Thermodynamic epimeric equilibration and crystallisation-induced dynamic resolution of lobelanine, norlobelanine and related analogues

Article abstract of DOI:10.1039/c4ob01787k

The step-economical synthesis of lobelanine involving a ring closing double aza-Michael (RCDAM) reaction is revisited and successfully extended to the synthesis of various configurationally more stable analogues. Owing to the presence of a configurationally labile β-aminoketone subunit, lobelanine is prone to self-catalyze mutarotation in solution. Through the synthesis of original lobelanine analogues, we studied the influence of (i) the size of the central heterocycle, (ii) the bulkiness of the nitrogen protecting group, and (iii) the phenacyl arm substituent on the thermodynamic equilibrium and its displacement by crystallisation-induced dynamic resolution (CIDR). We demonstrated that fine structural tuning combined with optimized CIDR conditions favours the first efficient diastereoselective synthesis of lobelanine's analogues.

Full text of DOI:10.1039/c4ob01787k

Volume 12 Number 48 28 December 2014 Pages 9723–9922
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
ISSN 1477-0520
PAPER
F. Le Bideau, D. Joseph et al.
Thermodynamic epimeric equilibration and crystallisation-induced
dynamic resolution of lobelanine, norlobelanine and related analogues

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Thermodynamic epimeric equilibration and
crystallisation-induced dynamic resolution of
lobelanine, norlobelanine and related analogues†
Cite this: Org. Biomol. Chem., 2014,
12, 9797
Z. Amara,a G. Bernadat,b P.-E. Venot,a P. Retailleau,c C. Troufflard,d E. Drège,a
F. Le Bideau*a and D. Joseph*a
The step-economical synthesis of lobelanine involving a ring closing double aza-Michael (RCDAM)
reaction is revisited and successfully extended to the synthesis of various configurationally more stable
analogues. Owing to the presence of a configurationally labile β-aminoketone subunit, lobelanine is
prone to self-catalyze mutarotation in solution. Through the synthesis of original lobelanine analogues,
we studied the influence of (i) the size of the central heterocycle, (ii) the bulkiness of the nitrogen protect-
ing group, and (iii) the phenacyl arm substituent on the thermodynamic equilibrium and its displacement
by crystallisation-induced dynamic resolution (CIDR). We demonstrated that fine structural tuning com-
bined with optimized CIDR conditions favours the first efficient diastereoselective synthesis of lobelanine’s
analogues.
Received 21st August 2014,
Accepted 23rd September 2014
DOI: 10.1039/c4ob01787k
www.rsc.org/obc
Introduction
(−)-Lobeline (Fig. 1),1 the most abundant alkaloid found in
Lobelia inflata, was first characterised2 and synthesized3 in
1929. Since then, this natural product has been associated
with a wide range of biological activities.4 Despite this long
and rich history of therapeutic uses and pharmacological pro-
perties, only a few analogues of (−)-lobeline, poorly functiona-
lized, have been hemi-synthesized to date.5
Until now, the most convergent total syntheses of (−)-lobe-
line involved enantioselective desymmetrization of the meso-
congeners lobelanidine6 or lobelanine.7 In both cases, the
natural product, lobelanine, plays a pivotal role. Surprisingly,
this key intermediate has never been fully characterised, and
Fig. 1 Examples of epimerisable Lobelia and Sedum alkaloids.
none of these convergent syntheses have been exploited to
prepare Lobelia alkaloid analogues. However, one might be dis-
couraged by the configurational instability exhibited by the
β-aminoketone pattern borne by, among others, Lobelia or
Sedum alkaloids (Fig. 1).8
During the development of the total synthesis of (−)-lobe-
line, today considered as the first biomimetic one, the pioneer-
ing chemists Schöpf and Lehmann demonstrated that the
lobelanine stability was strikingly dependent on weak acidic
conditions.9 Later, in 1958, Ebnöther reported that lobeline
congener free bases slowly epimerised in solution, but without
providing any pertinent spectroscopic information except
optical rotation.10 More recently, the mutarotation phenom-
enon of (−)-lobeline-free base in solution was clearly estab-
lished by Marazano,11 and the mechanism of self-catalyzed
retro-Michael addition was confirmed by Crooks (Scheme 1).12
Interestingly, Marazano also reported that a cis/trans-lobeline
mixture could be converted to the sole thermodynamically
stable cis epimer by treating the mixture with hydrochloric
acid.11 Based on this evidence, Stoltz and co-workers13 recently
developed an efficient crystallisation-induced dynamic resolu-
aUniversité Paris-Sud, UMR CNRS 8076 BioCIS, LabEx Lermit, Equipe de Chimie des
Substances Naturelles, 5, rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry,
France. E-mail: delphine.joseph@u-psud.fr
bUniversité Paris-Sud, UMR CNRS 8076 BioCIS, LabEx Lermit, Molécules Fluorées et
Chimie Médicinale, 5, rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry,
France
cInstitut de Chimie des Substances Naturelles, UPR CNRS 2301, Bât. 27, 1 avenue de
la Terrasse, F-91198 Gif-sur-Yvette, France
dUniversité Paris-Sud, UMR CNRS 8076 BioCIS, Service commun d’analyses, 5, rue
Jean-Baptiste Clément, F-92296 Châtenay-Malabry, France
†Electronic supplementary information (ESI) available: 1H and 13C NMR data for
all new compounds, 2D NMR experiments for cis-2a, cis-4a/cis-4b and cis-2d;
X-ray structural data and crystallographic information files (CIF) for compounds
cis-2a, cis-2d and cis-3d; calculation details for theoretical models. CCDC
964826, 964827 and 964828. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4ob01787k
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 9797–9810 | 9797

View Article Online
Paper
Organic & Biomolecular Chemistry
“economical” asymmetric syntheses focuses our attention on
the preparation of a series of ligands through stereoselective
desymmetrizing reactions of meso-compounds such as lobela-
nine or related analogues. We recently reported17 a solvent-free
diastereoselective synthesis of pyrrolidine analogues of lobela-
nine via a ring-closing double aza-Michael reaction (RCDAM).
RCDAM under more conventional conditions was first applied
by W. Parker and coworkers to the synthesis of lobelanine.18
Even though this RCDAM pathway could allow a direct and
straightforward introduction of oriented molecular diversity to
the lobelanine framework, its scope has never been studied
and broadened until now.
Scheme 1 Self-catalyzed epimerisation of lobelanine via
Michael process.
a retro-
In this particular context, we disclose herein a concise
study as well as new aspects of this reversible RCDAM reaction
to the preparation of diverse and original piperidine or pyrrol-
idine lobelanine analogues. Molecular determinants control-
ling the diastereomeric enrichment and inducing selective
crystallisation have been highlighted permitting the first
stereoselective access of lobelanine derivatives through a CIDR
process.
tion (CIDR) process14,15 allowing the selective precipitation of
the isomerically pure (−)-lobeline from the corresponding cis/
trans mixture.
Even if the lobeline mutarotation seems to be deciphered, a
big gap still remains in the understanding of lobelanine epi-
merisation and of its dynamic diastereomeric enrichment by
CIDR (Scheme 1). Moreover, consequences of the lobelanine
mutarotation on the stereochemical outcome of a desymme-
trizing process have not been studied so far. Surprisingly, the
existence of a cis/trans diastereomeric mixture of the lobela-
nine hydrochloride salts was only once mentioned by Birman
and co-workers.6b
As part of a fundamental research program aiming at study-
ing nAChR allosteric rearrangements,16 we pay particular atten-
tion to the development of a flexible series of structural
lobeline analogues. In nAChRs, the stereochemistry and ligand
shape can affect the binding properties as well as the agonist
versus antagonist activity. In this context, one of the key issues
in designing new ligands relies on control of their three-
dimensional geometry. Our continuing interest in developing
Results and discussion
The nonadienedione 1a was synthesized in a 9 : 1 diastereo-
meric ratio of, respectively, separable E,E19 and E,Z20 isomers.
The lower homologue, octadienedione 1b,21 was obtained in
its unique E,E configuration as previously described.17 Table 1
summarizes the results of RCDAM reactions between both bis-
(enones) and diverse primary amines of increasing steric hin-
drance. In both series, tritylamine was too bulky to react with
dienediones 1a or 1b even at elevated temperatures (Table 1,
entry 5). Piperidines 2a–d and pyrrolidines 3a–d were isolated,
after thermodynamic equilibrium had been reached. The cis/
Table 1 RCDAM addition of primary amines to bis(enones) 1a and 1b
Piperidine
Pyrrolidine
Entry
R
Conditions
Compd (yield)
cis : trans ratioa (%)
Compd (yield)
cis : trans ratioa (%)
1
2
3
4
5
H
MeOH–DCM 12 h, rt
THF, 15 min, rt
THF, 3 h, rt
2a (96%)b
2b (92%)
2c (96%)
2d (68%)b
—
93 : 7
45 : 55
23 : 67
100 : 0
—
3a (92%)b
3b (98%)b
3c (94%)
3d (97%)b
—
70 : 30
95 : 5
85 : 15
100 : 0
—
Me
Bn
Dpm
Tr
THF, 72 h, rt
THF, 3 h, refluxc
a Ratio was determined after equilibration of the crude reaction mixture in the solution in deuterated solvent (benzene, acetone, chloroform or
THF) by the 1H NMR experiment at room temperature. b Yield of the isolated sole cis-diastereomer after crystallisation-induced dynamic
resolution. c No reaction were observed at room temperature and reflux.
9798 | Org. Biomol. Chem., 2014, 12, 9797–9810
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
trans ratio was measured by 1H NMR experiments thanks to
the shielding of the 2,5- or 2,6-proton signals of the cis com-
pounds in the pyrrolidine or piperidine series, respectively.22,23
Epimeric equilibrium was shown to be influenced by both the
nature of nitrogen substituent and the ring size. However, we
observed that the course of a reaction, which is under thermo-
dynamic control, is independent of the dienedione configur-
ation. Therefore, Michael acceptors can be used as a single
isomer or diastereomeric mixture.24
A. Lobelanine epimeric equilibrium study
We first turned our attention towards the piperidine series and
access to lobelanine cis-2b and its epimer trans-2b. A commer-
cial solution of methylamine in THF was added to the nona-
dienedione 1a. Total conversion of the starting material was
obtained in only 15 minutes at room temperature. In good
agreement with results described earlier in pyrrolidine
series,17 the double aza-Michael adduct 2b was isolated in an
excellent yield using aprotic conditions, improving radically
the pioneering work of Parker et al. in protic solvents.18
1H NMR analysis of the crude reaction mixture showed two
sets of signals, reflecting the presence of two inseparable
diastereomers cis-2b and trans-2b, in a nearly equimolar ratio
(45 : 55) (Table 1, entry 2). This thermodynamic ratio proved to
be identical whatever aprotic deuterated solvent was used
(benzene, THF or chloroform). Moreover, the lobelanine cis :
trans ratio was comparable to those measured by Crooks12 for
the pseudo-meso lobeline, showing the similar behaviour of
these two congeners. Unpredictably, very slow crystallisation25
of the neat diastereomeric mixture of 2b occurred at room
temperature. 1H NMR determination of the diastereomeric
ratio revealed a noticeable enrichment (90 : 10) in favour of the
natural cis epimer. Thanks to this unexpected spontaneous
dynamic resolution, we anticipated that lobelanine might
be produced in diastereomerically pure form through a
selective crystallisation-induced disequilibration of the retro-
aza-Michael/aza-Michael cascade. As the solvent plays a crucial
role in the success or failure of such a CIDR process, the
RCDAM reaction was attempted in cyclohexane, ether, toluene,
or dichloromethane and under solvent-free conditions
in order to favour selective crystallisation of the cis-epimer.
Unfortunately, we did not find any suitable conditions under
which the solubility of the resulting lobelanine base permitted
its dynamic resolution by crystallisation, either in the course
of the reaction or after complete evaporation to dryness.
Scheme 2 Synthesis of the lobelanine hydrochloride isomeric salts
cis-4b, cis-4b’ and trans-4b and characteristic nOesy correlations.
trans-2b, only two enantiomeric hydrochloride salts are pro-
duced (Scheme 2).
By selective crystallisation from iPrOH, an inseparable
mixture of cis-4b(Meeq)–cis-4b′(Meax) (in a 3 : 1 ratio) was iso-
lated from the compound trans-4b that remained in solution.
All isomers cis-4b, cis-4b′ and trans-4b were fully characterised
by NMR spectroscopy and nOesy experiments (Scheme 2 and
ESI†). The general trend towards the preferential crystallisation
of the cis over the trans lobelanine diastereomers, both under
neutral and acidic forms, is in agreement with its behaviour
reported by Ebnöther10 and Birman.6b This observation might
be explained by the ability of symmetrical cis epimers to
crystallise as higher ordered structures than trans ones.
Subsequently, a solution of the 3 : 1 mixture of cis-4b–cis-4b′
in dichloromethane was washed with aqueous sodium bicar-
bonate. The released lobelanine base cis-2b was obtained with
a small amount of the epimer trans-2b (8%). Respectively,
basic treatment of trans-4b produced a 4 : 1 mixture of trans-2b
and cis-2b. For the first time, the structures of lobelanine and
epi-lobelanine were fully characterised by NMR. As expected,
both basic solutions slowly equilibrated towards the
starting thermodynamic 45 : 55 proportions of cis–trans
isomers (Scheme 2 and ESI†). As the stereoisomer trans-2b
seems to interconvert faster than cis-2b, the equilibration
process was monitored by 1H NMR at various temperatures
and concentrations using different solvents (Table 2 and ESI†).
As expected for a base self-catalyzed reaction involving an aza-
Michael step, the interconversion rate was shown to be concen-
tration-dependent (Table 2, entries 1 and 5). Similarly, an
increase of the reaction temperature provoked the acceleration
of the epimerisation process without modifying diastereomeric
proportions (Table 2, entries 2 and 3). Eventually, more polar
solvents also sped up the lobelanine epimerisation, similarly
to those earlier observed for lobeline:12 acetone-d6 allowed a
total return at thermodynamic equilibrium three times faster
than for the same reaction performed in CDCl3 (Table 2,
Inspired by the efficient late-stage CIDR of lobeline hydro-
chloride salts developed by Stoltz and co-workers,13 we pre-
pared the hydrochloride salt of lobelanine, anticipating that it
might precipitate more easily from the reaction mixture due to
its ionic character (Scheme 2). Washing a chloroform solution
of cis-2b and trans-2b (45 : 55) with aqueous HCl gave a crude
mixture of piperidinium salts 4b whose 1H NMR spectrum
revealed three separate signals in accordance with symmetry
considerations. From the diastereomer cis-2b, nitrogen quater-
nization generates two distinct N-invertomers with equatorial
or axial orientation of the N-methyl group (Scheme 2). From
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 9797–9810 | 9799

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 2 1H NMR monitoring of equilibration of lobelanine cis-2b
Entry
Concentration (M)
Solvent
Timea (h)
Temperature (°C)
cis : trans ratio
1
2
3
4
5
0.085
0.085
0.085
0.085
1
CDCl3
C6D6
C6D6
(CD3)2CO
CDCl3
15
10.5
3.5
7
27
27
40
27
27
47 : 53
46 : 54
45 : 55
46 : 54
45 : 55
2
a Reaction time required to reach thermodynamic equilibrium.
entries 1 and 4). Once more, these results highlighted the merisation of the norlobelanine cis-2a. Indeed, mutarotation
similarity of lobelanine behaviour towards lobeline.
was only complete after 12 hours of warming at 70 °C in C6D6
giving a stable 93 : 7 cis–trans ratio (Table 1, entry 1).
B. Effect of nitrogen substituents
We pursued our study by reacting successively the nonadie-
In order to seek out the limitations of our methodology coup- nedione 1a with benzylamine and diphenylmethylamine
ling RCDAM to CIDR, we studied the impact of the nitrogen (benzhydrylamine) as N-nucleophiles having increasing steric
substitution on both the thermodynamic RCDAM diastereo- hindrance. Moreover, these N-substituents could be easily
meric equilibration in solution and the dynamic resolution cleaved, offering other possibilities for molecular modulation.
efficiency (Table 1). Our attention had been first focused on With benzylamine, total disappearance of the starting material
the reversible conjugate addition of ammonia as an unsubsti- was observed after three hours at room temperature in THF
tuted source of nitrogen. RCDAM addition of aqueous (Table 1, entry 3). The cis/trans diastereomers 2c were obtained
ammonia to E,E- or E,Z-nonadienediones 1a at room tempera- in an unexpected reversed 23 : 67 cis–trans ratio. Despite many
ture gave the natural alkaloid norlobelanine 2a, in excellent attempts, it was impossible either to separate both diastereo-
yield and a 4 : 1 cis–trans ratio. The RCDAM addition was also mers by chromatographic techniques or to find optimal crys-
performed at −78 °C using liquid ammonia as the solvent. tallisation solvent conditions. Nevertheless, the epimer
After removal of ammonia by overnight return to room temp- characterisation was accomplished through 1H NMR experi-
erature, the diastereomers 2a were quantitatively obtained with ments conducted on the crude reaction mixture (see ESI†).27,28
similar thermodynamic proportions (77 : 23 cis–trans ratio).
By contrast, the conjugate addition of the more hindered
Selective crystallisation from diethylether led exclusively to the benzhydrylamine (Dpm-NH2) gave the piperidine 2d as the
isomerically pure natural norlobelanine, whose full character- single cis diastereomer (Table 1, entry 4). Cis-2d was fully
isation had never been reported to date (Table 1, entry 1). We characterised and its stereochemistry confirmed by single
fully characterised cis-2a by NMR spectroscopy, and its relative crystal X-ray analysis (Fig. 2B). In the crystal, the usual chair
configuration was confirmed by single crystal X-ray analysis conformation of the piperidine ring is maintained with the
(Fig. 2A). In its crystal structure, norlobelanine adopts a classi- bulky benzhydryl group in the equatorial position. The two
cal chair conformation in which the proton of the central phenacyl groups are placed in unfavorable axial orientations,
nitrogen forces both oxygen atoms of the phenacyl arms to leading to a strong 1,3-diaxial steric interaction (dC2⋯C6
=
face each other by the creation of stabilizing intramolecular 2.52 Å and dC7⋯C15 = 3.36 Å). Obviously, the conformation of
hydrogen bonds (dO⋯H = 2.53 and 2.35 Å, Fig. 2A). The driving 2d is stabilized by two symmetrical perpendicular edge-to-face
force implied by this stabilized H-bonded conformation could (T-shaped) π-stacking interactions,29 favoured by a matched
explain the success of the dynamic resolution and the slow epi- contribution of the aryl substituents. While the carbonyl elec-
tron-withdrawing group increases the para-hydrogen partial-
positive charge, the π-donating aminophenylmethyl substitu-
ent increases the negative π-electron cloud density of the
benzene ring below it.30 Similarly to norlobelanine, diastereo-
selectivity of the RCDAM addition of benzhydrylamine could
be justified by the formation of these stabilizing intramole-
cular noncovalent aryl–aryl interactions between phenacyl and
benzhydryl groups.
1H NMR monitoring of the benzhydrylamine reaction
allowed us to visualize the transient retroconjugate addition.
In the case of benzhydrylamine, we observed the transient for-
mation of diastereomeric double-adducts 6d,d′, which evolved
slowly towards the piperidine cis-2d through a tandem retro-
Michael/ring-closing aza-Michael process (Scheme 3). To
Fig. 2 Thermal ellipsoid plots of the molecular structure of (A) norlobe-
lanine cis-2a and (B) cis-2d (35% probability thermal ellipsoids). H atoms
have been omitted for clarity except the NH atom of cis-2a.26
9800 | Org. Biomol. Chem., 2014, 12, 9797–9810
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
towards the diminution of both amine and dienedione 1a,
until the total disappearance of the free amine with concomi-
tant production of cis-2d (Fig. 3D). These experiments proved
the existence of the retro-aza-Michael/ring closing aza-Michael
cascade through the sequential formation and consumption of
both RCDAM reactants.
C. Effect of ring contraction
With the aim of developing more configurationally stable
Lobelia alkaloid analogues,17 we proceeded to synthesize pyrro-
lidine analogues. The latter were prepared under the same
conditions mentioned above for the piperidine series (Table 1,
compounds 3a–d).
Scheme 3 Plausible equilibria leading to cis-2d.
First, the pyrrolidine norlobelanine analogue 3a was quanti-
tatively obtained as a mixture of cis/trans diastereomers by
RCDAM addition of ammonia. Selective crystallisation pro-
ceeds at low temperature in iPrOH, permitting the isolation of
the single diastereomer cis-3a in more than 90% yield (Table 1,
entry 1). cis-3a was fully characterised and its cis-configuration
confirmed by its X-ray analysis (Fig. 4A). Similarly to norlobel-
anine 2a, the X-ray structure shows that the configuration is
maintained through stabilizing intramolecular hydrogen
bonds between the nitrogen proton in a pseudo-equatorial
position and both carbonyl oxygen atoms facing it (dO⋯H
=
2.47 Å and 2.48 Å respectively).
The pyrrolidine lobelanine 3b was prepared in a quantitat-
ive yield and excellent 95 : 5 cis–trans ratio, confirming the
better configurational stability of pyrrolidine derivatives com-
pared to piperidines (Table 1, entry 2). RCDAM addition of
benzylamine to the bis(enone) 1b gave the pyrrolidine 3c in a
94% yield (Table 1, entry 3). Contrary to results observed for
the piperidine homologue 2c, the 85 : 15 cis–trans ratio of 3c
followed the general trend obtained for all 2,5-disubstituted
pyrrolidines, in favour of the thermodynamic epimer cis-3c.
Similarly to piperidine 2c, no optimal conditions were found
to induce crystallisation and thus to diastereomerically enrich
the mixture by dynamic resolution.
Fig. 3 1H NMR spectra (C6D6; 300 MHz) of (A) cis-2d. (B) cis-2d after
heating at 70 °C for 12 hours. (C) cis-2d after one week at room temp-
erature. (D) Crude reaction mixture after slow evaporation of the solvent
over an additional week.
confirm the formation of the double-adducts, we effected the
conjugate addition in the presence of two equivalents of benz-
hydrylamine. The double-adduct 6 was obtained as a major
product, but its separation from the cyclized compound cis-2d
and the starting primary amine proved impossible.31 Spon-
taneously, the double-adducts 6d,d′ evolved towards the
heterocycle cis-2d. The bulkiness of the benzhydryl group
seems responsible for the decrease in the cyclization rate to
benefit the double aza-conjugate addition. Its presence also
favored the evolution of double-adducts 6d,d′ towards the
cyclized species cis-2d, promoting the retro-Michael reaction in
the tandem process.
Finally, the conjugate addition of benzhydrylamine to 1b
followed by recrystallisation in cyclohexane afforded the pyrro-
lidine cis-3d as the sole isomer in 97% yield (Table 1, entry 4).
We demonstrated that cis-3d was much more stable than its
Interestingly, the retro-Michael reaction has also been
1
observed by H NMR experiments when the piperidine cis-2d
was heated at 70 °C in deuterated benzene (Fig. 3). After
12 hours (Fig. 3B), the 1H NMR spectrum revealed the pres-
ence of a large amount of dienedione 1a (1.18 and 1.82 ppm)
and benzhydrylamine (4.87 ppm) accompanying the starting
piperidine cis-2d (3.02, 3.38, 3.90 and 4.94 ppm). After one
week at room temperature, this solution (Fig. 3C) evolved
Fig. 4 Thermal ellipsoid plots of the molecular structure of (A) cis-3a
and (B) cis-3d17,32 (35% probability thermal ellipsoids). H atoms have
been omitted for clarity except for the NH atom.26
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 9797–9810 | 9801

View Article Online
Paper
Organic & Biomolecular Chemistry
higher homologue cis-2d in deuterated benzene solution even were obtained in excellent yields and a high diastereomeric
after one week at room temperature or 16 hours at 70 °C. The ratio. Application of optimal solvent conditions for the CIDR
pronounced stability of the cis-3d symmetrical configur- allowed the isolation of the unique configurationally stable cis-
ation17,32 is also insured by the presence of two stabilizing epimer except for compounds 9c (Table 3, entry 4) and 10d
perpendicular edge-to-face (T-shaped) π-stacking interactions (Table 3, entry 5), for which no suitable solvent or mixture of
(Fig. 4B).
solvents has been found.
These results indicated that the electronic nature of the
phenyl substituents did not dramatically influence the prefer-
ential crystallisation of cis-diastereomer.
D. Effect of phenyl substituents
Since even a slight modification in the structures of the
products might cause the target not to crystallise, we studied
the robustness of our synthetic sequence through the synthesis
of lobelanine analogues differing by the substitution of their
phenacyl arms. In order to evaluate the contribution of phenyl
substituents, we decided to prepare phenyl-substituted deriva-
tives of norlobelanine 2a and pyrrolidine lobelanine analogue
3b, both identified as configurationally stable in the solution.
The results are summarized in Table 3.
First, the required dienediones 7a–d and 8a–d were syn-
thesized as reported in the literature, respectively, starting
directly with a commercially available aqueous solution of glu-
taraldehyde33,34 or starting with 1,5-cyclooctadiene according
to our two-step procedure.24 Nonadienediones 7a–d were
reacted with ammonia and octadienediones 8b–d with methyl-
amine under conditions previously optimized for norlobel-
anine and lobelanine, respectively. The general trend observed
in the case of the phenyl compounds 2a and 3b (Table 1) was
verified for the synthesis of the diversely substituted phenyl
analogues 9a–d and 10a–d (Table 3, entries 2–5). The latter
E. Computational studies
With the aim of understanding the origin of the thermo-
dynamic equilibration and the observed stereoselectivity of the
CIDR process, DFT calculations at the B3LYP/6-31G* level35–39
were conducted (Table 4 and ESI†). For isolated structures, we
have experimentally demonstrated that the sterically hindered
environment of the nitrogen atom is necessary but not
sufficient to induce stereo-discrimination in the RCDAM reac-
tion. In contrast, the ability of the thermodynamic adduct to
precipitate was shown to be highly dependent on structural
modifications. Steric interactions in RCDAM adducts seem to
thermodynamically govern the conformational and configura-
tional swap-over that predisposes the equilibrium shift
towards the diastereomer presenting the more favourable
shape to crystallise.
First, DFT calculations broadly corroborate the experi-
mental findings, showing unambiguously that RCDAM trans-
adducts are kinetically produced and the more stable cis-
adducts are thermodynamically favoured in both pyrrolidine
and piperidine series (Table 4 and ESI†).40 They also suggest
that the epimeric barrier increases on passing from the piper-
idine to the pyrrolidine series, confirming that pyrrolidine
analogues are configurationally more stable than related
piperidines.
Table 3 Influence of phenyl substituents on configuration stability of
norlobelanine and pyrrolidine lobelanine derivatives
In the piperidine series, calculated global thermodynamic
trends were correctly predicted. The clear energetic drop in the
Table 4 Difference of DFT calculated energies between cis and trans
diastereomers and superimposition of calculated more stable cis-
structures
1H-piperidine
N-methylpyrrolidine
Compda
(Yield)
cis : trans
Compdb
cis : trans
ratioc (%)
Entry Ar
ratioc (%) (Yield)
1
2
3
4
5
Ph–H
p-Ph–F
2a (96%)d 93 : 7
9a (92%)d 89 : 11
9b (95%)d 91 : 9
3b (98%)d 95 : 5
10a (98%)d 93 : 7
10b (88%)d 93 : 7
10c (97%)d 90 : 10
p-Ph–Br
p-Ph–Me
9c (83%)
90 : 10
p-Ph–OMe 9d (85%)d 92 : 8
10d (99%)
93 : 7
ΔΔG0rel = ΔG0trans
−
)
ΔΔG0rel = ΔG0trans
Entry ΔG0cis (kcal mol−1
)
−
The reaction was performed until completion at room temperature:
a In MeOH–CH2Cl2 using a 28% ammonia solution (7 eq.). b In CH2Cl2
using methylamine (2 M in THF, 2 eq.). c Ratio were determined on the
crude reaction mixture by 1H NMR experiment in C6D6 at room
temperature. d Yield of isolated cis-diastereomer after dynamic
resolution by crystallisation.
Entry
R
ΔG0cis (kcal mol−1
1
2
3
H
Me
2.96
0.64
Dpm 0.99
4
5
6
2.58
2.19
2.54
9802 | Org. Biomol. Chem., 2014, 12, 9797–9810
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
calculated cis form predominance between norlobelanine 2a
(NH) and both lobelanine 2b (NMe) and benzhydrylpiperidine
2d (NDpm) is consistent with experimental findings, highlight-
ing the crucial role played by the stabilizing intramolecular
hydrogen bonds in the epimerisation process (Table 4, entries
1 and 2). Concerning benzhydrylpiperidine 2d (NDpm), the
difference between calculated relative enthalpies of cis and
trans diastereomers is not sufficient to satisfactorily explain
the experimentally observed diastereoselectivity (Table 4, entry
3). This could find an explanation in the particular mechanism
followed in the course of RCDAM addition of benzhydryl-
amine, which was proved to proceed according to a double
intermolecular aza-Michael/retro-Michael/intramolecular aza-
Michael cascade. This complex mechanism could directly
favour the cis diastereomer because of steric hindrance and
stabilizing π-stacking interactions avoiding the equilibration
step.
Fig. 5 Relative distances measured on theoretical models or on X-ray
structures between substituents in 1,2- or 1,3-interaction in both piper-
idine and pyrrolidine families.
By comparison, the calculated energetic profile for the pyr-
rolidine series is more satisfactory (Table 4, entries 4–6). As
the pyrrolidine system is less floppy than the corresponding
six-membered ring, steric interactions in the pyrrolidine
system can be strong enough to be considered as a crucial
factor in the dynamic thermodynamic resolution (Table 4,
pyrrolidines superimposition). Diastereomeric species possess
significantly different thermodynamic stabilities to provide
highly diastereoenriched products under convenient CIDR
conditions.
The results obtained by calculation also suggest that the
difference in intrinsic geometries for five and six-membered
rings gives rise to distinct, well-characterised and substituent-
controllable conformation families, which are of great
importance in the application of CIDR (Table 4, super-
impositions). In addition, conformations highly similar to
the X-ray crystallographic structures were produced by DFT
calculations: details of these comparisons are given in the
ESI.† In order to rationalize the molecular factors stabilizing
preferred shapes and influencing the epimeric equilibrium
shift, distances between the α-carbons of the phenacyl
arm and the nitrogen substituent (R) were measured on our
theoretical models or on X-ray structures when available
(Fig. 5). Calculations show that major conformational effects
are involved mainly through steric effects of the nitrogen
substituent.
In the piperidine series, the 1,2-diequatorial distance
(Fig. 5, A6) is shorter than the 1,2-axial-equatorial one (Fig. 5,
B6). Consistently, the more the R substituent bulkiness
increases (R = H→Bn), the more the proportion of trans dia-
stereomer in conformation B6 is preferentially formed in the
course of the RCDAM reaction. In the case of cis norlobelanine
(R = H), the classical conformation A6 with both phenacyl
arms in equatorial positions is preferred. This cis-configur-
ation is accentuated by the existence of two strong intramole-
cular hydrogen bonds, which favour the epimeric equilibrium
towards this double highly stabilized cis-diastereomer. For the
hindered benzhydryl substituent, 1,2-diequatorial interactions
become so important that phenacyl arms are shifted from
their ideal equatorial positions to the pseudo-axial ones,
showing the loss of the expected equatorial chair shape (Fig. 5,
C6). Moreover, this repulsion of the 1,3-diaxial substituents
is accompanied by flattening of the nitrogen pyramidal
arrangement.
In the pyrrolidine series, the ring strain shortens the 1,2-
interaction distances between the phenacyl arm in pseudo-axial
orientation and the N-substituent (Fig. 5, B5). In contrast, the
1,3-interaction distance between both phenacyl arms in the
pseudo-axial position is enhanced (Fig. 5, C5). Thus, for methyl
and benzyl groups, the conformations A5 for cis diastereomers
are favoured. In the case of hydrogen-substituted nitrogen,
diminished steric hindrance allows the formation of a signifi-
cant amount (30%) of trans diastereomers in conformation B5.
For the bulky benzhydryl group, detrimental 1,2-interactions
induce the anti-relative configuration between N-substituent
and phenacyl arms, the pseudo-axial orientation of phenacyl
arms and the flattening of the five-membered azacycle
(Fig. 5, C5).
In summary, calculations undoubtedly confirm that in both
analogous series, the cis diastereomers are thermodynamically
the most stable epimers. cis Diastereomers were produced
with enhanced diastereoselectivity by increasing the con-
tribution of steric interactions of the N-substituents and
by associating stabilizing intramolecular bonds or stackings.
Furthermore, calculations revealed some structural features:
minimizing steric effects enforces N-substituents to adopt
a restricted orientation (equatorial in piperidines and axial
in pyrrolidines) for which the distance between the α-carbons
of the N-substituents and phenacyl arms is maximal.
For similar reasons, the piperidine ring prefers a classical
chair conformation while pyrrolidine chooses
a planar
conformation. If the 1,2-anti/1,5-anti configuration is highly
conserved in the smaller azacycle pyrrolidine, it is not the
case for piperidine derivatives. Indeed, floppy six-membered
azacycles are able to counterbalance N-substituent steric
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 9797–9810 | 9803

View Article Online
Paper
Organic & Biomolecular Chemistry
1
hindrance by inversion of the chair conformation or the pyra- uated by H NMR spectroscopy of the crude reaction mixtures.
midal nitrogen.
The electrospray ionisation (ESI) and the atmospheric pressure
chemical ionisation (APCI) mass spectra were performed on an
Esquire-LC Brucker spectrometer. The X-ray crystallographic
data were measured at ambient temperature (293 K) on an
Enraf-Nonius Kappa-CCD diffractometer with graphite-mono-
Conclusions
This work confirms the efficiency of the RCDAM reaction in chromated Mo Kα radiation (λ = 0.71069 Å) or on a Rigaku
synthesizing α,α′-disubstituted piperidines and pyrrolidines MM007 HF copper (λ = 1.54187 Å) rotating-anode generator
under mild conditions. We highlight its high flexibility in equipped with Osmic confocal optics and a rapid II Curved
introducing molecular diversity. RCDAM addition was success- Image Plate at 200 K. Elemental analyses were performed with
fully applied to the straightforward preparation of a series of a Perkin-Elmer 2400 analyser. IR spectra were recorded as neat
structural analogues of lobelanine, differing by the size of the films on a Bruker Vector22 spectrophotometer. HRMS spectra
heterocycle core and the nature of substituents borne by the were obtained by the FAB method. Analytical thin layer
central nitrogen atom or the phenacyl arms. With respect to chromatography was performed on a Merck 60F-254 precoated
our interest in the synthesis of Lobelia alkaloid analogues tar- silica (0.2 mm) on glass and was revealed by UV light or
geting nAChRs, this easy-to-handle method of pharmaco- Kägi-Misher or Dragendorf reagent. Flash chromatography
modulation could offer new avenues in terms of structure– separations were performed on Merck Kieselgel (40–63 µm).
activity relationship studies and of pharmacokinetic,
pharmacodynamic, and safety properties optimization of lead according to the procedures reported in the literature and
Dienediones 1a,19,20 1b,21 and 7a–d19,20 were synthesized
compounds.
physical data were in accordance with the literature.
Arguably, our study demonstrates, through the synthesis of
these novel lobelanine analogues, that the mutarotation in
solution of the β-aminoketone motif can be thermodynami-
General procedures for the synthesis of norlobelanine 2a and
its analogues 3a and 9a–d
cally controlled. CIDR conditions in conjunction with the for- The appropriate dienedione (1a, 1b, 7a–d) was dissolved in a
mation of privileged constrained symmetric conformations DCM–MeOH mixture. An ammonia solution (28% in H2O) was
through intramolecular H-bonds, intramolecular π-stacking added at room temperature and the reaction mixture was
interactions, and/or heterocycle contractions allow the selec- allowed to stir for 12 hours. The crude reaction mixture
tive crystallisation of the thermodynamic cis-lobelanine ana- was dissolved in CH2Cl2 and washed with brine. The organic
logues in high diastereomeric excess and excellent yield. The layer was separated, dried over MgSO4 and evaporated under
noticeable advantages of this synthetic approach are that no vacuum.
external chiral agents are required and that it can be scaled-up
and experimentally set up easily.
Norlobelanine or 2,2′-(piperidine-2,6-cis-diyl)bis(1-phenyl-
ethanone) cis-2a. The reaction was carried out starting with 1a
These compounds constitute good candidates for the (1.04 g, 3.4 mmol) and an ammonia solution (3.4 mL,
stereoselective synthesis of pharmacologically relevant lobeline 24.5 mmol) in CH2Cl2–MeOH (3 mL/3 mL). Crystallisation of
analogues and open new opportunities for the development of the crude reaction mixture in diethylether allowed the iso-
stereocontrolled desymmetrizing process through crystallisa- lation of cis-2a (1.05 g, 96%). Orange solid. mp 119 °C (from
tion-induced asymmetric transformation (CIAT).
Et2O) (Lit.: 115–121 °C);21 1H NMR (CDCl3, 400 MHz): δ 7.93
(d, J = 7.7 Hz, 4H); 7.52 (t, J = 7.3 Hz, 2H), 7.42 (t, J = 7.8 Hz,
4H), 3.27 (m, 2H), 3.06 (dd, J = 16.7, 5.1 Hz, 2H), 3.03 (dd, J =
16.8, 7.3 Hz, 2H), 1.82 (dtt, J = 13.1, 6.0, 3.1 Hz, 1H), 1.71 (dtd,
J = 12.2, 6.0, 2.3 Hz, 2H), 1.49 (dtt, J = 13.1, 13.1, 3.7 Hz, 1H),
1.24 (ddd, J = 12.5, 12.5, 3.8 Hz, 2H); 13C NMR (CDCl3,
Experimental section
General experimental procedures
Commercial reagents were used without purification. Prior to 100 MHz): δ 199.0, 137.5, 132.9, 128.5, 128.1, 53.1, 45.8, 32.3,
use, THF, toluene and CH2Cl2 were purified by passage 24.5; Elemental anal. Found: C 77.87, H 7.10, N 4.2. Calcd for
through a drying column. Melting points were recorded on an C21H23NO2·1/5H2O: C 77.60, H 7.26, N 4.31%; IR (neat) νmax
/
electrothermal digital apparatus and were uncorrected. 1H cm−1 1689, 1677, 1285, 1223, 1001, 803, 758, 750, 689; HRMS
(respectively 13C) NMR spectra were recorded at 300 or (ESI): m/z: [M + H]+ calcd for C21H24NO2 322.1807, found
400 MHz (respectively 75 or 100 MHz). The chemical shifts for 322.1810.
1H NMR were recorded in ppm downfield from tetramethyl-
NMR spectra of the minor diastereomer trans-2a are par-
silane (TMS) with the solvent resonance as the internal stan- tially described, some of the signals being hidden by the
1
dard. The chemical shifts for 13C NMR were recorded in ppm major product cis-2a. H NMR (C6D6, 300 MHz): δ 7.95 (d, J =
downfield using the central peak of deuterated solvent as the 8.1, 1.2 Hz, 4H); 3.71 (m, 2H), 3.08 (dd, J = 16.8, 7.5 Hz, 2H);
internal standard. Coupling constants (J) are reported in Hz 13C NMR (CDCl3, 100 MHz): δ 199.4, 129.5, 128.5, 47.8, 43.0,
and refer to apparent peak multiplicities. NMR peak assign- 31.0, 19.9.
ments have been made on the basis of HMBC, HMQC, nOesy,
2,2′-(Piperidine-2,6-cis-diyl)bis(1-(4-fluoro-phenyl)-ethanone)
1
and H–1H COSY spectra. Diastereomeric ratios (dr) were eval- cis-9a. The reaction was carried out starting with 7a (154 mg,
9804 | Org. Biomol. Chem., 2014, 12, 9797–9810
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
0.45 mmol) and an ammonia solution (0.4 mL, 2.9 mmol) in
The minor diastereomer trans-9c was detected by the pres-
CH2Cl2–MeOH (0.4 mL/0.4 mL). Compound cis-9a was ence of two characteristic signals (1H NMR (CDCl3, 300 MHz):
obtained by crystallisation of the crude reaction mixture in δ 3.60 (m, 2H), 3.20 (dd, J = 14.3, 5.8 Hz, 2H)).
ethylacetate (148 mg, 92%) as a white solid. mp 131.3 °C (from
2,2′-(Piperidine-2,6-cis-diyl)bis(1-(4-methoxyphenyl)-ethanone)
1
AcOEt); H NMR (C6D6, 300 MHz): δ 7.57 (dd, J = 8.7, 5.4 Hz, cis-9d. The reaction was carried out starting with 7d (729 mg,
4H); 6.63 (t, J = 8.7 Hz, 4H), 3.25 (m, 2H), 2.66 (dd, J = 17.1, 2.0 mmol) and ammonia (2 mL, 14.4 mmol) in CH2Cl2–MeOH
7.5 Hz, 2H), 2.55 (dd, J = 17.1, 4.8 Hz, 2H), 1.70 (dt, J = 12.6, (2 mL/2 mL). Compound cis-9d was obtained by evaporation of
3.3 Hz, 1H), 1.54 (dd, J = 12.3, 2.7 Hz, 2H), 1.36 (qt, J = 12.9, the crude reaction mixture (648 mg, 85%) as a yellow solid. mp
3.6 Hz, 1H), 1.17 (qd, J = 12.0, 3.6 Hz, 2H); 13C NMR (CDCl3, 93.5 °C; H NMR (CDCl3, 300 MHz): δ 7.93 (d, J = 9.0 Hz, 4H);
1
100 MHz): δ 197.4, 165.7 (d, J = 1014 Hz), 133.48 (d, J = 9 Hz), 6.91 (d, J = 9.0 Hz, 4H), 3.86 (s, 3H), 3.26 (m, 2H), 3.05 (dd, J =
130.6 (d, J = 36 Hz), 115.6 (d, J = 87 Hz), 52.5, 45.5, 32.1, 24.3; 16.8, 5.1 Hz, 2H), 2.98 (dd, J = 16.8, 8.4 Hz, 2H), 1.82 (dt, J =
IR (neat) νmax/cm−1 2926, 2910, 2890, 2805, 1689, 1683, 1677, 12.9, 3.0, Hz, 1H), 1.69 (dd, J = 11.7, 2.1 Hz, 2H), 1.47 (qt, J =
1594, 1505, 1226, 1204, 1194, 1164, 1156, 848, 841, 828; MS 12.9, 3.6 Hz, 1H), 1.27 (bq, J = 9.6 Hz, 2H); 13C NMR (CDCl3,
(ESI): m/z: 358 [M + H]+; Elemental anal. Found: C 70.10, H 100 MHz): δ 197.6, 163.5, 130.4, 130.2, 113.7, 55.4, 53.0, 45.1,
5.94, N 3.85. Calcd for C21H21F2NO2·1/8H2O: C 70.13, H 5.96, 32.0, 24.4; IR (neat) νmax/cm−1 2944 (broad), 2839 (broad),
N 3.89%. HRMS (ESI): m/z: [M + H]+ calcd for C21H22F2NO2 1673, 1666, 1597, 1260, 1228, 1166, 830, 810, 733; GC-MS (ESI):
358.1619, found 358.1620.
m/z: 404 [M + Na]+; Elemental anal. Found: C 71.32, H 7.45,
The diastereomer trans-9a was detected by the presence of N 3.31. Calcd for C23H27NO4·1/3H2O: C 71.29, H 7.20, N
two characteristic signals (3.60 (m, 2H, CHN) and 2.68 (dd, J = 3.61%.
17.1, 8.1 Hz, 2H, CHHCO)).
The minor diastereomer trans-9d was detected by the pres-
2,2′-(Piperidine-2,6-cis-diyl)bis(1-(4-bromophenyl)-ethanone) ence of three characteristic signals (1H NMR (C6D6, 300 MHz):
cis-9b. The reaction was carried out starting with 7b (46 mg, δ 3.69 (m, 2H), 3.19 (s, 3H), 3.00 (dd, J = 16.2, 7.2 Hz, 2H)).
0.1 mmol) and an ammonia solution (0.1 mL, 0.72 mmol) in
2,2′-(Pyrrolidine-2,5-cis-diyl)bis(1-phenylethanone)
cis-3a.
CH2Cl2–MeOH (0.4 mL/0.4 mL). Compound cis-9b was The reaction was carried out starting with 1b (870 mg,
obtained by precipitation of the crude reaction mixture in 3.0 mmol) and an ammonia solution (3.0 mL, 21.6 mmol) in
AcOEt (45 mg, 95%) as a white solid. mp 226 °C (from AcOEt); CH2Cl2–MeOH (10 mL/3 mL). Crystallisation of the crude reac-
1H NMR (CDCl3, 300 MHz): δ 7.81 (d, J = 8.5 Hz, 4H); 7.59 (d, tion mixture in iso-propanol (−30 °C) allowed the isolation of
J = 8.5 Hz, 4H), 3.27 (m, 2H), 3.05 (dd, J = 17.4, 4.8 Hz, 2H), cis-3a (848 mg, 92%). Red brick solid. mp 103 °C (from
1
2.98 (dd, J = 17.4, 7.5 Hz, 2H), 1.83 (dt, J = 12.9, 3.0 Hz, 1H), iPrOH); H NMR (CDCl3, 300 MHz): δ 7.95 (d, J = 8.0 Hz, 4H),
1.69 (dd, J = 12.3, 2.4 Hz, 2H), 1.48 (qt, J = 12.9, 3.6 Hz, 1H), 7.56 (td, J = 7.6, 2.5 Hz, 2H), 7.44 (td, J = 6.9, 1.7 Hz, 4H), 3.71
1.25 (qd, J = 11.7, 3.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ (Q, J = 6 Hz, 2H), 3.21 (d, J = 6 Hz, 4H), 2.42 (bs, 1H), 2.05 (m,
198.0, 135.7, 131.8, 129.5, 128.3, 52.5, 45.4, 32.0, 24.3; IR 2H), 1.54 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 199.3, 136.9,
(neat) νmax/cm−1 2903 (broad), 1682, 1678, 1584, 1399, 1074, 132.9, 128.4, 127.9, 53.9, 45.7, 30.1; IR (neat) νmax/cm−1 2941,
1066, 985, 806, 798, 788; MS (ESI): m/z: 480 [M + H]+; Elemen- 1682–1678 (large), 1449, 1211, 1002, 753, 690; MS (ESI): m/z:
tal anal. Found:
C21H21Br2NO2: C 52.63, H 4.42, N 2.92%.
The minor diastereomer trans-9b was detected by the pres-
C
52.64,
H
4.39,
N
2.89. Calcd for 308 [M + H]+; HRMS (ESI): m/z: [M + H]+ calcd for C20H22NO2
308.1651, found 308.1649.
NMR spectra of the minor diastereomer trans-3a are par-
ence of two characteristic signals (1H NMR (C6D6, 300 MHz): δ tially described, most of the signals being hidden by the major
3.51 (m, 2H), 2.85 (dd, J = 14.1, 5.7 Hz, 2H)).
product cis-3a. 1H NMR (CDCl3, 300 MHz): δ 3.86 (q, J = 6.3 Hz,
2,2′-(Piperidine-2,6-cis-diyl)bis(1-(p-tolyl)ethanone)
cis-9c. 2H), 13C NMR (CDCl3, 100 MHz): δ 199.2, 133.0, 128.4, 127.9,
The reaction was carried out starting with 7c (202 mg, 53.4, 45.2, 31.5.
0.6 mmol) and ammonia (1 mL, 7.2 mmol) in CH2Cl2–MeOH
General procedure for the synthesis of lobelanine 2b and its
analogues 2c–d, 3b–d and 10a–d
(1 mL/3 mL). A 90/10 mixture of cis-9c–trans-9c was obtained
by evaporation of the crude reaction mixture (171 mg, 83%).
1
mp 103.5 °C; H NMR (CDCl3, 300 MHz): δ 7.84 (d, J = 8.2 Hz, Primary amine was added to a solution of the appropriate die-
4H); 7.23 (d, J = 8.2 Hz, 4H), 3.27 (m, 2H), 3.07 (dd, J = 17.4, nedione (1a, 1b or 8a–b) dissolved in a round bottom flask
4.8 Hz, 2H), 3.02 (dd, J = 17.4, 7.5 Hz, 2H), 2.40 (s, 3H), 1.80 capped with a rubber septum. The mixture was stirred at room
(dt, J = 12.9, 3.0, Hz, 1H), 1.68 (dd, J = 12.6, 2.4 Hz, 2H), 1.48 temperature to afford the corresponding diastereomeric
(qt, J = 12.9, 3.6 Hz, 1H), 1.27 (qd, J = 11.7, 3.6 Hz, 2H); 13C mixture of nitrogen-containing heterocycles after removal of
NMR (CDCl3, 100 MHz): δ 198.7, 143.9, 134.6, 129.2, 128.2, the volatiles under reduced pressure. For lobelanine, this
52.8, 45.3, 31.9, 24.3, 21.6; IR (neat) νmax/cm−1 2930 (broad), mixture was acidified (HCl) in order to isolate the corres-
1684, 1673, 1607, 1292, 1284, 1228, 1196, 1177, 821, 811; MS ponding hydrochloride salts.
(ESI): m/z: 350 [M + H]+; Elemental anal. Found: C 77.17, H
Compounds cis-2b, trans-2b and their hydrochloride salts
7.54, N 3.99. Calcd for C23H27NO2·1/2H2O: C 77.06, H 7.87, N cis-4b, cis-4b′ and trans-4b. The reaction was carried out in
3.91%. HRMS (ESI): m/z: [M + H]+ calcd for C23H28NO2 15 minutes at room temperature starting with 1a (1.7 g,
350.2120, found 350.2123.
5.6 mmol) and methylamine (2 M in THF, 4 mL, 8 mmol) in
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 9797–9810 | 9805

View Article Online
Paper
Organic & Biomolecular Chemistry
THF (11 mL). The ratio cis-2b : trans-2b (45/55) was measured 7.20–7.00 (m, 6H), 3.60–3.50 (m, 2H), 3.04 (dd, J = 15.9, 4.8 Hz,
by integration of the methyl signals of the brick red syrup 2H), 2.73 (dd, J = 15.9, 7.8 Hz, 2H), 2.15 (s, 3H), 1.70–1.25 (m,
obtained after evaporation of the crude reaction mixture. This 6H); 13C NMR (CDCl3, 75 MHz): δ 199.3, 137.0, 133.1, 128.5,
mixture was dissolved in CHCl3 (200 mL) and washed with 1 M 128.0, 54.8, 44.3, 38.8, 29.3, 19.4.
HCl (100 mL). The aqueous layer was extracted with CHCl3 (3 ×
50 mL) and the organic layers were dried with MgSO4 and νmax/cm−1 2929, 1680, 1448, 1208, 7538, 690.
cis-2b and trans-2b. MS (CI): m/z: 336 [M + H]+; IR (neat)
evaporated under reduced pressure. The residue was dissolved
2,2′-(1-Methylpyrrolidine-2,5-cis-diyl)bis(1-phenylethanone)
in iso-propanol and cooled at −30 °C. After two weeks at that cis-3b. The reaction was carried out starting with 1b (875 mg,
temperature, a solid 3 : 1 mixture of the inseparable lobelanine 3.0 mmol) and a 2 M solution of methylamine in THF (2 mL,
salts cis-4b and cis-4b′ (1.078 g, 52%) was filtered off and 4 mmol). Evaporation of the crude reaction mixture after
removal of solvent affords exclusively the salt trans-4b (0.920 g, 15 min gave an orange oil which was precipitated in Et2O–
44%). A 0.03 M solution of 3 : 1 cis-4b–cis-4b′ (respectively pentane to afford a creamy solid (951 mg, 98%) cis-3b contain-
trans-4b) in CH2Cl2 was washed with saturated NaHCO3, dried ing 5% of the corresponding racemic compound trans-3b.
with MgSO4 and concentrated under reduced pressure to Proton and carbon NMR spectra are in accordance with those
afford lobelanine cis-2b (containing 8% of trans-2b) (respecti- previously reported using another method.17a NMR spectra of
vely trans-2b containing 20% of cis-2b). These mixtures both the minor diastereomer trans-3b are partially described, most
equilibrate at room temperature to afford the initial ratio cis- of the signals being hidden by the major product cis-3b.
2b : trans-2b (45/55).
2,2′-(1-Methylpiperidine-2,6-cis-diyl)bis(1-phenylethanone) 8.7 Hz, 2H), 2.16 (s, 3H), 1.25–1.05 (m, 2H).
1H NMR (C6D6, 300 MHz): δ 3.61 (m, 2H), 2.57 (dd, J = 15.9,
hydrochloride cis-4b and cis-4b′. White solid. mp 189 °C
2,2′-(1-Methylpyrrolidine-2,5-cis-diyl)bis(1-(4-fluorophenyl)-
(from iPrOH) (Lit.: 193–196 °C).10 1H NMR (C6D6, 400 MHz): δ ethanone) cis-10a. The reaction was carried out starting with
12.88 (cis-4b′, bs, 1H), 12.35 (cis-4b, bs, 1H), 8.02 (cis-4b + cis- 8a (147 mg, 0.45 mmol) and a 2 M solution of methylamine in
4b′, d, J = 7.2 Hz, 4H), 7.65–7.55 (cis-4b + cis-4b′, m, 2H), 7.49 THF (0.5 mL, 1 mmol,) in CH2Cl2 (2 mL). Evaporation of the
(cis-4b + cis-4b′, t, J = 7.5 Hz, 4H), 4.23 (cis-4b′, bd, J = 16.1 Hz, crude reaction mixture after 15 min gave a creamy solid
2H), 4.13–4.10 (cis-4b′, m, 2H), 4.06 (cis-4b, dd, J = 18.9, 5.4 Hz, (157 mg, 98%) cis-10a containing 7% of the corresponding dia-
2H), 3.91 (cis-4b, m, 2H), 3.36 (cis-4b, dd, J = 18.9, 4.5 Hz, 2H), stereomer trans-10a. Crystallisation in AcOEt gave cis-10a as a
3.03 (cis-4b′, dd, J = 16.3, 11.4 Hz, 2H), 2.80 (cis-4b′, d, J = 4.9 creamy solid. mp 85.5 °C; 1H NMR (300 MHz, C6D6): δ 7.65
Hz, 3H), 2.57 (cis-4b, d, J = 4.8 Hz, 3H), 2.27 (cis-4b, qd, J = (dd, J = 9.0, 5.7 Hz, 4H), 6.66 (dd, J = 9.0, 8.7 Hz, 4H),
14.5, 3.0 Hz, 2H), 2.10 (cis-4b′, bd, J = 15.0 Hz, 2H), 2.00–1.50 3.00–2.80 (m, 4H), 2.61 (dd, J = 17.4, 9.0 Hz, 2H), 2.12 (s, 3H),
(cis-4b + cis-4b′, m, 4H); 13C NMR (C6D6, 100 MHz): δ major 2.01–1.95 (m, 2H), 1.38–1.28 (m, 2H); 13C NMR (75 MHz,
compound cis-4b 196.0, 135.4, 134.3, 129.0, 128.4, 61.8, 41.6, CDCl3): δ 197.4, 167.5, 133.6, 130.8 (d, J = 30 Hz), 115.7 (d, J =
38.4, 31.1, 22.9 minor compound cis-4b′, 194.9, 135.8, 133.9, 90 Hz), 63.1, 43.9, 39.3, 29.9; IR (neat) νmax/cm−1 1686, 1592,
128.9, 128.4, 61.0, 40.2, 27.9, 23.7, 22.4; IR (neat) νmax/cm−1 1502, 1410, 1365, 1341, 1296, 1209, 1195, 1159, 990, 837, 822,
2279, 1679, 1293, 1220, 758, 689; Elemental anal. Found: C 802; MS (ESI): m/z: 358 [M + H]+, Elemental anal. Found:
70.10, H 7.00, N 3.61. Calcd for C22H26ClNO2·1/3H2O: C 69.92, C 70.21, H 5.71, N 3.72. Calcd for C21H21F2NO2: C 70.57,
H 7.11, N 3.71%.
H 5.92, N 3.92%.
2,2′-((2R*,6R*)-1-Methylpiperidine-2,6-diyl)bis(1-phenylethan-
NMR spectra of the minor diastereomer trans-10a are par-
one) hydrochloride trans-4b. mp 177.9 (Litt = 175–178 °C).10 tially described, most of the signals being hidden by the major
1H NMR (C6D6, 300 MHz): δ 12.64 (bs, 1H), 8.10–7.95 (m, 4H), product cis-10a. 1H NMR (C6D6, 300 MHz): δ 3.58 (m, 2H), 2.48
7.65–7.50 (m, 2H), 7.52–7.40 (m, 4H), 4.33–4.20 (m, 1H), 4.21 (dd, J = 16.2, 8.7 Hz, 2H), 2.16 (s, 3H).
(dd, J = 18.0, 6.0 Hz, 1H), 4.05–3.95 (m, 1H), 3.81 (dd, J = 17.1,
2,2′-(1-Methylpyrrolidine-2,5-cis-diyl)bis(1-(4-bromo-phenyl)-
2.4 Hz, 1H), 3.46 (dd, J = 17.9, 7.8 Hz, 1H), 3.27 (dd, J = 17.3, ethanone) cis-10b. The reaction was carried out starting with
9.5 Hz, 1H), 2.78 (d, J = 5.0 Hz, 3H), 2.40–2.25 (m, 1H), 8b (218 mg, 0.5 mmol) and a 2 M solution of methylamine in
2.15–1.55 (m, 5H); 13C NMR (C6D6, 75 MHz): δ 195.8, 194.7, THF (0.5 mL, 1 mmol) in CH2Cl2 (2 mL). Crystallisation in
135.8, 135.6, 134.0, 128.8, 128.3, 128.1, 57.5, 55.9, 38.6, 37.0, CH2Cl2–cyclohexane gave cis-10b as a creamy solid (210 mg,
36.9, 25.5, 25.2, 17.6; Elemental anal. Found: C 67.65, H 6.98, 88%). mp 125.7 °C; 1H NMR (300 MHz, C6D6): δ 7.46 (d, J =
N 3.57. Calcd for C22H26ClNO2·H2O: C 67.77, H 7.24, N 3.59%.
10.8 Hz, 4H), 6.90 (d, J = 9.0 Hz, 4H), 3.09 (dd, J = 15.7, 4.2 Hz,
Lobelanine or 2,2′-(1-methylpiperidine-2,6-cis-diyl)bis(1-phenyl- 2H), 3.05–2.90 (m, 2H), 2.76 (dd, J = 15.7, 8.4 Hz, 2H), 2.16
ethanone) cis-2b. 1H NMR (C6D6, 400 MHz): δ 8.00–7.90 (m, (s, 3H), 2.02 (s, 3H), 2.05–1.96 (m, 2H), 1.45–1.30 (m, 2H);
4H), 7.60–7.50 (m, 2H), 7.50–7.35 (m, 4H), 3.35 (dd, J = 16.0, 13C NMR (75 MHz, CDCl3): δ 197.3, 136.5, 131.9, 129.9, 127.2,
4.4 Hz, 2H), 3.10–3.00 (m, 2H), 2.92 (dd, J = 16.0, 7.6 Hz, 2H), 63.3, 44.3, 39.5, 30.2; IR (neat) νmax/cm−1 1686, 1583, 1395,
2.24 (s, 3H), 1.75–1.55 (m, 4H), 1.55–1.25 (m, 2H); 13C NMR 1365, 1340, 1174, 1067, 1010, 988, 814, 804; MS (ESI): m/z: 480
(C6D6, 100 MHz): δ 198.9, 137.1, 133.1, 128.6, 128.1, 59.8, 44.6, [M + H]+, Elemental anal. Found: C 52.42, H 4.41, N 2.89.
36.6, 30.3, 24.0.
Calcd for C21H21Br2NO2: C 52.63, H 4.42, N 2.92%.
2,2′-((2R*,6R*)-1-Methylpiperidine-2,6-diyl)bis(1-phenylethanone)
The minor diastereomer trans-10b can be detected by
trans-2b. 1H NMR (C6D6, 300 MHz): δ 7.90–7.70 (m, 4H), the presence of three characteristic signals: 1H NMR (C6D6,
9806 | Org. Biomol. Chem., 2014, 12, 9797–9810
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
300 MHz): δ 3.54 (m, 2H), 2.42 (dd, J = 15.0, 7.5 Hz, 2H), 2.12
(s, 3H).
2,2′-(1-Methylpyrrolidine-2,5-cis-diyl)bis(1-(p-tolyl)-ethanone)
N
3.48. Calcd for C28H29NO2·1/3H2O:
N 3.35%.
2,2′-(1-Benzylpyrrolidine-2,5-cis-diyl)bis(1-phenyl-ethanone)
C 80.54, H 7.16,
cis-10c. The reaction was carried out starting with 8c (160 mg, cis-3c. The reaction was carried out starting with 1b (164 mg,
0.5 mmol) and a 2 M solution of methylamine in THF (0.5 mL, 0.56 mmol) and benzylamine (0.06 mL, 0.55 mmol) in THF
1 mmol) in CH2Cl2 (2 mL). Evaporation of the crude reaction (1 mL). Evaporation of the crude reaction mixture after 3 hours
mixture gave a 90/10 mixture of cis-10c and trans-10c. Crystalli- gave a yellow oil (206 mg, 94%) as a mixture of cis-3c (85%)
sation in AcOEt gave cis-10c as a creamy solid (170 mg, 97%). and the epimer trans-3c (15%).
1
mp 66.7 °C; H NMR (300 MHz, C6D6): δ 7.86 (d, J = 9.0 Hz,
1H NMR (CDCl3, 300 MHz): δ 7.71 (d, J = 7.4 Hz, 4H), 7.42
4H), 7.19 (d, J = 10.8 Hz, 4H), 2.9–2.8 (m, 4H), 2.57 (dd, J = (t, J = 7.2 Hz, 2H), 7.4–7.0 (m, 9H), 3.75 (s, 2H), 3.29 (m, 2H),
18.9, 9.0 Hz, 2H), 2.08 (s, 3H), 2.05–1.80 (m, 2H), 1.40–1.20 (m, 3.04 (dd, J = 15.9, 3.0 Hz, 2H), 2.80 (dd, J = 15.9, 10.2 Hz, 2H),
2H); 13C NMR (75 MHz, CDCl3): δ 198.1, 143.3, 135.8, 129.4, 2.00 (m, 2H), 1.53 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 199.5,
128.6, 63.5, 44.5, 39.5, 30.4, 21.4; IR (neat) νmax/cm−1 1675, 137.1, 132.9, 129.1, 128.5, 128.3, 128.2, 127.9, 127.1, 61.9, 58.6,
1604, 1408, 1364, 1339, 1297, 1183, 1115, 1041, 971, 803, 773; 45.6, 30.2; IR (neat) νmax/cm−1 3100–2750, 1682, 1597, 1579,
m/z: 350 [M + H]+; Elemental anal. Found: C 78.98, H 7.73, 1494, 1448, 1275, 771, 688; HRMS (ESI): m/z: [M + H]+ calcd for
N 3.93. Calcd for C23H27NO2: C 79.05, H 7.79, N 4.01%.
C27H27NO2 398.2120, found 398.2118.
NMR spectra of the minor diastereomer trans-10c are par-
NMR spectra of the minor diastereomer trans-3c are par-
tially described, most of the signals being hidden by the major tially described, most of the signals being hidden by the major
product cis-10c. 1H NMR (C6D6, 300 MHz): δ 3.67 (m, 2H), 2.62 product cis-3c. 1H NMR (C6D6, 300 MHz): δ 3.94 (d, J = 14.7 Hz,
(dd, J = 15.9, 8.7 Hz, 2H), 2.06 (s, 3H).
1H), 3.69 (d, J = 14.7 Hz, 1H), 3.53 (m, 2H), 3.20 (dd, J = 15.6,
2,2′-(1-Methylpyrrolidine-2,5-cis-diyl)bis(1-(4-methoxyphenyl)- 4.2 Hz, 2H); 13C NMR (CDCl3, 75 MHz): δ 200.0, 139.6, 128.1,
ethanone) cis-10d. The reaction was carried out starting with 57.6, 40.8, 28.7.
8d (100 mg, 0.28 mmol) and a 2 M solution of methylamine in
2,2′-(1-Benzhydrylpiperidine-2,6-cis-diyl)bis(1-phenylethan-
THF (0.25 mL, 0.5 mmol) in CH2Cl2 (1 mL). The evaporation one) cis-2d. Benzhydrylamine (200 μL, 1.2 mmol) was added
of the crude reaction mixture gave an oil (105 mg, 99%) con- in one portion into dienedione 1a (360 mg, 1.2 mmol) dis-
taining a 93/7 proportion of compounds cis-10d and trans-10d. solved in THF. The mixture was magnetically stirred at room
1H NMR (300 MHz, C6D6): δ 7.92 (d, J = 7.1 Hz, 4H), 6.65 (d, J = temperature for 72 h. Compound cis-2d (392 mg, 68%) was
7.1 Hz, 4H), 3.19 (s, 3H), 3.12 (dd, J = 15.3, 4.5 Hz, 2H), 3.1–2.9 obtained as white crystals by slow evaporation of the solvent.
(m, 2H), 2.80 (dd, J = 15.3, 8.1 Hz, 2H), 2.20 (s, 3H), 2.19 (m, mp 146 °C; 1H NMR (C6D6, 300 MHz): δ 7.74 (d, J = 7.2 Hz,
2H), 1.45 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 197.4, 163.5, 4H), 7.34 (d, J = 7.2 Hz, 4H), 7.2 (m, 12H), 5.04 (s, 1H), 3.89 (m,
130.4, 130.1, 113.7, 63.3, 55.4, 43.2, 39.1, 29.7; IR (neat) νmax
/
2H), 3.38 (dd, J = 14.7, 3.6 Hz, 2H), 3.02 (dd, J = 14.7, 10.5 Hz,
cm−1 1673, 1597, 1575, 1509, 1258, 1166, 1030, 827; MS (ESI) 2H), 1.80–1.25 (m, 6H); 13C NMR (CDCl3, 75 MHz): δ 199.8,
382 [M + H]+; HRMS (ESI): m/z: [M + H]+ calcd for C23H28NO4 142.7, 136.8, 132.8, 128.7, 128.6, 128.1, 128.0, 127.1, 71.1, 50.1,
382.2028; found, 382.2021.
40.2, 28.0, 14.3; IR (neat) νmax/cm−1 1669, 1596, 1579, 1456,
The minor diastereomer trans-10d was detected by the pres- 1446, 1281, 1269, 1080, 762, 748, 688; GC-MS (ESI): m/z: 488
ence of four characteristic signals (1H NMR (C6D6, 300 MHz): δ [M + H]+; Elemental anal. Found: C 83.61, H 6.64, N 2.84.
3.71 (m, 2H), 3.21 (s, 3H), 2.64 (dd, J = 15.6, 8.7 Hz, 2H), 2.45 Calcd for C34H33NO2: C 83.74, H 6.82, N 2.87%.
(s, 3H)).
2,2′-(1-Benzylpiperidine-2,6-cis-diyl)bis(1-phenyl-ethanone) Benzhydrylamine (200 μL, 1.2 mmol) was added in one
cis-2c and 2,2′-((2R*,6R*)-1-benzylpiperidine-2,6-diyl)bis- portion into dienedione 1a (180 mg, 0.6 mmol) dissolved in
3,7-Bis(benzhydrylamino)-1,9-diphenylnonane-1,9-dione 6d,d′.
(1-phenylethanone) trans-2c. The reaction was carried out C6D6. The mixture was magnetically stirred at room tempera-
starting with dienedione 1a (152 mg, 0.5 mmol) and benzyl- ture for 2 h and analyzed without further purification. The
amine (0.06 mL, 0.55 mmol) in THF (1 mL). After 5 hours at 1H NMR spectra showed the presence of unreacted benzhydryl-
room temperature, an inseparable mixture of cis-2c and trans- amine, small amounts of cis-2d and one major mixture of dia-
1
2c (23/67) (198 mg, 96%) was obtained. 1H NMR ((CD3)2CO, stereomers 6d,d′: amber oil; H NMR (300 MHz, C6D6): δ 7.82
300 MHz): δ 8.10–7.90 (cis-2c + trans-2c, m, 8H), 7.70–7.00 (cis- (m, 4H), 7.44 (m, 8H), 7.16–7.11 (m, 8H), 7.10–7.00 (m, 10H),
2c + trans-2c, m, 22H), 3.94 (cis-2c, s, 2H), 3.87 (trans-2c, d, J = 4.99 (s, 2H), 3.22 (m, 2H), 2.92 (dd, J = 5.3, 4.6, Hz, 1H), 2.87
14.3 Hz, 1H), 3.80 (trans-2c, d, J = 14.3 Hz, 1H), 3.61–3.50 (cis- (dd, J = 5.3, 4.6, Hz, 1H), 2.71 (dd, J = 6.0, 4.5, Hz, 1H), 2.67
2c + trans-2c, m, 4H), 3.31 (cis-2c, dd, J = 16.0, 3.6 Hz, 2H), (dd, J = 6.0, 4.5, Hz, 2H), 1.42–1.34 (m, 6H); 13C NMR (75 MHz,
3.10–3.05 (trans-2c, m, 4H), 3.10 (cis-2c, dd, J = 16.0, 9.3 Hz, C6D6): δ 199.0, 144.8, 137.8, 132.6, 126.9–128.8, 64.6, 52.4,
2H), 1.75–1.30 (cis-2c + trans-2c, m, 12H); 13C NMR (75 MHz, 52.3, 43.2, 43.1, 35.0, 34.9, 22.2, 21.96; IR (neat) νmax/cm−1
CDCl3): δ 199.3, 199.1, 142.0, 140.5, 137.0, 132.9, 128.5, 1683, 1447, 744, 704; GC-MS (CI): m/z: 671 [M + H]+.
128.3, 128.2, 128.1, 127;4, 126.9, 126.7, 126.5, 58.3, 53.1,
2,2′-(1-Benzhydrylpyrrolidine-2,5-cis-diyl)bis(1-phen-ylethan-
52.7, 43.8, 41.2, 40.9, 28.2, 26.6, 21.8, 19.8; IR (neat) νmax/cm−1 one) cis-3d. Benzhydrylamine (110 μL, 0.6 mmol) was added
2962, 2852, 1673, 1528, 1012, 798, 790, 687; GC-MS (ESI): in one portion into dienedione 1b (190 mg, 0.6 mmol) dis-
m/z: 434 [M + Na]+; Elemental anal. Found: C 80.56, H 7.47, solved in THF (0.6 mL). The mixture was magnetically stirred
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 9797–9810 | 9807

View Article Online
Paper
Organic & Biomolecular Chemistry
at room temperature for 72 h. Compound cis-3d (290 mg, 97%) a yellow solid (250 mg, 31%). mp 151.5 °C. 1H NMR (CDCl3,
was obtained as white crystals by slow evaporation of the 300 MHz): δ 7.93 (d, J = 9.0 Hz, 4H), 7.01–6.93 (m, 4H), 6.93 (d,
solvent. The 1H NMR spectrum was in accordance with the J = 8.4 Hz, 4H), 3.86 (s, 6H), 2.56 (m, 4H); 13C NMR (75 MHz,
previously published description of this compound.17a
CDCl3): δ 188.8, 163.4, 145.4, 130.8, 130.6, 126.5, 113.8, 55.5,
31.3; IR (neat) νmax/cm−1 1650, 1614, 1593, 1509, 1342, 1308,
1262, 1246, 1170, 1008, 998, 632; MS (ESI) 373 [M + Na]+;
General procedure for the synthesis of dienediones 8a–d
These compounds were synthesized according to a slightly Elemental anal. Found:
C
71.56,
H
6.26. Calcd for
modified procedure of a reported synthesis of ester ana- C22H22O4·H2O: C 71.72, H 6.57%.
logues.17 A solution of the appropriate phosphorous ylide in
Computational methods
dichloromethane was added to freshly distilled succinic
aldehyde obtained by ozonolysis of 1,5-cyclooctadiene. The
reaction mixture was stirred at room temperature for 4 days,
evaporated and the crude residue was purified by flash
chromatography using a mixture of cyclohexane–AcOEt varying
from 90/10 to 80/20.
Conformations of reactants and products were fully optimized
without constraint using the DFT35,36 method with the
hybrid Becke3LYP functional37,38 and the 6-31G* base39 as
implemented in the Gaussian 09 software package.41
Vibrational analysis within the harmonic approximation
was performed at the same level of theory upon geometrical
optimization convergence, and local minima were character-
ised by the absence of imaginary frequency. Thermodynamic
quantities at 298.15 K were calculated using the zero-point
and thermal energy corrections derived from unscaled
frequencies.
(2E,6E)-1,8-Bis(4-fluorophenyl)octa-2,6-diene-1,8-dione 8a.33
The reaction was carried out starting with the phosphorous
ylide (5.4 g, 13.5 mmol) and succinaldehyde (0.5 g, 5.8 mmol)
in CH2Cl2 (30 mL). Compound 8a was obtained as a yellow
1
solid (1.28 g, 67%). mp 139.1 °C. H NMR (CDCl3, 300 MHz):
δ 7.95 (dd, J = 8.1, 5.4 Hz, 4H), 7.12 (t, J = 8.4 Hz, 4H), 7.05 (dt,
J = 15.7, 5.7 Hz, 2H), 6.90 (d, J = 15.7 Hz, 2H), 2.57 (m, 4H); 13
C
NMR (75 MHz, CDCl3): δ 188.7, 165.6 (d, J = 1020 Hz), 147.4,
134.0 (d, J = 10 Hz), 131.1 (d, J = 40 Hz), 126.4, 115.7 (d, J =
87 Hz), 31.2; IR (neat) νmax/cm−1 1670, 1619, 1596, 1506, 1225,
984, 838, 819; MS (ESI): m/z: 349 [M + Na]+; Elemental anal.
Found: C 73.18, H 4.96. Calcd for C20H16F2O2·1/6H2O: C 72.94,
H 5.00%.
Acknowledgements
The authors are grateful to K. Leblanc and C. Troufflard for
performing microanalyses and mass measurements. The
authors thank the French Ministry of Superior Education and
Research for the grants of Z.A. and P.-E.V. The LabEx Lermit,
the Université Paris-Sud, the French Ministry of Superior Edu-
cation and Research and the CNRS are gratefully acknowledged
for financial support. The IT department of the Université
Paris-Sud is acknowledged for providing computing resources.
(2E,6E)-1,8-Bis(4-bromophenyl)octa-2,6-diene-1,8-dione 8b.34
The reaction was carried out starting with the phosphorous
ylide (4.9 g, 10.6 mmol) and succinaldehyde (0.398 g,
4.6 mmol) in CH2Cl2 (15 mL). Compound 8b was obtained as
a yellow solid (893 mg, 43%). mp 179.2 °C. 1H NMR (CDCl3,
300 MHz): δ 7.78 (d, J = 8.4 Hz, 4H), 7.59 (d, J = 8.4 Hz, 4H),
7.04 (dt, J = 15.3, 6.3 Hz, 2H), 6.89 (d, J = 15.3 Hz, 2H), 2.57 (m,
4H); 13C NMR (75 MHz, CDCl3): δ 189.2, 147.7, 136.4, 131.9,
130.0, 128.0, 126.4, 31.2; IR (neat) νmax/cm−1 1661, 1605, 1581,
1421, 1398, 1270, 1068, 1009, 980, 824, 746; MS (ESI): m/z: 471
[M + Na]+; Elemental anal. Found: C 53.44, H 3.57. Calcd for
C20H16Br2O2: C 53.60, H 3.60%.
Notes and references
1 (a) F.-X. Felpin and J. Lebreton, Tetrahedron, 2004, 60,
10127–10153; (b) F.-X. Felpin and J. Lebreton, J. Org. Chem.,
2002, 67, 9192–9199; (c) A. Locati, M. Berthelot, M. Evain,
J. Lebreton, J.-Y. Le Questel, M. Mathé-Allainmat,
A. Planchat, E. Renault and J. Graton, J. Phys. Chem. A,
2007, 111, 6397–6405.
(2E,6E)-1,8-Di-p-tolylocta-2,6-diene-1,8-dione 8c.34 The reac-
tion was carried out starting with the phosphorous ylide
(4.63 g, 14.5 mmol) and succinaldehyde (0.500 g, 5.8 mmol) in
CH2Cl2 (30 mL). Compound 8c was obtained as a yellow solid
(810 mg, 44%). mp 116.1 °C. 1H NMR (CDCl3, 300 MHz): δ
7.84 (d, J = 8.4 Hz, 4H), 7.26 (d, J = 8.4 Hz, 4H), 7.06 (dt, J =
15.3, 6.0 Hz, 2H), 6.95 (d, J = 15.3 Hz, 2H), 2.57 (m, 4H); 13C
NMR (75 MHz, CDCl3): δ 190.0, 146.8, 143.6, 135.1, 129.2,
128.6, 126.7, 31.2, 21.6; IR (neat) νmax/cm−1 1663, 1600, 1273,
1186, 981, 819, 747, 732; MS (ESI) 341 [M + Na]+; Elemental
anal. Found: C 82.69, H 6.72. Calcd for C22H22O2: C 82.99,
H 6.96%.
2 H. Wieland and O. Dragendorff, Justus Liebigs Ann. Chem.,
1929, 473, 83–101.
3 (a) H. Wieland and I. Drishaus, Justus Liebigs Ann. Chem.,
1929, 473, 102–118; (b) H. Wieland, W. Koschara and
E. Dane, Justus Liebigs Ann. Chem., 1929, 473, 118–126;
(c) G. Scheuing and L. Winterhalder, Justus Liebigs Ann.
Chem., 1929, 473, 126–136.
4 (a) G. Zheng, L. P. Dwoskin, A. G. Deaciuc, S. D. Norrholm
and P. A. Crooks, J. Med. Chem., 2005, 48, 5551–5560;
(b) D. K. Miller, P. A. Crooks, G. Zheng, V. P. Grinevich,
S. D. Norrholm and L. P. Dwoskin, J. Pharmacol. Exp. Ther.,
2004, 310, 1035–1045; (c) D. K. Miller, P. A. Crooks and
L. P. Dwoskin, Neuropharmacology, 2000, 39, 2654–2662;
(2E,6E)-1,8-Bis(4-methoxyphenyl)octa-2,6-diene-1,8-dione 8d.34
The reaction was carried out starting with the phosphorous
ylide (2.4 g, 5.8 mmol) and succinaldehyde (0.200 g,
2.3 mmol) in CH2Cl2 (15 mL). Compound 8d was obtained as
9808 | Org. Biomol. Chem., 2014, 12, 9797–9810
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
(d) L. P. Dwoskin and P. A. Crooks, Biochem. Pharmacol., 18 W. Parker, R. A. Raphael and D. I. Wilkinson, J. Chem. Soc.,
2002, 63, 89–98; (e) M. Kaniaková, J. Lindovský, J. Krůšek,
S. Adámek and F. Vyskočil, Eur. J. Pharmacol., 2011, 658,
108–113.
1959, 2433–2437 (lobelanine is obtained in 27% yield
under ethanolic reaction conditions).
19 J. Montgomery, A. V. Savchenko and Y. Zhao, J. Org. Chem.,
1995, 60, 5699–5701.
5 (a) M. Hojahmat, D. B. Horton, S. D. Norrholm,
D. K. Miller, V. P. Grinevich, A. G. Deaciuc, L. P. Dwoskin 20 L.-C. Wang, H.-Y. Jang, Y. Roh, V. Lynch, A. J. Schultz,
and P. A. Crooks, Bioorg. Med. Chem., 2010, 18, 640–649;
(b) D. Flammia, M. Dukat, M. I. Damaj, B. Martin and
X. Wang and M. J. Krische, J. Am. Chem. Soc., 2002, 124,
9448–9453.
R. A. Glennon, J. Med. Chem., 1999, 42, 3726–3731; 21 G. P. Black, P. J. Murphy and N. D. A. Walshe, Tetrahedron,
(c) D. K. Miller, J. Pharmacol. Exp. Ther., 2004, 310, 1035–
1045.
6 (a) R. Chênevert and P. Morin, Bioorg. Med. Chem., 2009,
1998, 54, 9481–9488.
22 H. P. Hamlow, S. Okuda and N. Nakagawa, Tetrahedron
Lett., 1964, 37, 2553–2557.
17, 1837–1839; (b) V. B. Birman, H. Jiang and X. Li, Org. 23 E. Breuer and D. Melumad, Tetrahedron Lett., 1973, 38,
Lett., 2007, 9, 3237–3240. 1601–1602.
7 F. D. Klingler and R. Sobotta, US pat, 2006014791, 2006 24 L. Cabral dos Santos, Z. Bahlaouan, K. El Kassimi,
(assigned to Boehringer Ingelheim); F. D. Klingler, Acc.
Chem. Res., 2007, 40, 1367–1376.
C. Troufflard, F. Hendra, S. Delarue-Cochin, M. Zahouily,
C. Cavé and D. Joseph, Heterocycles, 2007, 73, 751–768.
8 Biomimetic Organic Synthesis, ed. E. Poupon and 25 Self-catalyzed dynamic resolution of an equimolar
B. Nay, Wiley-VCH Verlag GmbH & Co. KGaA, 1st edn,
2011, vol. 1.
diastereomeric mixture of lobelanine was observed over
two months affording the single cis-lobelanine.
9 C. Schöpf and G. Lehmann, Justus Liebigs Ann. Chem., 1935, 26 Rendering of all X-ray structures was performed with
518, 1–37.
mercury: C. F. Macrae, I. J. Bruno, J. A. Chisholm,
P. R. Edgington, P. McCabe, E. Pidcock, L. Rodriguez-
Monge, R. Taylor, J. van de Streek and P. A. Wood, J. Appl.
Crystallogr., 2008, 41, 466–470.
10 A. Ebnöther, Helv. Chim. Acta, 1958, 41, 386–396.
11 D. Compère, C. Marazano and B. C. Das, J. Org. Chem.,
1999, 64, 4528–4532.
12 G. Zheng, L. P. Dwoskin and P. A. Crooks, J. Org. Chem., 27 R. K. Hill and T. H. Chan, Tetrahedron, 1965, 21, 2015–
2004, 69, 8514–8516. 2019.
13 S. Krishnan, J. T. Bagdanoff, D. C. Ebner, Y. K. Ramtohul, 28 L.-H. Yan, F. Dagorn, E. Gravel, B. Séon-Méniel and
U. K. Tambar and B. M. Stoltz, J. Am. Chem. Soc., 2008, 130,
13745–13754.
E. Poupon, Tetrahedron, 2012, 68, 6276–6283.
29 C. D. Sherrill, Acc. Chem. Res., 2013, 46, 1020–1028.
14 For recent examples of the CIDR concept (also called asym- 30 M. O. Sinnokrot and C. D. Sherrill, J. Am. Chem. Soc., 2004,
metric transformation of second kind) see: (a) K. J. Park, 126, 7690–7697.
Y. Kim, M.-S. Lee and Y. S. Park, Eur. J. Org. Chem., 2014, 31 Diastereomers 6d,d′ were identified by NMR and mass
1645–1652; (b) H. Lubin, C. Dupuis, J. Pytkovicz and spectrometry in the crude reaction mixture.
T. Brigaud, J. Org. Chem., 2013, 78, 3487–3492; 32 CCDC number of cis-3d: 854591.
(c) P. Jakubec, P. Petrás, A. Duris and D. Berkes, Tetrahedron: 33 C. E. Aroyan, A. Dermenci and S. J. Miller, J. Org. Chem.,
Asymmetry, 2010, 21, 69–74; (d) P. Jakubec, D. Berkes,
A. Kolarovic and F. Povazanec, Synlett, 2006, 4032–4040.
15 For reviews of the CIDR concept see: (a) N. G. Anderson,
2010, 75, 5784–5796.
34 J.-J. Gong, T.-Z. Li, K. Pan and X.-Y. Wu, Chem. Commun.,
2011, 47, 1491–1493.
Org. Process Res. Dev., 2005, 9, 800–813; (b) K. M. J. Brands 35 W. Kohn and L. Sham, Phys. Rev., 1965, 140, A1133–A1138.
and A. J. Davies, Chem. Rev., 2006, 106, 2711–2733; 36 P. Hohenberg and W. Khon, Phys. Rev., 1964, 136, B864–
(c) S. Caddick and K. Jenkin, Chem. Soc. Rev., 1996, 25,
447–456.
B871.
37 A. D. Becke, J. Chem. Phys., 1993, 98, 5648–5652.
16 (a) M. S. Prevost, S. Delarue-Cochin, J. Marteaux, C. Colas, 38 C. Lee, W. Yang and R. G. Parr, Phys. Rev. B: Condens.
C. Van Renterghem, A. Blondel, T. Malliavin, P.-J. Corringer Matter, 1988, 37, 785–789.
and D. Joseph, J. Med. Chem., 2013, 56, 4619–4630; 39 W. J. Hehre, L. Radom, P. V. R. Schleyer and J. A. Pople,
(b) C. Colas, X. Brotel, N. Duclert-Savatier, M. Nilges, Ab Initio Molecular Orbital Theory, Wiley, New York, 1986.
D. Joseph and T. E. Malliavin, Lett. Drug Des. Discovery, 40 DFT calculations did not suffice to comprehensively
2012, 9, 54–62; (c) A. Taly, C. Colas, T. Malliavin,
A. Blondel, M. Nilges, P.-J. Corringer and D. Joseph, J. Mol.
Graphics Modell., 2011, 30, 100–109.
explain the reverse diastereomeric ratio measured for
benzyl piperidine 2c.
41 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,
17 (a) Z. Amara, E. Drège, C. Troufflard, P. Retailleau and
D. Joseph, Org. Biomol. Chem., 2012, 10, 7148–7157;
(b) Z. Amara, E. Drège, C. Troufflard, P. Retailleau,
M.-E. Tran Huu-Dau and D. Joseph, Chem. – Eur. J., 2014,
DOI: 10.1002/chem.201404589.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 9797–9810 | 9809

View Article Online
Paper
Organic & Biomolecular Chemistry
H. Nakai, T. Vreven, J. A. Montgomery Jr., J. E. Peralta,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas,
J. B. Foresman, J. V. Ortiz, J. Cioslowski and D. J. Fox, Gaus-
sian 09, Revision A.02, Gaussian, Inc., Wallingford CT, 2009.
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand,
K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
9810 | Org. Biomol. Chem., 2014, 12, 9797–9810
This journal is © The Royal Society of Chemistry 2014