresponding ketone 23
according to the Dess–Martin procedure in 71% yield.
Condensation of (S)-phenylglycinol on compound 23 in
refluxing benzene afforded the expected bicyclic oxazo-
lidine 24 in 64% yield, as a single isomer. Catalytic
hydrogenation in the presence of Pd(OH)2 yielded the
disubstituted piperidine 25 with an excellent diastereomeric
excess (deO98%) in the favor of the cis disubstituted
piperidine. Indeed, this compound exhibited NMR data
identical with those reported in the literature for the cis (2S,
6S) isomer.20 However, the measured absolute optical
rotation ([a]2D0 C16 (c 0.64, CHCl3)) did not agree with
that previously reported20,21 (lit.20 [a]2D0 C23 (c 0.52,
CHCl3)). In order to secure the enantiomeric excess of
(C)-25, we synthesized by the same method, the
3. Conclusion
In conclusion, the reported study enabled us to prepare
enantiopure pyrrolidine and piperidine b-amino esters by
chemio- and diastereoselective controlled reductions from
bicyclic chiral b-enamino esters. In particular, our strategy
gives access to cis disubstituted heterocycles that are useful
intermediates in the synthesis of alkaloids as illustrated by
our formal synthesis of (C)-calvine. Further efforts to
develop the synthetic applications of these b-amino esters
are underway in our laboratory.
4. Experimental
4.1. General
Unless otherwise specified, materials were purchased from
commercial suppliers and used without further purification.
THF was distilled from sodium/benzophenone ketyl
immediately prior to use. CH2Cl2 was distilled from calcium
hydride. All reactions were carried out under argon. Thin

S. Calvet-Vitale et al. / Tetrahedron 61 (2005) 7774–7782
7779
layer chromatography analyses were performed on Merck
precoated silica gel (60 F254) plates and column chroma-
tography on silica gel Gerudan SI 60 (40–60 mm) (Merck).
Melting points are uncorrected. IR: Philips PU 9700. Chiral
gas chromatographies were performed on a capillary
Chrompack CP-Chirasil-DEX CB column and achiral ones
on a Chrompack CP-SIL5. Optical rotation: Perkin-Elmer
For (2R)-8b. [a]D20 C18 (c 0.5, CHCl3). IR (neat) nmax
1
1740 cmK1. H NMR d 1.37–1.72 (m, 6H), 1.98 (s, 3H),
2.37–2.52 (m, 2H), 2.62–2.77 (m, 2H), 3.10–3.15 (m, 1H),
3.63 (s, 3H), 4.05 (t, 1H, JZ6.25 Hz), 4.34 (m, AB part of
ABX spectrum, 2H, JABZ11.5 Hz), 7.23–7.35 (m, 5H). 13
NMR d 20.8, 21.0, 25.0, 29.6, 34.2, 44.8, 51.5, 53.3, 62.6,
66.0, 127.5, 128.3 (2C), 139.0, 170.8, 173.1.
C
´
241 polarimeter. Elemental analysis: Service Regional de
Microanalyse de l’Universite P. et M. Curie. HMRS were
´
4.2.3. (2S, 5S)-[1-(Hydroxy-1-(S)-phenyl-ethyl)-5-
methyl-pyrrolidin-2-yl]-acetic acid methyl ester (12a).
The general procedure was followed for the reduction of
compound 2 (312 mg, 1.14 mmol). Purification of the crude
product by silica gel column chromatography (cyclohexane/
AcOEt 8:2) afforded 12a (266 mg, 84%) as an oil: [a]D25
C23 (c 0.98, CHCl3). IR (neat) nmax 3400, 1730 cmK1. 1H
NMR 1.2 (d, 3H, JZ6 Hz), 1.31–1.48 (m, 3H), 1.70–1.77
recorded on a JEOL MS 700 mass spectrometer. NMR:
1
Bruker ARX 250 spectrometer (250 and 62.9 MHz for H
and 13C, respectively). Spectra were recorded in CDCl3 as
solvent. Chemical shifts (d) were expressed in ppm relative
to TMS at dZ0 for 1H and to CDCl3 at dZ77.1 for 13C and
coupling constants (J) in Hertz.
(m, 1H), 2.41 (m, AB part of ABX spectrum, 2H, JAB
Z
4.2. General procedure for NaBH(OAc)3 mediated
reductions
14.25 Hz), 3.07–3.15 (m, 1H), 3.27 (br s, 1H), 3.47–3.54 (m,
1H), 3.66 (s, 3H), 3.59–3.73 (m, 1H), 3.83–3.96 (m, 2H),
7.21–7.38 (m, 5H). 13C NMR d 21.0, 30.3, 32.0, 43.1, 51.4,
54.3, 58.3, 61.6, 63.4, 127.7, 128.2, 128.7, 136.7, 172.5.
Anal. Calcd for C16H23NO3: C, 69.29; H, 8.36; N, 5.05.
Found: C, 69.27; H, 8.23; N, 5.07.
A solution of NaBH(OAc)3 was prepared by portionwise
addition of NaBH4 (5 mmol) to glacial acetic acid (25 mol)
at 0 8C. After the hydrogen evolution ceased (30 min), a
solution of the substrate (1 mmol) in acetonitrile (4 mL) was
added. After stirring for 48 h at room temperature, the
solvents were evaporated in vacuo. The residue was
dissolved in CH2Cl2 and the organic layer was neutralized
with saturated aqueous Na2CO3 solution. The organic layer
was washed with brine, dried over Na2SO4 and concentrated
in vacuo.
4.2.4. (6S)-[1-(2-Hydroxy-1-(S)-phenyl-ethyl)-6-methyl-
piperidin-2-yl]-acetic acid methyl ester (17). The general
procedure was followed for the reduction of compound 4
(161 mg, 0.5 mmol). Purification of the crude product by
silica gel column chromatography (cyclohexane/AcOEt
8:2) afforded 17 (146 mg, 89%) as an inseparable oily 8:2
mixture of isomers. IR (neat) nmax 3440, 1735 cmK1. For
4.2.1. (2S)-[1-(2-Hydroxy-1-(S)-phenyl-ethyl)-pyrroli-
din-2-yl]-acetic acid methyl ester (6a). The above general
procedure was followed for the reduction of compound 1
(312 mg, 1.2 mmol). Purification of the crude product by
silica gel column chromatography (cyclohexane/AcOEt
8:2) afforded 6a5 (303 mg, 95%) as a solid.
1
major (2S,6S)-17a. H NMR d 1.02 (d, 3H, JZ6.75 Hz),
1.28–1.61 (m, 6H), 1.93 (br s, 1H), 2.56 (m, AB part of ABX
spectrum, 2H, JABZ14.5 Hz), 2.93–3.07 (m, 1H), 3.55–
3.68 (m, 1H), 3.70 (s, 3H), 3.69–3.74 (m, 1H), 3.85–3.92
(m, 2H), 7.28–7.35 (m, 5H). 13C NMR d 14.7, 19.0, 27.7,
30.4, 38.6, 49.8, 49.9, 51.6, 62.5, 66.3, 127.5, 128.4, 129.0,
1
140.1, 173.4. For minor (2R,6S)-17d. H NMR (only the
4.2.2. [1-(2-Acetoxy-1-(S)-phenyl-ethyl)-piperidin-2-yl]-
acetic acid methyl ester (8). The general procedure was
followed for the reduction of compound 3 (130 mg,
0.5 mmol) to give a 60:40 mixture of (2S)-7b5 and (2R)-
7b isomers (132 mg), which were inseparable by silica gel
column chromatography. The crude mixture of isomers 7
(132 mg) was stirred overnight in pyridine (9 mL) and
acetic anhydride (3 mL). The solvents were evaporated in
vacuo and the residue was dissolved in CH2Cl2. The organic
layer was washed with water and brine, dried over Na2SO4
and evaporated in vacuo. Silica gel chromatography
(cyclohexane/AcOEt 9:1) allowed the separation of the
two isomers (2S)-8a (79 mg, 52%) and (2R)-8b (53 mg,
34%) as colorless oils.
more significant signals are reported) d 1.29 (d, 3H, JZ
7 Hz), 3.73 (s, 3H). 13C NMR d 20.3, 20.9, 26.1, 30.6, 37.7,
49.3, 49.6, 51.7, 59.1, 60.7, 127.9, 128.3, 129.1, 140.9,
173.1. HRMS (CI) calcd m/z for C17H26NO3 (MHC):
292.1913. Found: 292.1907.
4.3. General procedure for Pd(OH)2 catalyzed hydro-
genation and in situ carbamatation by Boc2O
A solution of the substrate (1 mmol) in methyl acetate
(40 mL) was subjected to hydrogenation (1 atm) in the
presence of Pd(OH)2/C (0.5 equiv in weight) and Boc2O
(2.1 equiv), at room temperature. The progress of the
reaction was monitored by GC. The reaction mixture was
filtered, the residue thoroughly washed with MeOH and the
combined filtrates were concentrated in vacuo.
For (2S)-8a. [a]D20 C20 (c 1.075, CHCl3). IR (neat) nmax
1
1730 cmK1. H NMR d 1.38–1.60 (m, 5H), 1.71–1.77 (m,
1H), 1.98 (s, 3H), 2.36–2.40 (m, 2H), 2.65 (m, AB part of
ABX spectrum, 2H, JABZ14.25 Hz), 3.45–3.52 (m, 1H),
3.66 (s, 3H), 3.96 (t, 1H, JZ6 Hz), 4.38 (m, AB part of ABX
spectrum, 2H, JABZ11.5 Hz), 7.20–7.36 (m, 5H). 13C NMR
d 20.7, 20.9, 25.6, 29.9, 32.5, 44.9, 51.5, 53.4, 62.7, 65.1,
127.3, 128.0, 128.3, 141.0, 170.8, 173.2. Anal. Calcd for
C18H25NO4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.45; H,
7.95; N, 4.11.
4.3.1. 2-Methoxycarbonylmethyl-pyrrolidine-1-carb-
oxylic acid tert-butyl ester (9). The general procedure
was followed for the reduction of compound 1 (42 mg,
0.16 mmol). Purification of the crude product by silica
gel column chromatography (cyclohexane/AcOEt 8:2)
afforded 96 (28 mg, 71%) as an oily mixture of
enantiomers.

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4.3.2. 2-Methoxycarbonylmethyl-piperidin-1-carboxylic
acid tert-butyl ester (10). The general procedure was
followed for the reduction of compound 3 (94 mg,
0.34 mmol). Purification of the crude product by silica gel
column chromatography (cyclohexane/AcOEt 8:2) afforded
103c (62 mg, 70%) as an oily mixture of enantiomers.
thoroughly washed with MeOH and the organic layer was
concentrated in vacuo.
4.4.1. (3-Phenyl-hexahydro-oxazolo[3,2-a]pyridine-5-
yl)-acetic acid methyl ester (11). The general procedure
was followed for the reduction of compound 3 (158 mg,
0.58 mmol) to give a 85:15 mixture of isomers 11a, 11c and
11b, 11d. Purification of the crude product by silica gel
column chromatography (cyclohexane/AcOEt 8:2) allowed
the isolation of (5S)-11a,11c (107 mg, 67%) as an oily 65:35
mixture of epimers at C-8a and (5R)-11b,11d (23 mg, 14%)
as 82:18 mixture of epimers at C-8a. IR (neat) nmax
4.3.3. 2-Methoxycarbonylmethyl-5-methyl-pyrrolidine-
1-carboxylic acid tert-butyl ester (13). From crude 12.
The general procedure was followed for the reduction of
compound 12 (51 mg, 0.18 mmol). Purification of the crude
product by silica gel column chromatography (cyclohexane/
AcOEt 85:15) afforded an inseparable 95:5 mixture 13a and
13c (44 mg, 94%) as an oil. For (2S,5S)-13a (from the
mixture). IR (neat) nmax 1725, 1690 cmK1. 1H NMR d 1.18
(d, 3H, JZ6 Hz), 1.44 (s, 9H), 1.51–1.55 (m, 1H), 1.67–
1.74 (m, 1H), 1.92–2.05 (m, 2H), 2.30 (dd, 1H, JZ9.5,
15 Hz), 2.75–3.05 (m, 1H), 3.65 (s, 3H), 3.75–3.90 (m, 1H),
4.05–4.15 (m, 1H). 13C NMR d 21.8, 28.5, 29.7, 31.5, 40.3,
51.5, 54.1, 55.4, 79.3, 154.5, 172.0. HRMS (CI) calcd m/z
for C13H24NO4 (MHC): 256.1705. Found: 256.1706.
1735 cmK1
.
For major isomer of 11a, 11c. 1H NMR d 1.26–1.48 (m, 2H),
1.51, 1.67 (m, 2H), 1.78–1.88 (m, 2H), 2.0–2.10 (m, 1H),
2.19–2.28 (m, 1H), 2.84–2.92 (m, 1H), 3.49 (s, 3H), 3.57–
3.63 (m, 1H), 3.75–3.84 (m, 2H), 4.13–4.19 (m, 1H), 7.22–
7.40 (m, 5H). 13C NMR d 22.2, 30.0, 32.4, 40.5, 51.4, 57.9,
65.4, 74.6, 95.6, 126.6, 127.3, 128.6, 143.5, 172.4. For
1
minor isomer of 11a, 11c. H NMR d 1.26–1.66 (m, 3H),
1.77–1.85 (m, 2H), 2.0–2.1 (m, 1H), 2.48 (m, AB part of
ABX spectrum, 2H, JABZ15.25 Hz), 2.98–3.06 (m, 1H),
3.62 (s, 3H), 3.67–3.71 (m, 1H), 4.34–4.44 (m, 2H), 4.49 (t,
1H, JZ3 Hz), 7.22–7.40 (m, 5H). 13C NMR d 17.9, 26.9,
30.6, 41.4, 51.4, 55.1, 66.1, 70.0, 89.1, 127.0, 127.5, 128.6,
142.5, 172.5. HRMS (CI) calcd m/z for C16H22NO3 (MHC):
276.1600. Found: 276.1598.
From compound 2. The general procedure was followed for
the reduction of compound 2 (111 mg, 0.4 mmol). Purifi-
cation of the crude product by silica gel column
chromatography (cyclohexane/AcOEt 85:15) afforded 13a,
ent-13a and 13c (69 mg, 66%) as an inseparable oily
mixture of isomers.
1
For major isomer of 11b, 11d. H NMR d 1.47–1.78 (m,
From compound 16. The general procedure was followed
for the reduction of compound 16 (233 mg, 1.5 mmol) using
PtO2 (50 mg) in the place of Pd(OH)2. The crude product
was chromatographed on silica gel (cyclohexane/AcOEt
85:15) to give an inseparable 85:15 mixture of ent-13a and
13c (231 mg, 60%).
5H), 2.0–2.1 (m, 1H), 2.47 (m, AB part of ABX spectrum,
2H, JABZ14.25 Hz), 3.44–3.50 (m, 1H), 3.57 (s, 3H), 3.60–
3.66 (m, 1H), 3.88–4.00 (m, 1H), 4.10–4.22 (m, 2H), 7.22–
7.38 (m, 5H). 13C NMR d 17.9, 28.8, 29.1, 31.5, 49.7, 51.7,
61.6, 73.4, 87.5, 127.8, 127.9, 128.7, 138.9, 173.1. For
minor isomer of 11b, 11d (only the more significant signals
are reported). 1H NMR d 2.70 (m, 1H), 4.38–4.59 (m, 4H).
4.3.4. 2-Methoxycarbonylmethyl-6-methyl-piperidin-1-
carboxylic acid methyl ester (19a). A solution of 4
(107 mg, 0.37 mmol) dissolved in MeOH (10 mL) was
subjected to hydrogenation (1 atm) in the presence of
Pd(OH)2/C (53 mg) at room temperature for 12 h. The
reaction mixture was filtered and the residue washed with
MeOH. Concentration in vacuo afforded a crude oil, which
was dissolved in CH2Cl2 (8 mL). To the ice-cooled solution
was added a 0.4 M aqueous solution of Na2CO3 (1.85 mL).
Methylchloroformate (53 mg, 0.56 mmol) dissolved in
CH2Cl2 (1 mL) was added dropwise, and the reaction
mixture was stirred at room temperature overnight. CH2Cl2
was added (15 mL) and the organic layer was successively
washed with water (3!10 mL) and brine (10 mL) The
combined organic layer was dried over Na2SO4 and
concentrated in vacuo. Silica gel column chromatography
(cyclohexane/AcOEt 7:3) afforded compound 19a3b
(75 mg, 88%) as an oil: [a]2D0 C44 (c 0.85, CHCl3) (lit.3b
[a]2D0 C41 (c 1.16, CHCl3)).
4.4.2. (5S, 8aR)-(8a-Methyl-3-phenyl-hexahydro-oxa-
zolo[3,2-a]pyridine-5-yl)-acetic acid methyl ester (20a).
The general procedure was followed for the reduction of
compound 4 (215 mg, 0.75 mmol). Purification of the crude
product by silica gel column chromatography (cyclohexane/
AcOEt 8:2) afforded 20a (188 mg, 87%) as an oil: [a]D20
C99 (c 1.225, CHCl3). IR (neat) nmax 1730 cmK1. 1H NMR
d 1.39 (s, 3H), 1.55–1.86 (m, 6H), 2.42 (m, AB part of ABX
spectrum, 2H, JABZ15 Hz), 3.20–3.30 (m, 1H), 3.52 (s,
3H), 3.66–3.73 (m, 1H), 4.20–4.30 (m, 2H), 7.25–7.38 (m,
5H). 13C NMR d 17.7, 25.6, 27.9, 32.8, 41.1, 51.4, 53.6,
67.5, 71.1, 94.2, 127.2, 127.4, 128.4, 142.4, 172.4. Anal.
Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C,
70.33; H, 7.89; N, 4.79.
4.4.3. (5R)-2,2-Dimethyl-5-pyrrolidin-2-ylidene-[1,3]
dioxane-4,6-dione (15). To a solution of lactim ether 14
(2.26 g, 20 mmol) in CHCl3 (30 mL) was added Meldrum’s
acid (2.88 g, 20 mmol) and Ni(acac)2 (10 mg). The reaction
mixture was stirred at reflux temperature overnight. The
solvent was removed in vacuo and the crude product
crystallized in EtOH to afford the expected compound 1522
(3.97 g, 88%), as a solid. MpZ150 8C: [a]2D8 C26 (c 1.08,
4.4. General procedure for PtO2 catalyzed
hydrogenation
A solution of the substrate (1 mmol) dissolved in MeOH
(30 mL) was subjected to hydrogenation (1 atm) in the
presence of PtO2 (0.25 equiv in weight) at room temperature
for 24 h. The reaction mixture was filtered, the residue
1
CHCl3). IR (neat) nmax 3270, 1690, 1640, 1590 cmK1. H
NMR d 1.35 (d, 3H, JZ6.5 Hz), 1.69 (s, 3H), 1.71 (s, 3H),

S. Calvet-Vitale et al. / Tetrahedron 61 (2005) 7774–7782
7781
2.27–2.41 (m, 1H), 3.20–3.34 (m, 1H), 3.47–3.60 (m, 1H),
4.06–4.20 (m, 1H), 10 (br s, 1H). 13C NMR d 21.2, 26.6,
26.7, 29.1, 34.8, 56.8, 81.3, 103.1, 163.1, 166.4, 175.9.
4.4.7. (8aR)-(8a-Pentyl-3-phenyl-hexahydro-oxazolo-
[3,2-a]pyridine-5-ylidene]-acetic acid methyl ester (24).
A solution of ketone 23 (400 mg, 1.78 mmol) and (S)-
phenylglycinol (294 mg, 2.94 mmol) in benzene (20 mL) in
˚
the presence of 4 A molecular sieves (5 g), was refluxed for
4.4.4. (5R)-Pyrrolidin-2-ylidene-acetic acid methyl ester
(16). A solution of compound 15 (2 g, 8.8 mmol) and
sodium methylate (8.8 mmol) in MeOH (50 mL) was
refluxed for 12 h. The cooled reaction mixture was
concentrated in vacuo and the residue dissolved in water
(40 mL). The solution was neutralized to pHZ6 by addition
of a chilled 1 N HCl aqueous solution. The aqueous layer
was extracted with CHCl3 (3!50 mL), the combined
organic layer was dried over Na2SO4. Concentration in
vacuo gave 16 (1.23 g, 93%), which was pure enough to be
used in the next step without further purification.
Chromatography on silica gel (cyclohexane/AcOEt 80:20)
afforded an analytical sample of 16 as an oil: [a]2D9 K11 (c
24 h. The reaction mixture was cooled to room temperature,
filtered and the solvent removed in vacuo. Silica gel column
chromatography of the residue (cyclohexane/AcOEt 85:15)
afforded pure 24 (390 mg, 64%) as a colorless oil: [a]D20
1
C161 (c 0.375, CHCl3). IR (neat) nmax 1720 cmK1. H
NMR d 0.87 (t, 3H, JZ6.5 Hz), 1.24–1.86 (m, 11H), 2.27–
2.34 (m, 1H), 2.68–2.77 (m, 1H), 3.49 (s, 3H), 3.65–3.78
(m, 2H), 4.33 (s, 1H), 4.46 (t, 1H, JZ8.5 Hz), 4.75 (t, 1H,
JZ8.5 Hz), 7.15–7.39 (m, 5H). 13C NMR d 13.9, 16.1, 22.6,
24.0, 24.4, 31.1, 31.9, 35.1, 49.9, 62.5, 70.2, 86.0, 96.1,
125.4, 127.5, 128.9, 138.8, 159.4, 169.0. HRMS (CI) calcd
m/z for C21H30NO3 (MHC): 344.2226. Found: 344.2225.
1
1.315, CHCl3). IR (neat) nmax 3350, 1655, 1600 cmK1. H
NMR d 1.23 (d, 3H, JZ6.25 Hz), 1.44–1.58 (m, 1H), 2.06–
2.18 (m, 1H), 2.56–2.67 (m, 2H), 3.64 (s, 3H), 3.89 (sext,
1H, JZ6.5 Hz), 4.48 (s, 1H), 7.9 (br s, 1H). 13C NMR d
21.2, 29.9, 31.8, 49.5, 54.7, 75.6, 165.5, 170.6. Anal. Calcd
for C8H13NO2: C, 61.91; H, 8.44; N, 9.03. Found: C, 61.60;
H, 8.51; N, 9.10.
4.4.8. (2S, 6S)-(6-Pentyl-piperidin-2-yl)-acetic acid
methyl ester (25). A solution of compound 25 (0.47 g,
1.37 mmol) dissolved in MeOH (25 mL) was subjected to
hydrogenation (1 atm) in the presence of Pd(OH)2 (94 mg),
at room temperature for 6 h. The reaction mixture was
filtered over a Celitew pad, the residue thoroughly washed
with MeOH and the solvent removed in vacuo. The residue
was dissolved in 1 N NaOH aqueous solution (10 mL) then
extracted with CH2Cl2. The organic layer was washed with
brine and water, dried over Na2SO4 and concentrated in
vacuo. Silica gel column chromatography of the residue
(eluted with AcOEt/MeOH 9:1) afforded pure piperidine
2520 (203 mg, 66%): [a]D20 C16 (c 0.64, CHCl3).
4.4.5. 7-Hydroxy-dodec-2-ynoic acid methyl ester (22).
To a solution of compound 2119 (1.75 g, 11.35 mmol) in
anhydrous Et2O (50 mL), cooled at K78 8C, was added
dropwise a 2 M solution of n-PentMgBr in Et2O (6.8 mL,
13.6 mmol). The reaction mixture was allowed to warm to
K5 8C over 3.5 h and then quenched with aqueous saturated
NH4Cl solution (20 mL). The aqueous layer was extracted
with Et2O (3!40 mL). The organic layers were combined
and then washed with brine (30 mL) and dried over Na2SO4.
Concentration in vacuo gave a crude product, which was
purified by silica gel column chromatography (cyclohexane/
AcOEt 8:2) to give compound 22 (1.33 g, 52%), as a
4.4.9. (2S, 6S)-2-Methoxycarbonylmethyl-6-pentyl-
piperidine-1-carboxylic acid methyl ester (26). To an
ice-cooled solution of 25 (57 mg, 0.25 mmol) in CH2Cl2
(5 mL) was added a 0.4 M aqueous solution of Na2CO3
(1.25 mL). Methylchloroformate (0.1 mL, 1.3 mmol) was
added dropwise, and the reaction mixture was stirred at
room temperature overnight. CH2Cl2 was added (15 mL)
and the organic layer was successively washed with water
(3!10 mL) and brine (10 mL). The combined organic layer
was dried over Na2SO4 and concentrated in vacuo. Silica gel
column chromatography (cyclohexane/AcOEt 85:15)
afforded compound 2618,20 (60 mg, 85%) as an oil: [a]2D0
C24 (c 0.985, CHCl3).
1
colorless oil. IR (neat) nmax 1730, 2260, 3430 cmK1. H
NMR d 0.90 (t, 3H, JZ6.5 Hz), 1.31–1.65 (m, 13H), 2.39 (t,
2H, JZ7 Hz), 3.55–3.70 (m, 1H), 3.77 (s, 3H). 13C NMR d
14.0, 18.6, 22.6, 23.7, 25.3, 31.3, 36.3, 37.5, 52.6, 71.2,
73.0, 89.6, 154.2. Anal. Calcd for C13H22O3: C, 68.99; H,
9.80. Found: C, 68.81; H, 9.88.
4.4.6. 7-Oxo-dodec-2-ynoic acid methyl ester (23). To a
solution of alcohol 22 (1 g, 4.42 mmol) in CH2Cl2 (20 mL)
was added a Dess–Martin periodinane solution in CH2Cl2
(15% in weight, 17 g, 6 mmol). The reaction mixture was
stirred at room temperature for 3 h. To the reaction mixture
were successively added Et2O (30 mL), an aqueous
saturated NaHCO3 solution (45 mL) and sodium thiosulfate
(3 g). The aqueous layer was extracted with Et2O (3!
30 mL). The combined organic layers were washed with a
saturated NaHCO3 solution (30 mL) and then brine (30 mL)
before drying over Na2SO4 and concentrating in vacuo.
Silica gel column chromatography (cyclohexane/AcOEt
90:10) gave pure 23 (0.7 g, 71%) as a colorless oil. IR (neat)
References and notes
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1
nmax 1720, 1735, 2270 cmK1. H NMR d 0.89 (t, 3H, JZ
7 Hz), 1.24–1.36 (m, 4H), 1.58 (quint, 2H, JZ7 Hz), 1.85
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´
2. David, O.; Calvet, S.; Chau, F.; Vanucci-Bacque, C.; Fargeau-

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