Chirality and numbering of substituted tropane alkaloids

Article abstract of DOI:10.3390/molecules16097199

The strict application of IUPAC rules for the numbering of tropane alkaloids is not always applied by authors and there is hence a lot of confusion in the literature. In most cases, the notation of 3, 6/7-disubstituted derivatives has been chosen arbitrar

Full text of DOI:10.3390/molecules16097199

Molecules 2011, 16, 7199-7209; doi:10.3390/molecules16097199
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Chirality and Numbering of Substituted Tropane Alkaloids
Munir Humam 1, Tarik Shoul 1, Damien Jeannerat 2, Orlando Muñoz 3 and Philippe Christen 1,*
1
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne,
Quai Ernest-Ansermet 30, CH-1211 Geneva 4, Switzerland;
E-Mails: munir_humam@hotmail.com (M.H.); t.shoul@hotmail.com (T.S.)
2
Department of Organic Chemistry, University of Geneva, Quai Ernest-Ansermet 30,
CH-1211 Geneva 4, Switzerland; E-Mail: damien.jeannerat@unige.ch
3
Departamento de Química, Facultad de Ciencias, Universidad de Chile, Casilla 653, Santiago,
Chile; E-Mail: omunoz@uchile.cl
* Author to whom correspondence should be addressed; E-Mail: philippe.christen@unige.ch;
Tel.: +41-22-379-65-61; Fax: +41-22-379-33-99.
Received: 12 July 2011; in revised form: 16 August 2011 / Accepted: 17 August 2011 /
Published: 25 August 2011
__________________________________________________________________________________
Abstract: The strict application of IUPAC rules for the numbering of tropane alkaloids is
not always applied by authors and there is hence a lot of confusion in the literature. In most
cases, the notation of 3, 6/7-disubstituted derivatives has been chosen arbitrarily, based on
NMR and MS data, without taking into account the absolute configuration of these two
carbons. This paper discusses the problem and the relevance of CD and NMR to determine
1
molecular configurations. We report on the use of H-NMR anisochrony (Δδ) induced by
the Mosher’s chiral auxiliary reagents (R)-(-)- and (S)-(+)-α-methoxy-α-trifluoromethyl-
phenylacetyl chlorides (MTPA-Cl), to determine the absolute configuration of (3R,6R)-3α-
hydroxy-6β-senecioyloxytropane, a disubstituted tropane alkaloid isolated from the aerial
parts of Schizanthus grahamii (Solanaceae). These analytical tools should help future
works in correctly assigning the configuration of additional 3, 6/7 disubstituted tropane
derivatives.
Keywords: tropane alkaloids; Schizanthus; molecular configuration; Mosher’s esters;
(3R,6R)-3α-hydroxy-6β-senecioyloxytropane
__________________________________________________________________________________

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1. Introduction
Unambiguous identification and structure elucidation of bioactive natural products is of paramount
importance for understanding their physical and chemical properties. While relative configuration
of chiral centres can usually be assigned by NMR (NOESY and/or NOE) experiments [1], the
determination of the absolute configuration is much more difficult to obtain. The NMR spectra of
enantiomers being identical, one has to introduce chirality in the medium to break the symmetry.
Among the different possibilities, the use of chiral lanthanide shift reagents (LSI) [2], chiral polymers
[3] or chiral ions [4] allows, in the best case, to observe a split between the enantiomer signals. A more
reliable method consists in using chiral auxiliary reagents such as Mosher's (R)-(-)- and (S)-(+)-α-
methoxy-α-trifluoromethylphenylacetyl acetic acid (MTPA) combined with NMR measurements. It is
often employed for the characterization of various natural products bearing secondary alcohols, amines
or carboxylic functions [5–7]. Circular dichroism is another technique sensitive to the chirality of
molecules, but the correlation with the configuration is not straightforward and has to be applied with
some precautions [4]. Only X-ray crystallography [8] provides direct access to the chirality of
compounds but obviously relies on the ability to form crystals of the compounds of interest.
In many cases, the absolute configuration of isolated compounds is not mentioned in the original
articles, and often misleading information is provided either by improper structural drawings or
assuming, but not specifying, that the reported compounds have the same configuration as those
previously reported. Tropane alkaloids are a well-known and important class of natural products
because of their pharmacological activities as anticholinergic agents. They are widely distributed in the
Solanaceae, Erythroxylaceae, Convolvulaceae, Proteaceae and Rhizophoraceae plant families. These
alkaloids encompass a wide range of mono-, di- and trisubstituted derivatives, having in common the
tropane (8-azabicyclo[3.2.1]octane) nucleus as the key structural element (Figure 1a). They are often
esterified with various aliphatic and aromatic acids [9].
Figure 1. Tropane nucleus numbering, a, c and e: clockwise; b, d and f: anticlockwise.

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There is a lot of confusion in the literature about the numbering of the tropane skeleton [9]. The
IUPAC recommendations [10] stipulate that the skeleton be numbered clockwise, starting from the C-1
being at the “back” when the C-3 hydroxyl is to the right (Figure 1a). However, depending on the
substituent in position C-6/C-7, the C-1 must be at the “front” and the numbering then be
anticlockwise so that the carbon bearing the substituent has the lowest possible number (Figure 1b).
Except for 1-hydroxytropane, most of the monosubstituted alkaloids are derived from tropine
(3-hydroxytropane) esterified at the C-3 position. The latter, containing chiral centres (C-1 and C-5), is
an optically inactive symmetrical molecule and can be regarded as a meso compound. Most of tropane
alkaloids are either disubstituted in C-3, C-6 (often described in the literature as a C-3, C-7) Figure 1c
and 1d) or trisubstituted in C-3, C-6 and C-7 [9,11] (Figure 1e and 1f). In most cases, the notation of 3,
6/7-disubstituted derivatives has been chosen arbitrarily without taking into account the absolute
configuration of these two positions. Typical examples are the 3,6/7-disubstituted tropane alkaloids
identified by GC-MS only [12,13]. Most of these compounds have been identified under achiral
conditions by their retention times, Kovats or Van den Dool indices, fragmentation patterns and
sometimes by comparison with reference compounds whose structures have not themselves been
unambiguously characterized. None of these methods distinguish the enantiomers.
Within the tropane alkaloid family, many compounds are 3α,6β/7β-tropanediol derivatives that can
exist as two stereoisomeric (3R,6R) or (3S,6S) species. This stereoisomerism is not well documented
and most of these molecules do not have a defined absolute configuration. Only a few compounds have
been studied by X-ray diffraction analysis, most of the time in the form of salts [14–16]. Frequently,
the configuration has been obtained using optical methods and NMR of derivatized compounds.
In this work, we report on the use of NMR spectroscopy using Mosher’s chiral auxiliary reagent
to determine the absolute configuration of 3α-senecioyloxy-6β-hydroxytropane (Figure 1c and
1d: R= senecioyloxy; R’=hydroxyl), a typical representative disubstituted alkaloid originating from the
genus Schizanthus. The method is an alternative to circular dichroism (CD) [17–19].
2. Determination of the Configuration Using Optical Properties
Regarding stereochemistry, the specific rotation [α] of a compound is usually sufficient to
determine its absolute configuration. The sign of the angle is opposite for pairs of enantiomers and
allows one to distinguish them. However, for the tropane alkaloids, the sign of the specific rotation is
known in only a few cases. This is due, in part, to the difficulty to deduce a rule correlating signs and
configurations. Some attempts have been made, but these sometimes have led to missassignments [20],
which have been corrected later [21,22]. In principle, the hydrolysis of tropane esters, leading to
3,6/7-tropanediol should solve the problem, because R,R enantiomer is levorotatory (−24°) [18,23].
However, this method proved unreliable, probably because of the difficulty to ensure a defined
conformation of the OH groups, as the latter are very sensitive to any protonation of the amine and to
the presence of water or other hydrogen donors or acceptors in the solvent [24].
In principle the full electronic circular dichroism (eCD) [17,19] spectra of compounds should be
more informative, especially when UV-active chromophores are present. The experimental spectra can
then be compared to computer simulations based on the 3D structure of the compound. However
difficulties arise when the molecules are conformationally labile because it then requires one take into

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account the conformational space. This has been applied to esters of 3,6/7 tropanes [19] and
α,β-conjugated esters [17]. The disadvantage of this method is that it is a computationally demanding
task, especially when different conformations have to be Boltzmann weighted. Furthermore, it requires
the presence of substituents containing chromophores. Conversely, the main advantage of the method
is that it is non-destructive and it opens the possibility of working by analogy with similar compounds
as long as the structure and dynamic can be assumed to be very similar.
Vibrational circular dichroism (vCD) spectra [25] are used very similarly to eCD. They should be
easier to use because simulations are computationally less demanding than those of eCD spectra and
more general, because they do not require UV-active chromophores. Moreover, vibrational spectra
have more transitions than electronic spectra, providing more opportunities to observe optical activity.
This method has been applied in a few cases, including a disputed case where [α]D was not conclusive
[18] and it demonstrated that the methyl esters of 3,6-tropanediols could be reliably used to determine
the molecular configuration [26].
The result of this comparison between experimental and simulated CD spectra seems to indicate
that diesters are conformationally stable enough to have their relevant structures calculated and can be
used for simulation and determination of the molecular configuration. This means that in principle the
Kramers-Kronig relation could be exploited to determine the molecular configuration based on
simulated eCD and [α]D of compounds. However, only a systematic study of a reasonable number of
tropane derivatives and validation with alternative methods can assess whether this will be possible
when the computer power limitations will be circumvented.
3. Determination of the Configuration Using Mosher’s Reagent
Nuclear magnetic resonance (NMR) is intrinsically insensitive to chirality because enantiomers
have identical spectra. The derivatization with chiral auxiliaries produces however changes in the
chemical shifts of the neighbouring nuclei (anisotropy) which can be rationalized to determine the
absolute configuration. α-Methoxy-α-trifluoromethylphenylacetate (MTPA, or Mosher’s reagent)
[27–29] is very commonly used and has been applied to the determination of the absolute
stereochemistry of disubstituted tropanes [30]. We illustrate here the use of MTPA to determine the
molecular configuration of the 3,6-disubstituted tropanes.
The absolute configuration of 3α-senecioyloxy-6β-hydroxytropanes 1a or 1b (Figure 2), was
tentatively determined by circular dichroism (CD). However, because this compound had a very weak
Cotton effect, an alternative method was used. Compound 1 was converted into diastereomeric esters 2
and 3 (Figure 2) using (S)- and (R)-MTPA chlorides, respectively. The absolute configuration of 1 was
determined by comparison of the 1H-NMR spectra of 2 and 3 according to Dale and Mosher [28].

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Figure 2. Structures of 3α-senecioyloxy-6β-hydroxytropane 1 and its (R)- and (S)-Mosher’s
esters 2 and 3.
Comparing to 1, two different spectra were obtained for these diastereomeric esters (Table 1). We
observe that in both esters, all the tropane moiety protons are shielded, except for H-3 which is not
modified and H-6, which is the only deshielded proton. Anisochrony (Δδ), expressed as the difference
between the chemical shifts of the nuclei affected (Δδ = δR − δS), is observed for H-5 and Hexo-7 (+0.1
and −0.12, respectively), and for C-5 and C-7 (−0.4 and +0.7, respectively). Therefore, protons in close
proximity to the phenyl group are shielded. As shown in Table 1, the proton at C-7 is shielded in the
(R)-MTPA derivative, confirming the structure 2a and excluding structure 2b. On the other hand, the
C-5 proton is shielded in the (S)-MTPA derivative, which corresponds to 3a and not to 3b (Figure 2).
Accordingly, the spectral non-equivalence (Δδ = δR − δS) between the diastereoisomers gave a positive
value for H-5 and a negative value for Hexo-7. This demonstrated unambiguously that the substitution
is on C-6 with (R) configuration and inducing (R) configuration on C-3. Thus, the absolute
configuration of 3α-senecioyloxy-6β-hydroxytropane is (3R,6R).
The result obtained herein was in-line with that previously reported by CD applied to a disubstituted
alkaloid [(3R,6R)-3α-trans-hydroxysenecioyloxy-6β-senecioyloxytropane] isolated from the aerial

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parts of Schizanthus tricolor [17]. The latter, together with 1 and three other isomers isolated from
S. grahamii [33,34], all present a negative [α]D. In the absence of chiral carbon(s) on the lateral
chain(s), this result suggests that the absolute configuration of tropane alkaloids with a negative [α]D
have a (R)-configuration.
1
13
Table 1. H- and C-NMR data of compounds 1a, 2a and 3a in CDCl3 (500 MHz, δ in
ppm, J in Hz).
1a
2a ((R)-MTPA ester)
3a ((S)-MTPA ester)
δ (H)
δ (C)
δ (H)
δ (C)
δ (H)
δ (C)
H–1
Hendo–2
Hexo–2
3.79 (s)
2.56-2.45 (m) 32.1
1.88 (d)
61.0
3.32 (br s)
2.14-2.13 (m)
1.71-1.67 (m)
60.4
35.3
3.31 (br s)
2.14-2.13 (m)
1.72-1.69 (m)
60.8
35.8
(J2exo,2endo = 15)
H–3
5.05 (s)
63.0
5.05 (t)
(J = 4.85)
2.20-2.19 (m)
1.93-1.91 (m)
65.5
34.0
5.05 (t)
(J = 4.96)
2.21-2.20 (m)
1.97-1.95 (m)
65.5
34.4
Hendo–4
Hexo–4
2.56-2.45 (m) 30.6
2.03 (d)
(J4exo,4endo = 15)
H–5
H–6
3.67 (s)
4.80 (dd)
(J6,7exo = 5)
68.9
72.6
3.24 (s)
5.73 (dd)
(J6,7endo = 7.48,
J6,7exo= 2.97)
2.65 (dd)
66.1
82.0
3.14 (s)
5.76 (dd)
(J6,7endo = 7.57,
J6,7exo= 2.95)
2.63 (dd,)
66.4
82.0
Hendo–7
2.85 (dd)
37.5
35.5
34.8
(J7endo,7exo = 10,
J7endo,6 = 5)
2.30-2.25 (m)
2.90 (s)
(J7endo,7exo = 14,
J7endo,6 = 7.5)
2.12-2.09 (m)
2.34 (s)
(J7endo,7exo = 14,
J7endo,6 = 7.9)
2.24 (br s)
2.24 (s)
Hexo–7
H3C–N
H–10
37.5
115.6
40.5
116.1
40.8
116.0
5.65 (s)
5.71 (t)
5.70 (s)
(4J = 1.29)
2.20 (s)
H–12
H–13
2.19 (s)
1.93 (s)
20.3
27.4
20.3
27.5
2.20 (s)
1.94 (s)
20.3
27.4
1.94 (s)
H3C–O
Hortho–Ph
Hmeta–Ph
Hpara–Ph
3.56 (s)
55.4
3.58 (s)
55.4
7.55-7.53 (m)
7.43-7.41 (m)
7.43-7.41 (m)
127.4
128.5
129.7
7.55-7.53 (m)
7.43-7.41 (m)
7.43-7.41 (m)
127.2
128.4
129.6

Molecules 2011, 16
Figure 3. The anisotropy generated by the MTPA’s aromatic ring depends on the
7205
configuration and conformation of the auxiliary reagent. To have a significant effect, the
phenyl group must produce a direct influence and thus be in a rigid conformation. Earlier
experimental [5,27–29,31] and theoretical [32] studies showed that the ester group is
oriented anti-periplanar relative to the CF3 group, and syn-periplanar with respect to the
proton of the chiral carbon. The ester, the CF3 groups as well as the C-H bond of the chiral
carbon are coplanar which makes this part of the molecule rigid.
4. Experimental
4.1. Plant Material
Schizanthus grahamii Gill. was collected in Rengo (Central Chile) and authenticated by Professor
Fernanda Pérez (Departamento de Botánica, Facultad de Ciencias, Universidad de Chile); a voucher
specimen (no. 22234) has been deposited in the Faculty of Chemistry at the same University. The
stem-bark (2.6 kg) was extracted with ethanol (4 × 3.5 L) at room temperature and the filtered
alcoholic solution was evaporated to dryness. The residue was taken up in 0.1 M HCl and washed with
dichloromethane. The aqueous solution was made alkaline to pH 12 with NH4OH and further extracted
with dichloromethane yielding a gummy alkaline residue (6.6 g). Further purification on an aluminium
oxide column was performed according to Muñoz et al. [35], leading to a purified fraction containing
compound 1, together with three other isomers. These four isomers, present also in other species of the
genus [36], were isolated as described by Bieri et al. [33].

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4.2. Chemical and Reagents
Ethyl acetate, dichloromethane, chloroform, pyridine, NaHCO3, HCl, (R)-(-)- and (S)-(+)-MTPA-Cl
were purchased from Fluka (Buchs, Switzerland).
4.3. Apparatus
1H- and 13C-NMR spectra were recorded in CDCl3 using a 500 MHz Bruker DRX instrument
(Bruker, Dübendorf, Switzerland) equipped with a QNP probehead. Chemical shift values (δ) are
reported in parts per million ppm related to tetramethylsilane used as internal standard and coupling
constants (J) are in Hertz.
4.4. Preparation of Mosher’s Esters
3α-Senecioyloxy-6β-hydroxytropane 1 (5.5 mg in 2 mL dichloromethane) was treated with pyridine
(0.2 mL) and (S)-(+)-α-methyl-α-trifluoromethylphenylacetic acid chloride [(S)-(+)-MTPA-Cl,
100 mg]. The mixture was stirred at room temperature under an atmosphere of nitrogen for 6 h. The
reaction mixture was then dried using N2 speed-vacuum. The residue was dissolved in a solution of
10% HCl and washed with ethyl acetate (3 × 20 mL). The aqueous phase was made alkaline with a
saturated solution of NaHCO3 and extracted with CHCl3 (3 × 20 mL). The organic layer was separated
and the solvent was evaporated to give (R)-Mosher’s ester derivative 2 (1.5 mg, 15% yield). The
(S)-Mosher’s ester derivative 3 (1.5 mg, 15% yield) was prepared using (R)-(-)-MTPA-Cl under the
same conditions described above.
5. Conclusions
The absolute configurations of naturally-occurring tropane alkaloids should be determined by NMR
and/or CD whenever they cannot be reasonably assumed to be identical to those of previously
determined compounds. In any case, it should be clearly stated if the chirality has been determined and
specified. Even if [α]D cannot be used to reliably determine absolute configuration, it should always be
reported in order to permit future comparison with experimental and simulated data. Numbering of this
kind of molecules should always be established according to their absolute configuration and defined
as 3,6-disubstituted compounds.
Acknowledgements
The authors would like to thank André Pinto for technical assistance in measuring NMR spectra.
Funding at the Organic Chemistry Department of the University of Geneva comes from the
Département de l'Instruction Publique (DIP) and the Swiss NSF 200020-135089 and 206021-128746.
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