Stereoselective synthesis and in vivo evaluation of the analgesic activity of polysubstituted bispidines

Article abstract of DOI:10.1002/ejoc.201200919

Hetero-Michael addition on a chiral β'-amino α,β- unsaturated ketone gave, after some structural modifications, β,β'-diamino ketals. Mannich-type reactions of these diamines with an aldehyde led, with high diastereoselectivity, to trisubstituted piperidines. Another highly stereoselective Mannich cyclization, with an N-acyliminium ion generated in situ from the corresponding imide, allowed the preparation of original polycyclic bispidine derivatives. The antinociceptive effect of the three compounds prepared was evaluated in vivo by using the writhing test. If the biological results for the analgesic properties were disappointing, compared with the bispidine HZ2, which has a high affinity for opioid receptors, the modularity of the approach offered the possibility of introducing many substituents for new applications, which was promising because the bispidine core has been described to have many different activities. Total stereoselective synthesis of bispidine derivatives is achieved by using as two successive Mannich reactions key steps. This process constitutes a powerful approach toward the preparation of a polycyclic bispidine backbone with high enantioselectivity.

Full text of DOI:10.1002/ejoc.201200919

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Date: 17-09-12 10:19:28
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FULL PAPER
DOI: 10.1002/ejoc.201200919
Stereoselective Synthesis and In Vivo Evaluation of the Analgesic Activity of
Polysubstituted Bispidines
Aurélie Plas,[a,b] Fabien Marchand,[c] Alain Eschalier,[c] Yves Troin,*[a,b] and
Pierre Chalard*[a,b]
Keywords: Natural products / Alkaloids / Nitrogen heterocycles / Synthesis design / Cyclization / Medicinal chemistry
Hetero-Michael addition on a chiral βЈ-amino α,β-unsatu-
rated ketone gave, after some structural modifications, β,βЈ-
diamino ketals. Mannich-type reactions of these diamines
with an aldehyde led, with high diastereoselectivity, to tri-
substituted piperidines. Another highly stereoselective Man-
nich cyclization, with an N-acyliminium ion generated in situ
from the corresponding imide, allowed the preparation of
original polycyclic bispidine derivatives. The antinociceptive
effect of the three compounds prepared was evaluated in
vivo by using the writhing test. If the biological results for
the analgesic properties were disappointing, compared with
the bispidine HZ2, which has a high affinity for opioid recep-
tors, the modularity of the approach offered the possibility of
introducing many substituents for new applications, which
was promising because the bispidine core has been de-
scribed to have many different activities.
For example (–)-cytisine (Figure 1), due to its similarity
to nicotine, has been identified as a selective nicotinic ace-
tylcholine receptor agonist[3] and this property has been
used in the elaboration of new smoking cessation agents.[4]
(–)-Sparteine, which is obtained from Cytisus scoparius, is
well known in chemistry for its use in asymmetric synthesis
of chiral molecules[5] or for its ability to form stable com-
plexes with transition-metal ions.[6] On the other hand, the
bispidine core was also found to be an agonist for the κ
opioid receptors[7] (KOR), which are receptors of choice for
pain release because they do not give rise to physical depen-
dence or respiratory problems.[8] A great deal of work, espe-
cially by molecular modeling, synthesis, and conforma-
tional behavior,[9] has led to the synthesis of compounds
HZ1 and HZ2 (Figure 1), which have a high affinity for
KOR (Ki = 0.015 μm),[10] and are simply prepared by a
double Mannich[11] reaction starting from methyl-3-oxo-
glutarate.
Introduction
The bispidine backbone, namely, 3,7-diazabicyclo[3.3.1]-
nonane, constitutes a building block found in various natu-
ral products, such as lupin alkaloids,[1] and also in some
biologically active compounds[2] Figure 1).
Therefore, the stereoselective synthesis of a bispidine core
with a chirally modified backbone for the preparation of
ligands for asymmetric synthesis became an interesting,
challenging endeavor and different approaches were devel-
oped,[12] leading to a panel of compounds with two, three,
or four fused cycles. In these syntheses, chirality was
brought through different strategies, from chiral nitrogen
appendages to stereoselective alkylation of the bispidine nu-
cleus. However, despite tremendous progress made in the
stereoselective synthesis of chiral bispidines, not all of the
approaches described offer such flexibility in changing and
controlling the different stereogenic centers of the bispidine
backbone. Having embarked on the stereoselective synthesis
of substituted piperidines many years ago,[13] we envisaged
developing a new access to the bispidine core using our
Figure 1. Some lupin alkaloids and bispidines HZ1 and HZ2,
which have analgesic activities.
[a] Institut de Chimie de Clermont-Ferrand (ICCF), Ecole
Nationale Supérieure de Chimie de Clermont-Ferrand
(ENSCCF),
BP 10448, 63000 Clermont-Ferrand, France
Fax: +33-4-73407008
E-mail: pierre.chalard@ensccf.fr
Homepage: http://iccf.univ-bpclermont.fr
[b] UMR 6296, ICCF, CNRS,
63171 Aubière, France
[c] Neurodol, U1107, Inserm/UdA, Faculté de Médecine et de
Pharmacie,
BP 38, 63001 Clermont-Ferrand, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200919.
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A. Plas, F. Marchand, A. Eschalier, Y. Troin, P. Chalard
FULL PAPER
methodology. We describe herein the synthesis of bispidine able overall yield in eight steps and their enantiopurity was
analogues together with the results of preliminary investi- evaluated by derivatization [on (R)-11a] with chiral (R)-α-
gations into their biological behavior. The general stereose- methylbenzyl isocyanate.[18]
lective synthetic approach planned to prepare bispidines de-
rivatives followed the strategy developed in our laboratory
(Scheme 1). In this route, the bispidine core I was con-
structed by an intramolecular Mannich reaction between
piperidine II and an aldehyde (R4CHO). For the prepara-
tion of II, a second Mannich reaction between β,βЈ-diamino
ketal III and aldehyde R2CHO was envisaged and should
predominantly deliver the 2,3-anti isomer.[14] For the prepa-
ration of III, a hetero-Michael reaction on the activated
double bond of IV was planned. Finally, the precursor of
compound IV could be the β-amino ester V, itself obtained
by stereoselective heteroaddition on an α,β-unsaturated es-
ter VI.
Scheme 3. Synthesis of keto-protected β,βЈ-diamino ketals 11.
HNPht = o-phthalimide, pTsOH = p-toluenesulfonic acid, TFAA
= trifluoroacetic acid, DMAP = 4-(dimethylamino)pyridine.
A comparison of the 1H NMR signals obtained for both
methyl groups of (R)-α-methylbenzyl isocyanate derivatives
from racemic 11a and its isomeric (R)-11a form, demon-
Scheme 1. General retrosynthetic analysis. PG = protecting group.
strated an excellent stereoisomeric ratio, proving that no ra-
cemization occurred during the synthesis (Figure 2).
The next step was the first Mannich condensation, al-
Results and Discussion
lowing elaboration of the piperidine ring. Therefore, con-
β-Amino esters 2a,b (94% ee) were available on a large densation of amines 11a,b with crotonaldehyde under the
scale from α,β-unsaturated esters 1a,b and lithium N- standard conditions developed by our group (intramolec-
benzyl-(R)-phenylethylamide, according to the procedure ular Mannich-type cyclization)[19] gave the corresponding
developed by Davies et al.[15] (Scheme 2).
piperidines (+)-12a and (–)-12b as single diastereomers
(Scheme 4).[17]
However, in the case of (–)-12b, the modest yield ob-
served for the cyclization could be explained by the forma-
tion of a byproduct, which was identified as enone 13
(25%). Compound 13 was probably generated by a retro-
Mannich reaction, which was encouraged by delocalization
of the double bond formed with the aromatic ring, resulting
in elimination of the nitrogen moiety (Scheme 5). Thus, for
further transformations, only piperidine (+)-12a was used.
The stereochemistry of piperidines 12a,b was confirmed by
careful examination of the coupling constants between H-
5/H-6 and H-2/H-3. For compound (+)-12a, the value of
3JH-2,H-3 (10.3 Hz) proved that these two protons were in
Scheme 2. Steroselective synthesis of β-amino esters 3 (Z = benzyl-
oxycarbonyl).
Deprotection of the nitrogen atom with Pearlman’s cata- axial positions; therefore, the two substituents on C-2 and
lyst, followed by reaction with benzyl chloroformate under C-3 were in a trans orientation. Moreover, the signal of H-
Schotten–Bauman conditions[16] afforded amino esters 3a,b 6 showed a trans diaxial coupling constant with H-5ax
in good overall yields. Because the use of vinylmagnesium (11.9 Hz), proving that the substituents on the C-2 and C-
bromide on Weinreb amide was inefficient at introducing 6 positions of the piperidine were in a cis orientation. NMR
the vinyl part, we tried a different route,[17] as described in spectra of piperidine (–)-12b presented coupling constants
Scheme 3. Compounds 11a,b were obtained with a respect- in the same order for H-2, H-5, and H-6.
2
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Analgesic Activity of Poly-substituted Bispidines
Figure 2. Determination of the stereoisomeric purity of keto-protected β,βЈ-diamino ketal (–)-11a.
tecting the nitrogen atom of piperidine (+)-12a with benzyl
chloroformate. Indeed the formation of a carbamate on pip-
eridine resulted in chair interconversion to minimize A1,3
constraints.[20] Cleavage of the ketal group on 14 with hy-
drochloric acid in acetone afforded N-protected piperidone
15. The next step was to prepare the second piperidine ring
through another Mannich cyclization. We initially consid-
ered deprotecting the amino group to obtain the imine,
which is involved in the Mannich reaction. Unfortunately,
regardless of the conditions used [NaBH4/MeOH
(4 equiv.),[21] K2CO3/MeOH/H2O (4 equiv.),[22] basic resin
IRA 401/MeOH[23] (5 equiv.)] and despite the disappear-
ance of the starting material, we were unable to isolate the
desired primary amine 16, probably due to its great instabil-
ity (Scheme 6).
Scheme 4. Synthesis of polysubstituted piperidines 12 by a stereo-
selective Mannich reaction.
Scheme 5. Formation of piperidine (–)-12b and enone 13.
Having a unique stereoisomer, in which all the substitu-
ents were in an equatorial position, in hand, we now envis-
aged implementation of the second Mannich reaction. To
achieve this cyclization, all of the substituents had to be in
an axial position; a required configuration for the forma-
tion of the bispidine framework. This was achieved by pro- Scheme 6. Synthesis of piperidines 15 and 17.
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To overcome this problem, we decided to retain the
acetal group. under these conditions, deprotection of the
amino group was cleanly realized with IRA 401 in meth-
anol,[23] giving compound 17 in excellent yield. To achieve
the second Mannich reaction, we first tried the same experi-
mental conditions as those used for the first cyclization
(pTsOH, CH2Cl2), but regardless of the aldehyde involved
in imine preparation, only degradation products were ob-
tained. One reason for this failure could be attributed to
the reactivity of the iminium species, which, in acidic me-
dium and over a longer time, led to degradation of the start-
ing materials. Therefore, reactivity had to be reinforced and
that is why we decided to use an acyliminium ion rather
than an iminium ion. Cyclizations involving acyliminium
chemistry have undergone a sizeable expansion, particularly
in alkaloids synthesis.[24] A convenient way to obtain an
Scheme 8. Stereoselective synthesis of bispidine (+)-23.
acyliminium ion is the partial reduction of imides to amido conditions, Mannich cyclization occurred, leading to the
alcohols, which can be further dehydrated in acidic condi- tetrahydrocytisine[29] derivative (+)-23 in 45% yield. Com-
tions. To obtain a substrate with greater flexibility, we rea- pound (+)-23 was obtained as a unique diastereoisomer,
soned that the double bond had to be reduced. Therefore, proving that the cyclization was favored on one face of the
we decided to change the reaction order, as described in acyliminium ion, and thus, permitted the total control of
Scheme 7.
the two stereogenic centers formed. It should be noted that,
under these conditions, acetal deprotection occurred simul-
taneously. Complete analysis of NMR spectroscopic data
for compound (+)-23 allowed us to determine the relative
configuration of each asymmetric carbon (Figure 3).
The signal of proton H-2 was a broad quadruplet (cou-
pled to the methyl group), as a consequence, H-2 and H-1
were in equatorial positions, resulting in a very weak cou-
pling constant. The same reasoning as that used for the
signal of proton H-4 led logically to the same conclusion:
H-4 and H-5 were also in equatorial positions. These results
were in complete agreement with results given in the litera-
ture.[20] The signal of H-11a had three coupling constants
of 10.5, 5.9, and 1.5 Hz. Because H-1 was in an equatorial
position, the value of 10.5 Hz must correspond to a trans-
Scheme 7. Synthesis of 3-methylaminopiperidine (+)-20.
The double bond of piperidine (+)-12a was first hydro- diaxial coupling, proving that H-11a was necessarily in an
genated with ammonium formate in the presence of palla- axial (or pseudo-axial) position. A NOESY experiment on
dium, giving (+)-18. N-Protection of the piperidine followed (+)-23 confirmed these deductions. H-11a presented a very
by cleavage of the trifluoroacetamide led to the target com- strong coupling with axial H-6, which was only possible if
pound (+)-20 in an overall yield of 65%. Condensation of H-11a was in an axial position. Thus, compound (+)-23 had
glutaric anhydride on piperidine (+)-20, following published a double chair conformation with both methyl and propyl
procedures,[25] gave imide (–)-21 in a moderate yield of 50%, groups in axial positions and the absolute configurations of
but this is in accordance with those obtained for similar chiral carbons were 1S,2R,4S,5S,11aR. Encouraged by this
transformations.[26] Reduction of the imide to an amido result, we wanted to explore the scope of this cyclization
alcohol is generally realized with NaBH4 in polar sol- using another acyl iminium ion and notably the one issued
vents[27] or with lithium triethyl borohydride.[28] When these from partial reduction of a phthalimide group. Condensa-
conditions were applied to compound (–)-21, the reaction tion of piperidine (+)-20 with phthalic anhydride in the
gave a mixture of two diastereoisomers 22, which were di- presence of a catalytic amount of triethylamine[30] gave
rectly engaged without purification to generate the acyl- compound (–)-24 in good yield. The latter was reduced with
iminium ion in situ in the next step; the key cyclization NaBH4 and here again the amido alcohol 25 thus formed
(Scheme 8).
was used without purification. Cyclization was also effective
An attempt at cyclization under the same conditions as with MeSO3H and led to a mixture of three compounds,
those used for the synthesis of piperidine (+)-12a led to the (–)-26, (–)-27, and 28 (global yield 75%), which were sepa-
disappearance of compound 22; however, the formation of rated by column chromatography (Scheme 9).
the expected bispidine was not effective. We reasoned that
In the same manner as that used for bispidine (+)-23, the
this failure could be attributed to the size of the counterion relative configuration of the stereogenic centers of bispid-
and decided to change pTsOH to MeSO3H. Under these ines (–)-26 (35%), (–)-27 (30%), and 28 (10%) was deduced
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Analgesic Activity of Poly-substituted Bispidines
1
Figure 3. H NMR spectra and relative configuration of bispidine (+)-23.
to total control of the stereochemistry in the two isomers
obtained. As expected, compound (–)-26 could be smoothly
transformed into keto deprotected bispidine (–)-27 in 80%
yield by treatment with a 6 n aqueous solution of hydro-
chloric acid in acetone for 2 d. The 1H and 13C NMR spec-
tra of the compound obtained were identical to those ob-
tained previously and the optical rotation, [α]D, was the
same. Careful examination of all coupling constants showed
that, in (–)-27, the bispidine core was in a double chair con-
formation with the methyl and propyl substituents in an
axial position, whereas in 28 a boat–chair conformation
was obtained in which the newly created ring, with the
phthalimido group, adopted a boat conformation[31] (Fig-
ure 4). Thus, the absolute configuration of bispidine (–)-27
was 1S,2R,4S,5S,12bS, whereas that of compound 28 was
1S,2R,4S,5S,12bR.
Figure 4. Conformation of bispidines (–)-27 and 28.
Scheme 9. Stereoselective synthesis of bispidines (–)-26, (–)-27, and
28.
Finally, the three keto-deprotected bispidines, (+)-23,
(–)-27, and 28, previously prepared were submitted to N-
deprotection by hydrogenation in the presence of palladium
from a careful study of the 1H NMR spectra and confirmed on charcoal and resulted in the bispidines (+)-29, (–)-30,
by NOESY experiments. Moreover, due to the presence of and (+)-31, respectively, in good yield (Scheme 10).
benzyl carbamate, these bispidines existed as two rotamers
Here again, coupling constant analysis showed that there
[55:45 for (–)-26; 65:35 for (–)-27, and 65:35 for 28]. Bispid- was no conformational change during the deprotection
ines (–)-26 and (–)-27 also had the same relative configura- step. Although compounds (+)-29 and (–)-30 were isolated
tion, and thus, we can conclude that cyclization was largely as single conformers in a double chair form, bispidine (+)-
favored on one face of the acyliminium ion (6.5:1) and led 31 was obtained as a mixture of two conformers, A and B
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A. Plas, F. Marchand, A. Eschalier, Y. Troin, P. Chalard
FULL PAPER
analgesic effect in comparison with that of morphine at the
same concentration. It is worth noting that, at the same
concentration, bispidine HZ2 lowered the abdominal con-
striction response to 95%.[9b] These bad results could be
attributed to the lack of pyridine rings substituents, which
were necessary for good activity. However, the flexibility of
our synthetic approach should allow the preparation of de-
rivatives possessing good pharmacophore substituents.
Conclusions
Scheme 10. N-Deprotection of bispidines (+)-23, (–)-27, and 28.
We have described the preparation of new bispidines de-
rivatives, through a highly modular approach, using a
double Mannich reaction. The key to the efficient construc-
tion of these scaffolds was the asymmetric double cycliza-
tion, which allowed total control of the stereogenic centers.
Although the biological results for the analgesic properties
were disappointing, the modularity of the approach offers
the possibility of introducing many substituents and opens
up the possibility of new applications because the bispidine
core has been described for many different activities.
(90:10), indicating that conformational change did not oc-
cur as rapidly on the NMR timescale. Conformer (+)-31A
still had the boat–chair conformation, whereas conformer
(+)-31B had a twist-chair conformation. Significant pop-
ulation of (+)-31B (10%) was observed by the NMR chemi-
cal shifts of protons H-12b and H-1, the shifts of which
were strongly dependent on the conformation (Figure 5).
Experimental Section
General: Experimental procedures are provided only for selected
key steps. The synthetic procedures for the preparation of com-
pounds 3Ϫ11, 14, 15, and 17 are provided in the Supporting Infor-
mation.
2,2,2-Trifluoro-N-({(7S,8S,10R)-10-methyl-8[(E)-prop-1-enyl]-1,5-di-
oxa-9-azaspiro[5.5]undecan-7-yl}methyl)acetamide [(+)-12a]: MgSO4
(5.00 g), followed by freshly distilled crotonaldehyde (1.45 mL,
17.6 mmol, 2.0 equiv.), were added to a stirred solution of amine
(R)-11a (2.50 g, 8.80 mmol, 1.0 equiv.) in dichloromethane
(120 mL). The resulting mixture was heated at gentle reflux until
complete disappearance (TLC monitoring, 1 h) of the amine, then
it was cooled to room temperature and transferred by cannula to
a solution of dry pTsOH (4.3 g, 22.4 mmol, 2.0 equiv.) in toluene
(100 mL). The resulting mixture was heated at 40 °C for 14 h. After
cooling to room temperature, a saturated aqueous solution of
Na2CO3 (100 mL) was added and the aqueous phase was extracted
with ethyl acetate (3ϫ40 mL). The combined organic extracts were
dried with Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by column chromatography (cyclo-
hexane/ethyl acetate, 1:1, 3:7, 0:1) to give (+)-12a as a yellow oil
Figure 5. Conformational analysis of bispidines (+)-29, (–)-30, and
(+)-31.
The biological activities of compounds (+)-29, (–)-30,
and (+)-31 were assayed, using the writhing test,[32] to com-
pare them with the results described for compound HZ2.[9b]
Abdominal constriction in mice was elicited with acetic acid
and the antinociceptive effect of the drugs was evaluated
through the lessening of abdominal cramps. The results ob-
tained are given in Figure 6 and show that the new bispid- (1.5 g, 50%). Rf = 0.43 (cyclohexane/ethyl acetate, 0:1). [α]2D5
ines derivatives (+)-29, (–)-30, and (+)-31 exhibited a weak
=
1
+16.9 (c = 1.03, CHCl3). H NMR (400.1 MHz, CDCl3): δ = 7.98
(br. s, 1 H), 5.62 (dq, J = 15.3, 7.6 Hz, 1 H), 5.30 (dd, J = 15.3,
8.4 Hz, 1 H), 4.10 (td, J = 12.6, 2.3 Hz, 1 H), 4.00 (td, J = 12.6,
2.3 Hz, 1 H), 3.85 (m, 2 H), 3.57 (m, 1 H), 3.48 (m, 1 H), 3.19 (dd,
J = 10.3, 8.4 Hz, 1 H), 2.84 (dqd, J = 11.9, 6.2, 2.3 Hz, 1 H), 2.78
(dd, J = 13.3, 2.3 Hz, 1 H), 2.02 (m, 1 H), 1.66 (d, J = 7.6 Hz, 3
H), 1.52 (ddd, J = 10.3, 7.8, 3.2 Hz, 1 H), 1.42 (m, 2 H), 1.10 (d,
J = 6.2 Hz, 3 H), 1.02 (dd, J = 13.3, 11.9 Hz, 1 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 156.4 (q, J = 36.4 Hz), 131.6, 130.2, 116.3
(q, J = 263 Hz), 99.6, 59.5, 59.3, 58.2, 48.1, 47.3, 37.1, 36.0, 25.6,
22.4, 18.0 ppm. IR: ν = 3335, 2926, 1720, 1539, 1379, 1182, 1087
˜
cm–1. HRMS (ESI): calcd. for C15H24N2O3F3 [M + H]+: 337.1739;
found 337.1737.
Mannich-Type Cyclization of Compound (S)-11b with Crotonalde-
hyde: MgSO4 (3.00 g), followed by freshly distilled crotonaldehyde
Figure 6. Analgesic effect of bispidines derivatives and morphine.
6
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Analgesic Activity of Poly-substituted Bispidines
(280 μL, 3.38 mmol, 1.5 equiv.), were added to a stirred solution of
amine (S)-11b (780 mg, 2.25 mmol, 1.0 equiv.) in dichloromethane
(50 mL). The resulting mixture was heated at gentle reflux until
complete disappearance (TLC monitoring, 1 h) of the amine, then
it was cooled to room temperature and transferred by cannula to
a solution of dry pTsOH (856 mg, 4.50 mmol, 2.0 equiv.) in toluene
(80 mL). The resulting mixture was heated for 90 min. After cool-
ing to room temperature, a saturated aqueous solution of Na2CO3
(50 mL) was added and the aqueous phase was extracted with ethyl
acetate (3ϫ60 mL). The combined organic extracts were dried with
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (cyclohexane/ethyl
acetate, 9:1, 8:2, 7:3, 1:1) to give 313 mg of (–)-12b as a white solid
(35%) and 150 mg of enone 13 (25%) as a yellow oil.
solution was stirred at room temperature for 3 h. The aqueous
phase was extracted with dichloromethane (3 ϫ10 mL) and the
combined organic extracts were dried with Na2SO4, filtered, and
concentrated in vacuo. Purification by column chromatography
(cyclohexane/ethyl acetate, 8:2) on silica gel gave (+)-19 (606 mg,
70%) as a yellow oil. Rf = 0.38 (cyclohexane/ethyl acetate, 7:3).
1
[α]2D5 = +20.7 (c = 1.12, CHCl3). H NMR (400.1 MHz, CDCl3): δ
= (ppm) 7.46 (br. s, 1 H), 7.34–7.28 (m, 5 H), 5.18 (d, J = 12.5 Hz,
1 H), 5.05 (d, J = 12.5 Hz, 1 H), 4.15–4.01 (m, 3 H), 3.93–3.83 (m,
3 H), 3.55 (ddd, J = 13.6, 8.5, 5.2 Hz, 1 H), 3.44 (m, 1 H), 2.76
(dd, J = 14.3, 6.9 Hz, 1 H), 1.95 (m, 2 H), 1.73–1.62 (m, 2 H),
1.57–1.51 (m, 1 H), 1.47 (dt, J = 13.5, 2.6 Hz, 1 H), 1.36–1.29 (m,
1 H), 1.26 (m, 4 H), 0.87 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = (ppm) 157.2 (q, J = 36.3 Hz), 152.6, 116.2
(q, J = 286 Hz), 136.8, 128.6, 127.9, 127.0, 98.7, 67.1, 60.2, 59.9,
2,2,2-Trifluoro-N-({(7S,8S,10R)-10-phenyl-8-[(E)-prop-1-enyl]-1,5-
dioxa-9-azaspiro[5.5]undecan-7-yl}methyl)acetamide [(+)-12b]: Rf =
0.40 (cyclohexane/ethyl acetate, 9:1); m.p. 113 °C. [α]2D5 = –16.7 (c
53.1, 47.1, 46.6, 41.0, 39.9, 30.5, 25.1, 21.90, 19.7, 13.8 ppm. IR: ν
˜
= 3032, 2962, 1722, 1701, 1674, 1548, 1417, 1417, 1309 cm–1
.
HRMS (ESI): calcd. for C23H31N2O5F3Na [M + Na]+: 495.2083;
found 495.2098.
1
= 1.20, CHCl3). H NMR (400.1 MHz, CDCl3): δ = 7.86 (s, 1 H),
7.31–7.11 (m, 5 H), 5.52 (dq, J = 15.2, 6.4, 1 H), 5.28 (dd, J =
15.2, 8.6, 1 H), 4.03–3.88 (m, 2 H), 3.83 (dd, J = 11.7, 5.0, 1 H),
3.71 (m, 2 H), 3.56–3.39 (m, 2 H), 3.22 (dd, J = 11.0, 8.6, 1 H),
2.80 (d, J = 13.4, 1 H), 1.94 (m, 1 H), 1.63–1.47 (m, 5 H, H), 1.40–
1.27 (m, 2 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 156.4 (q,
J = 36.7 Hz), 143.6, 131.7, 130.1, 128.7, 127.8, 126.9, 116.2 (q, J =
286 Hz), 99.6, 59.5, 59.3, 58.7, 57.0, 48.1, 37.0, 36.4, 25.6,
(7S,8S,10R)-Benzyl 7-(Aminomethyl)-10-methyl-8-propyl-1,5-dioxa-
9-azaspiro[5.5]undecane-9-carboxylate [(+)-20]: Amberlite IRA 401
(9.20 g, 5.7 equiv.) was added to a solution of compound (+)-19 in
methanol (50 mL). The resulting mixture was stirred until comple-
tion (TLC monitoring). The resin was removed by filtration and
washed with methanol. The filtrate was concentrated in vacuo and
gave (+)-20 as a pale yellow oil (468 mg, 95%). A sample of the
crude product was purified by column chromatography (ethyl acet-
ate/methanol, 8:2) on silica gel for analysis. Rf = 0.18 (ethyl acetate/
methanol, 8:2). [α]2D5 = +1.4 (c = 1.07, CHCl3). 1H NMR
(400.1 MHz, CDCl3): δ = (ppm) 7.35 (m, 5 H), 5.14 (s, 2 H), 4.29
(m, 1 H), 4.23 (m, 1 H), 3.99 (ddd, J = 13.0, 9.6, 3.5 Hz, 1 H),
3.91–3.78 (m, 3 H), 2.90 (dd, J = 13.1, 5.5 Hz, 1 H), 2.60 (m, 1 H),
2.37 (dd, J = 14.3, 7.3 Hz, 1 H), 1.85 (m, 2 H), 1.53–1.75 (m, 6 H),
1.28 (m, 5 H), 0.89 (t, J = 7.1 Hz, 3 H) ppm. 1 3 C NMR
(100.6 MHz, CDCl3): δ = (ppm) 156.2, 137.2, 128.6, 127.9, 127.1,
98.7, 67.1, 59.7, 59.6, 53.3, 49.0, 46.7, 41.8, 40.2, 31.9, 25.3, 21.9,
17.9 ppm. IR: ν = 3348, 3028, 1705, 1600, 1496, 1450, 1562, 1203,
˜
1176, 979 cm–1. HRMS (ESI): calcd. for C20H26N2O3F3 [M + H]+:
399.1896; found 399.1915.
2,2,2-Trifluoro-N-[(4E)-3-oxo-5-phenylpent-4-en-1-yl]acetamide
(13): Rf = 0.48 (cyclohexane/ethyl acetate, 9:1). 1H NMR
(400.1 MHz, CDCl3): δ = (ppm) 7.59 (d, J = 16.5 Hz, 1 H), 7.56
(m, 2 H), 7.45–7.38 (m, 3 H), 7.14 (br. s, 1 H), 6.74 (d, J = 16.5 Hz,
1 H), 3.70 (m, 1 H), 3.01 (t, J = 5.4 Hz, 1 H) ppm.
2,2,2-Trifluoro-N-{[(7S,8S,10R)-10-phenyl-8-propyl-1,5-dioxa-9-
azaspiro[5.5]undecan-7-yl]methyl}acetamide [(+)-18]: 10% Pd/C
[50 mg/mmol of (+)-12a] then ammonium formate (1.02 g,
16.2 mmol, 5.0 equiv.) were added to a solution of (+)-12a (1.10 g,
3.23 mmol, 1.0 equiv.) in methanol (60 mL). The resulting suspen-
sion was heated at reflux for 2 h. After cooling to room tempera-
ture, the catalyst was removed by filtration through Celite. The resi-
due was concentrated in vacuo to afford compound (+)-18 (1.08 g,
95%) as a white solid, which was used in the next step without any
purification. A sample of the crude product (100 mg) was purified
by column chromatography (cyclohexane/ethyl acetate, 0:1) on sil-
ica gel for analysis. Rf = 0.38 (cyclohexane/ethyl acetate, 0:1); m.p.
20.2, 14.1 ppm. IR: ν = 3337, 3032, 2962, 1690, 1604, 1495, 1454,
˜
1342, 1309 cm–1. HRMS (ESI): calcd. for C21H33N2O4 [M + H]+:
377.2440; found 377.2445.
(7S,8S,10R)-Benzyl 7-[(2,6-Dioxopiperidin-1-yl)methyl]-10-methyl-
8-propyl-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylate [(–)-21]:
Glutaric anhydride (120 mg, 0.99 mmol, 1.1 equiv.) was added to a
solution of amine (+)-20 (340 mg, 0.90 mmol, 1.0 equiv.) in toluene
(15 mL) . The mixture was heated at reflux for 3 h until completion
(TLC monitoring), before addition of acetyl chloride (0.29 mL,
4.06 mmol, 5.0 equiv.). After 1 h (TLC monitoring), toluene was
removed under pressure. The residue was dissolved in dichloro-
methane (10 mL) and washed with a solution of 1 m HCl (15 mL)
then water (10 mL). The organic layers were dried with Na2SO4,
filtered, and concentrated in vacuo. Purification by column
chromatography (cyclohexane/ethyl acetate, 4:6) on silica gel gave
(–)-21 (200 mg, 50% on 2 steps) as a yellow oil. Rf = 0.74 (cHex/
60.4–61.4 °C. [α]2D5
= +38.8 (c =
1.08, CHCl3). 1H NMR
(400.1 MHz, CDCl3): δ = 7.92 (br. s, 1 H), 4.11 (td, J = 12.5,
2.5 Hz, 1 H), 4.01 (td, J = 12.5, 2.5 Hz, 1 H), 3.91–3.79 (m, 2 H),
3.73–3.61 (m, 2 H), 2.86–2.69 (m, 3 H), 2.03 (m, 1 H), 1.54 (m, 1
H), 1.49–1.36 (m, 3 H), 1.35–1.19 (m, 3 H), 1.11 (d, J = 6.2 Hz, 3
H), 0.95 (dd, J = 13.9, 12.1 Hz, 1 H), 0.89 (t, J = 6.9 Hz, 3 H)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 156.8 (q, J = 36.2 Hz),
116.1 (q, J = 283 Hz), 100.2, 59.4, 59.3, 53.0, 48.5, 47.4, 36.3, 35.8,
EtOAc, 0:1). [α]2D5
= –69.3 (c =
0.92, CHCl3). 1H NMR
(400.1 MHz, CDCl3): δ = (ppm) 7.40–7.27 (m, 5 H), 5.15 (m, 2 H),
4.65 (m, 1 H), 4.29 (m, 1 H), 4.13 (m, 4 H), 3.71 (m, 1 H), 3.61
(m, 1 H), 2.60 (m, 2 H), 2.53 (m, 2 H), 2.01–1.89 (m, 3 H), 1.80
(m, 1 H), 1.62 (m, 2 H), 1.33–1.25 (m, 6 H), 1.20 (d, J = 6.7 Hz, 3
H, H7), 0.89 (t, J = 7.2 Hz, 3 H) ppm. Rotamer A: 13C NMR
35.4, 25.7, 22.6, 18.5, 14.1 ppm. IR: ν = 3402, 2966, 1721, 1539,
˜
1205, 1141, 1066 cm–1. HRMS (ESI): calcd. for C15H26N2O3F3 [M
+ H]+: 339.1896; found 339.1902.
(7S,8S,10R)-Benzyl 10-Methyl-8-propyl-7-[(2,2,2-trifluoroacet-
amido)methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylate (100.6 MHz, CDCl3): δ = (ppm) 172.6, 156.2, 153.3, 137.1, 128.6,
[(+)-19]: Compound (+)-18 (485 mg, 1.43 mmol, 1.0 equiv.) was 128.0, 127.8, 96.5, 67.2, 63.7, 63.6, 51.9, 47.4, 42.1, 40.1, 37.0, 33.1,
dissolved in dichloromethane (7 mL) and water (7 mL). Then, so-
dium carbonate (304 mg, 2.87 mmol, 2.0 equiv.) and benzyl chloro-
formate (430 μL, 2.87 mmol, 2.0 equiv.) were added. The resulting
33.0, 28.6, 23.3, 21.1, 19.9, 17.3, 14.1 ppm. Rotamer B: 13C NMR
(100.6 MHz, CDCl3): δ = (ppm) 172.4, 155.4, 152.2, 137.1, 128.6,
128.0, 127.8, 96.0, 67.1, 63.7, 63.6, 52.6, 47.0, 42.2, 40.6, 36.7, 33.1,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20919
/KAP1
Date: 17-09-12 10:19:28
Pages: 11
A. Plas, F. Marchand, A. Eschalier, Y. Troin, P. Chalard
added. The mixture was extracted with ethyl acetate (3ϫ10 mL).
FULL PAPER
33.0, 28.8, 23.3, 21.2, 19.8, 17.2, 14.0 ppm. IR: ν = 3031, 2967,
˜
1735, 1694, 1678, 1452, 1411, 1130 cm–1. HRMS (ESI): calcd. for The organic layers were dried with Na2SO4, filtered, and concen-
C26H36N2O6Na [M + Na]+: 495.247; found 495.2454.
trated in vacuo. Methanesulfonic acid (70.0 μL, 1.07 mmol,
2.0 equiv.) was added to a solution of 25 (272 mg, 0.53 mmol,
1.0 equiv.) in anhydrous dichloromethane. The resulting mixture
was stirred for 90 min before a solution of NaHCO3 was added
(5 mL). The aqueous material was extracted with dichloromethane
(2ϫ10 mL) and the combined organic extracts were dried with
Na2SO4, filtered, and concentrated in vacuo. Purification by col-
umn chromatography (cyclohexane/ethyl acetate, 1:1, 4:6, 3:7, then
2:8) on silica gel gave ketal 26 (91 mg, 35%), ketone 27 (72 mg,
30%), and ketone 28 (25 mg, 10%).
Synthesis of Compound (–)-23: A 1 m solution of LiEt3BH (650 μL,
0.65 mmol, 1.3 equiv.) at –78 °C was added to a solution of (–)-
21 (236 mg, 0.50 mmol, 1.0 equiv.) in anhydrous dichloromethane
(10 mL). The mixture was stirred at this temperature for 1 h before
a saturated aqueous solution of NH4Cl (5 mL) was added. The
mixture was extracted with dichloromethane (3ϫ10 mL). The or-
ganic layers were dried with Na2SO4, filtered, and concentrated in
vacuo to give 22. Methanesulfonic acid (62.0 μL, 0.94 mmol,
2.0 equiv.) was added to a solution of 22 (224 mg, 0.47 mmol,
1.0 equiv.) in anhydrous dichloromethane (10 mL). The resulting
mixture was stirred for 90 min before a solution of NaHCO3 was
then added (5 mL). The aqueous phase was extracted with dichlo-
romethane (2ϫ10 mL) and the combined organic extracts were
dried with Na2SO4, filtered, and concentrated in vacuo. Purifica-
tion by column chromatography (cyclohexane/ethyl acetate, 4:6,
3:7, 2:8, then 0:1) on silica gel gave (+)-23 (80.2 mg, 45%) as a
white solid. Rf = 0.40 (cyclohexane/ethyl acetate, 7:3); m.p. 97 °C.
Synthesis of Compound (–)-26: Rf = 0.28 (cyclohexane/ethyl acetate,
3:7). [α]2D5 = –19.6 (c = 1.01, CHCl3). Rotamer A: 1H NMR
(400.1 MHz, C6D6): δ = 8.05 (d, J = 7.3 Hz, 1 H), 7.51 (d, J =
7.3 Hz, 1 H), 7.25–7.01 (m, 5 H), 6.92 (m, 1 H), 6.87 (d, J = 7.6 Hz,
1 H), 5.25 (d, J = 12.0 Hz, 1 H), 5.16 (d, J = 12.0 Hz, 1 H), 4.72
(d, J = 3.6 Hz, 1 H), 4.46 (dd, J = 12.9, 1.8 Hz, 1 H), 4.43 (t, J =
7.6 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 1 H), 3.46–3.32 (m, 4 H), 3.29
(dd, J = 12.9, 4.1 Hz, 1 H), 2.47 (d, J = 3.6 Hz, 1 H), 1.98 (dd, J
= 4.1, 1.8 Hz, 1 H), 1.75–1.68 (m, 1 H), 1.59 (m, 1 H), 1.50–1.30
(m, 3 H), 1.26 (d, J = 7.1 Hz, 3 H), 1.05 (m, 1 H), 0.80 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 167.0,
154.7, 143.5, 137.1, 133.6, 131.6, 128.7, 128.3, 128.2, 127.6, 124.1,
121.4, 98.2, 67.4, 60.4, 59.6, 59.3, 58.8, 47.6, 43.8, 42.7, 38.3, 34.4,
25.2, 22.0, 20.7, 14.2 ppm. Rotamer B: 1H NMR (400.1 MHz,
C6D6): δ = 7.80 (d, J = 7.3 Hz, 1 H), 7.51 (d, J = 7.3 Hz, 1 H),
7.25–7.01 (m, 5 H), 6.92 (m, 1 H), 6.82 (d, J = 7.6 Hz, 1 H), 5.03
(d, J = 12.8 Hz, 1 H), 4.77 (d, J = 12.8 Hz, 1 H), 4.76 (d, J =
3.9 Hz, 1 H), 4.72 (t, J = 7.4 Hz, 1 H), 4.53 (dd, J = 13.3, 1.9 Hz,
1 H), 3.94 (q, J = 7.1 Hz, 1 H), 3.46–3.32 (m, 4 H), 3.20 (dd, J =
3.9, 13.3 Hz, 1 H), 2.30 (d, J = 3.9 Hz, 1 H), 2.16 (dd, J = 3.9,
1.9 Hz, 1 H), 1.90–1.80 (m, 1 H), 1.70 (m, 1 H), 1.50–1.30 (m, 3
H), 1.21 (d, J = 7.1 Hz, 3 H), 1.05 (m, 1 H), 0.96 (t, J = 7.1 Hz, 3
H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 166.8, 154.6, 143.4,
136.7, 133.5, 131.3, 128.5, 128.2, 127.7, 127.5, 123.9, 121.3, 98.2,
66.8, 60.4, 59.6, 59.3, 58.5, 47.5, 43.8, 42.3, 37.7, 33.3, 25.2, 21.1,
[α]2D5 = +74.6 (c = 0.90, CHCl3). H NMR (400.1 MHz, C6D6): δ
1
= (ppm) 7.44 (m, 2 H), 7.27–7.04 (m, 3 H), 5.31 (q, J = 7.1 Hz, 1
H), 5.21 (d, J = 11.8 Hz, 1 H), 5.16 (d, J = 11.8 Hz, 1 H), 5.12 (dd,
J = 13.5, 1.9 Hz, 1 H), 4.50 (t, J = 7.4 Hz, 1 H), 2.96 (ddd, J =
10.5, 5.9, 1.5 Hz, 1 H), 2.51 (dd, J = 13.5, 3.2 Hz, 1 H), 2.36 (dd,
J = 13.1, 5.5 Hz, 1 H), 2.28 (m, 1 H), 1.96 (dd, J = 3.2, 1.9 Hz, 1
H), 1.73 (d, J = 1.5 Hz, 1 H), 1.61 (m, 1 H), 1.38–1.25 (m, 3 H),
1.15–1.05 (m, 3 H), 1.01 (d, J = 7.7 Hz, 3 H), 0.97 (m, 1 H), 0.65
(t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
211.3, 170.2, 155.9, 136.5, 128.6, 128.2, 128.1, 68.2, 61.2, 60.5, 56.8,
50.8, 50.0, 48.9, 38.7, 32.7, 27.2, 21.6, 20.5, 19.8, 13.8 ppm. IR: ν
˜
.
= 3027, 2955, 1722, 1693, 1647, 1500, 1446, 1350, 1091 cm–1
HRMS (ESI): calcd. for C23H30N2O4Na [M + Na]+: 421.2103;
found 421.2113.
(7S,8S,10R)-Benzyl 7-[(1,3-Dioxoisoindolin-2-yl)methyl]-10-methyl-
8-propyl-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylate [(–)-24]:
A round-bottomed flask equipped with a Dean–Stark apparatus
was charged with compound (+)-20 (430 mg, 1.14 mmol,
1.0 equiv.), phthalic anhydride (186 mg, 1.25 mmol, 1.1 equiv.), and
triethylamine (16 μL, 0.11 mmol, 0.1 equiv.) in toluene (15 mL).
The mixture was heated at reflux for 3 h. After cooling, water
(10 mL) was added. The mixture was extracted with ethyl acetate
(2ϫ10 mL). The organic layer was dried with Na2SO4, filtered, and
concentrated in vacuo. Purification by column chromatography
(cyclohexane/ethyl acetate, 8:2) on silica gel gave (–)-24 (404 mg,
80%) as a white foam. Rf = 0.35 (cyclohexane/ethyl acetate, 8:2).
20.3, 14.0 ppm. IR: ν = 3034, 2960, 1693, 1682, 1467, 1456, 1417,
˜
1305, 1111 cm–1. HRMS (ESI): calcd. for C29H34N2O5Na [M +
Na]+: 513.2365; found 513.2349.
Synthesis of Compound (–)-27: Rf = 0.52 (cyclohexane/ethyl acetate,
3:7). [α]2D5 = –65.4 (c = 1.00 CHCl3). Rotamer A: 1H NMR
(400.1 MHz, C6D6): δ = 7.96 (d, J = 7.3 Hz, 1 H), 7.45 (d, J =
7.5 Hz, 1 H), 7.25–7.01 (m, 5 H), 6.85 (m, 1 H), 6.67 (d, J = 7.0 Hz,
1 H), 5.20 (d, J = 12.0 Hz, 1 H), 5.06 (d, J = 12.0 Hz, 1 H), 4.60
(d, J = 13.4 Hz, 1 H), 4.48 (t, J = 7.3 Hz, 1 H), 4.35 (q, J = 7.2 Hz,
1 H), 4.03 (d, J = 3.6 Hz, 1 H), 2.87 (dd, J = 13.4, 2.2 Hz, 1 H),
2.43 (d, J = 3.6 Hz, 1 H), 1.92 (d, J = 2.2 Hz, 1 H), 1.40–1.20 (m,
2 H), 1.20–0.90 (m, 2 H), 0.87 (d, J = 7.2 Hz, 3 H), 0.62 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 210.7,
167.0, 154.8, 141.2, 136.5, 133.0, 132.4, 129.6, 128.5, 128.1, 127.7,
124.6, 121.6, 68.1, 63.5, 61.6, 55.6, 51.4, 48.3, 45.6, 39.0, 21.6 (C9),
19.8, 13.7 ppm. Rotamer B: 1H NMR (400.1 MHz, C6D6): δ = 7.69
(d, J = 7.3, 1 H), 7.20–6.90 (m, 7 H), 6.58 (d, J = 7.6, 1 H), 4.94
(d, J = 12.4, 1 H), 4.87 (t, J = 6.3, 1 H), 4.79 (d, J = 12.4, 1 H),
4.70 (d, J = 13.0, 1 H), 4.00 (m, 2 H), 2.88 (dd, J = 13.0, 2.2, 1
H), 2.31 (d, J = 2.4, 1 H), 2.08 (d, J = 2.2, 1 H), 1.40–1.20 (m, 2
H), 1.20–0.90 (m, 2 H), 0.76–0.81 (m, 6 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 210.6, 166.7, 154.6, 141.2, 136.2, 133.0,
132.1, 129.3, 128.4, 128.3, 127.9, 124.3, 121.6, 67.5, 63.5, 62.2, 54.9,
1
[α]2D5 = –25.1 (c = 1.04, CHCl3). H NMR (400.1 MHz, CDCl3): δ
= 7.72 (m, 2 H), 7.62 (m, 2 H), 7.34–7.11 (m, 5 H), 5.09 (m, 2 H),
4.33 (m, 1 H), 4.00 (m, 1 H), 3.89–3.52 (m, 6 H), 2.81 (m, 1 H),
2.26 (m, 1 H), 1.70–1.49 (m, 5 H), 1.20 (m, 7 H), 1.07 (m, 1 H)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 168.5, 156.0, 137.1,
133.9, 132.2, 130.5, 128.3, 127.6, 123.3, 97.8, 67.1, 59.6, 59.5, 48.8,
46.6, 39.5, 39.0, 38.0, 33.4, 25.0, 21.2, 20.2, 13.9 ppm. IR: ν = 3025,
˜
2960, 1772, 1716, 1690, 1504, 1415, 1394, 1113 cm–1. HRMS (ESI):
calcd. for C29H34N2O6Na [M + Na]+: 529.2315; found 529.2334.
Mannich-Type Cyclization of Compound 24: NaBH4 (32.0 mg,
0.83 mmol, 1.5 equiv.) was slowly added portionwise at –20 °C, un-
der an inert atmosphere, to a solution of 24 (280 mg, 0.55 mmol,
1.0 equiv.) in tetrahydrofuran/methanol (4 mL/6 mL). The reaction
mixture was stirred at this temperature for 30 min and the tempera-
ture was then allowed to rise to 0–5 °C for 1 h. Water (4 mL) and
a saturated aqueous solution of NaHCO3 (5 mL) were successively
51.1, 48.2, 45.5, 38.8, 22.3, 20.0, 13.9 ppm. IR: ν = 3028, 2956,
˜
1702, 1697, 1602, 1501, 1415, 1340, 1114 cm–1. HRMS (ESI): calcd.
for C26H29N2O4 [M + H]+: 433.2127; found 433.2137.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20919
/KAP1
Date: 17-09-12 10:19:28
Pages: 11
Analgesic Activity of Poly-substituted Bispidines
1
Synthesis of Compound 28: Rf = 0.69 (cyclohexane/ethyl acetate,
[α]2D5 = –117 (c = 1.06, CHCl3). H NMR (400.1 MHz, C6D6): δ =
3:7). Rotamer A: 1H NMR (400.1 MHz, C6D6): δ = 7.78 (d, J = 7.93 (m, 1 H), 7.06–7.02 (m, 2 H), 6.68 (m, 1 H), 4.41 (dd, J =
7.6 Hz, 1 H), 7.30–6.92 (m, 7 H), 6.59 (d, J = 7.4 Hz, 1 H), 5.16
13.2, 2.0 Hz, 1 H), 4.02 (d, J = 3.6 Hz, 1 H), 2.85 (dd, J = 13.2,
(d, J = 12.2 Hz, 1 H), 5.11 (d, J = 12.2 Hz, 1 H), 5.07 (m, 1 H), 3.0 Hz, 1 H), 2.69 (td, J = 5.1, 3.6 Hz, 1 H), 2.53 (dd, J = 3.6,
4.87 (dd, J = 13.6, 10.8 Hz, 1 H), 4.28 (d, J = 1.8 Hz, 1 H), 4.06
(t, J = 8.0 Hz, 1 H), 2.95 (dd, J = 13.6, 2.5 Hz, 1 H), 2.52 (d, J =
2.2 Hz, 1 H), 2.15 (m, 1 H), 1.97 (qd, J = 6.4, 2.2 Hz, 1 H), 1.18–
0.97 (m, 5 H), 0.75 (t, J = 6.4 Hz, 3 H), 0.55 (d, J = 6.4 Hz, 3 H)
1.8 Hz, 1 H), 2.24 (dd, J = 10.8, 2.5 Hz, 1 H), 1.50–1.15 (m, 4 H), ppm. 13C NMR (100.6 MHz, C6D6): δ = 209.3, 167.1, 142.1, 134.1,
1.11 (d, J = 7.2 Hz, 3 H), 0.66 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 207.2, 166.2, 156.8, 144.7, 136.0, 132.5,
131.5, 129.1, 128.8, 128.6, 128.3, 124.2, 121.8, 68.4, 64.3, 62.8, 58.7,
133.5, 131.5, 124.2, 122.2, 62.5, 60.8, 57.4, 52.0, 51.0, 44.3, 39.8,
23.7, 18.5, 14.3 ppm. IR: ν = 3433, 2958, 1732, 1693, 1593, 1465,
˜
1415, 1296 cm–1. HRMS (ESI): calcd. for C18H23O2N2 [M + H]+:
299.1760; found 299.1754.
1
57.3, 47.3, 43.8, 37.7, 20.5, 20.2, 13.8 ppm. Rotamer B: H NMR
(400.1 MHz, C6D6): δ = 7.78 (d, J = 7.6 Hz, 1 H), 7.30–6.92 (m, 7
H), 6.50 (d, J = 7.1 Hz, 1 H), 5.24 (d, J = 12.3 Hz, 1 H), 5.11 (d,
J = 12.3 Hz, 1 H), 4.87 (dd, J = 13.6, 10.9 Hz, 1 H), 4.70 (q, J =
7.3 Hz, 1 H), 4.52 (t, J = 7.3 Hz, 1 H), 4.18 (d, J = 1.6 Hz, 1 H),
3.07 (dd, J = 13.6, 2.5 Hz, 1 H), 2.42 (d, J = 1.6 Hz, 1 H), 2.38
(dd, J = 10.9, 2.5 Hz, 1 H), 1. 50–1.15 (m, 4 H), 1.05 (d, J = 7.3 Hz,
3 H), 0.77 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 207.2, 166.1, 156.6, 144.5, 136.3, 132.4, 131.6, 129.0,
128.8, 128.7, 128.6, 124.3, 121.7, 68.4, 64.6, 63.1, 58.6, 56.9, 47.3,
Synthesis of Compound (+)-31: Ketone 28 (25.3 mg, 0.06 mmol,
1.0 equiv.) was added to a suspension of 10% Pd/C (3 mg, 50 mg/
mmol of 28) in methanol (2 mL). The mixture was placed on a Parr
apparatus and stirred under a hydrogen atmosphere (60 psi) for 1 d.
The catalyst was removed by filtration through Celite. The residue
was concentrated in vacuo. Purification by column chromatography
(cyclohexane/ethyl acetate, 3:7) gave 31 as a white foam (12 mg,
70%). Rf = 0.39 (cyclohexane/ethyl acetate, 3:7). [α]2D5 = +57.1 (c =
0.25, CHCl3). Conformer A: 1H NMR (400.1 MHz, C6D6): δ =
7.89 (d, J = 7.1 Hz, 1 H), 7.08 (td, J = 7.4, 1.1 Hz, 1 H), 7.00 (td,
J = 7.4, 3.5 Hz, 1 H), 6.79 (d, J = 7.5 Hz, 1 H), 4.96 (dd, J = 13.1,
10.6 Hz, 1 H), 4.60 (d, J = 2.2 Hz, 1 H), 3.13 (dd, J = 13.1, 2.1 Hz,
1 H), 2.93 (qd, J = 6.5, 1.9 Hz, 1 H), 2.40 (q, J = 2.0 Hz, 1 H),
2.70 (m, 1 H), 2.24 (dq, J = 10.6, 2.0 Hz, 1 H), 1.40–1.25 (br. s, 1
H), 1.20 (m, 1 H), 1.00–0.82 (m, 3 H), 0.75 (t, J = 7.1 Hz, 3 H),
0.71 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (100.6 MHz, C6D6): δ =
207.6, 146.5, 141.3, 134.6, 131.6, 128.5, 124.4, 121.6, 61.4, 59.3,
43.6, 37.6, 21.2, 20.3, 13.9 ppm. IR: ν = 3017, 2968, 1704, 1692,
˜
1605, 1509, 1418, 1346, 1112 cm–1. HRMS (ESI): calcd. for
C26H28N2O4 Na[M + Na]+: 455.1947; found 455.1928.
Deprotection of Ketal (–)-26: A 6 n solution of hydrochloride acid
(0.50 mL, 3.14 mmol, 14 equiv.) was added to a solution of (–)-26
(110 mg, 0.22 mmol, 1.0 equiv.) in acetone (5 mL). The mixture was
stirred at room temperature for 4 d. After evaporation of acetone,
the residue was dissolved in ethyl acetate (10 mL) and treated with
an aqueous saturated solution of Na2CO3. The aqueous phase was
extracted with ethyl acetate (3ϫ10 mL). The combined organic ex-
tracts were dried with Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 4:6) to give ketone (–)-27 as a
white foam (71 mg, 80%). The spectroscopic data of the compound
thus obtained were identical with those previously described (vide
supra).
1
57.7, 50.0, 49.1, 43.9, 32.8, 19.8, 18.9, 13.9 ppm. Conformer B: H
NMR (400.1 MHz, C6D6): δ = 7.89 (d, J = 7.1 Hz, 1 H), 7.08 (td,
J = 7.4, 1.1 Hz, 1 H), 7.00 (td, J = 7.4, 3.5 Hz, 1 H), 6.79 (d, J =
7.5 Hz, 1 H), 4.71 (dd, J = 13.3, 10.5 Hz, 1 H), 4.45 (s, 1 H), 3.33
(dd, J = 13.3, 2.6 Hz, 1 H), 3.01 (qd, J = 7.1, 2.3 Hz, 1 H), 2.54
(dd, J = 2.3, 2.0 Hz, 1 H), 2.39–2.34 (m, 2 H), 1.40–1.25 (br. s, 1
H), 1.20 (m, 1 H), 1.00–0.82 (m, 9 H) ppm. IR: ν = 3433, 2958,
˜
1732, 1693, 1593, 1465, 1415, 1296 cm–1. HRMS (ESI): calcd. for
C18H23N2O2 [M + H]+: 299.1760; found 299.1759.
Synthesis of Compound (+)-29: Compound (+)-23 (70.2 mg,
0.17 mmol, 1.0 equiv.) was added to a solution 10% Pd/C [9.00 mg,
50 mg/mmol of (+)-23] in methanol (2 mL) . The mixture was
placed on a Parr apparatus and stirred under a hydrogen atmo-
sphere (60 psi) for 2 d. The catalyst was removed by filtration
through Celite. The residue was concentrated in vacuo. Purification
by column chromatography (cyclohexane/ethyl acetate, 3:7) gave
(+)-29 as a white foam (28.2 mg, 70%). Rf = 0.28 (cyclohexane/
ethyl acetate, 0:1). [α]2D5 = +101 (c = 0.52, CHCl3). 1H NMR
(400.1 MHz, C6D6): δ = 4.94 (dd, J = 13.2, 2.5 Hz, 1 H), 2.97 (dd,
J = 12.1, 4.2 Hz, 1 H), 2.86 (m, 2 H), 2.48 (dd, J = 13.2, 2.5 Hz, 1
H), 2.32 (d, J = 15.9 Hz, 1 H), 2.19 (dt, J = 5.4, 2.5 Hz, 1 H), 1.93
(m, 1 H), 1.86 (dd, J = 4.2, 2.0 Hz, 1 H), 1.27–1.05 (m, 5 H), 1.00–
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for compounds 3–11; 1H, and 13C
NMR spectra of all compounds.
Acknowledgments
We thank the Ministère de la Jeunesse, de l’Education Nationale et
de la Recherche for financial support.
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˜
(ESI): calcd. for C15H25N2O2 [M + H]+: 265.1916; found 265.1912.
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 17-09-12 10:19:28
Pages: 11
A. Plas, F. Marchand, A. Eschalier, Y. Troin, P. Chalard
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Received: July 11, 2012
Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20919
/KAP1
Date: 17-09-12 10:19:28
Pages: 11
Analgesic Activity of Poly-substituted Bispidines
Stereoselective Synthesis
A. Plas, F. Marchand, A. Eschalier,
Y. Troin,* P. Chalard* .................... 1–11
Stereoselective Synthesis and In Vivo
Evaluation of the Analgesic Activity of Po-
lysubstituted Bispidines
Total stereoselective synthesis of bispidine
derivatives is achieved by using as two suc-
cessive Mannich reactions key steps. This
process constitutes a powerful approach to-
ward the preparation of a polycyclic bispid-
ine backbone with high enantioselectivity.
Keywords: Natural products / Alkaloids /
Nitrogen heterocycles / Synthesis design /
Cyclization / Medicinal chemistry
Eur. J. Org. Chem. 0000, 0–0
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