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Review
Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University, Staszica 6, PL 20-081 Lublin, Poland
Abstract:
Secondary metabolites of Solanaceae plants, sharing tropane skeleton as a common structural feature, are sharply divided into two
classes: tropine and ecgonine derivatives. The first group, represented by well known alkaloids: atropine and scopolamine, which are
considered to be model anticholinergic drugs, continues to provide inspiration in the search for more selective muscarinic receptor
antagonists. The second class accommodates one of the principal drugs of abuse, cocaine. Synthesis of much needed cocaine antago-
nists, despite extensive research, has not been particularly successful. Therefore, new concepts of cocaine abuse treatment resort to
immunotherapy and biotechnology. Contemporary pharmaceutical industry manufactures over 20 active pharmaceutical substances
containing tropane moiety in their structure, which are applied as mydriatics, antiemetics, antispasmodics, anesthetics and broncho-
dilators. There are two sources of raw materials for this industrial activity: natural products isolated from cultivated transgenic plants
(mainly scopolamine and atropine from Australian Duboisia) and chemical synthesis based on common intermediate: tropinone,
which can be further transformed by synthetic means to the following classes of compounds: tropine and its esters (tropeines),
scopine and nortropine derivatives, and tropane quaternary ammonium salts. This survey focuses on new developments in chemistry
and pharmacology of tropane derivatives, particularly in view of their prospective industrial applications as therapeutics.
Key words:
tropane alkaloids, tropinone, tropines, tropeines, antiemetic drugs, antispasmodics, mydriatics, cholinergic muscarinic
antagonists, tropane quaternary ammonium salts, tropane chemical syntheses, stereochemistry of tropane derivatives
Abbreviations: AcCoA – acetyl coenzyme A, ACh – acetyl- LC-MS/MS – liquid chromatography with tandem mass spec-
choline, AChR – acetylcholine receptor, API – active pharma- trometry detection, MR – muscarinic receptor, NET – norepi-
ceutical ingredient, ATC – anatomotherapeutic classification nephrine transporter, NMR – nuclear magnetic resonance,
WHO, ATP – adenosine triphosphate, BChE – butyrylcholines- PNS – peripheral nervous system, SAR – structure-activity re-
terase, CNS – central nervous system, CocE – cocaine esterase, lationship, sc – subcutaneous, SERT – serotonin transporter,
DA – dopamine, DAT – dopamine transporter, H6H – 6-hydro- TR – tropine reductase
xytropine hydroxylase, im – intramuscular, iv – intravenous,
* Dedicated to the memory of Professor Osman Achmatowicz (18991988), an eminent organic chemist and the author of seminal papers
on alkaloid chemistry.
medical application: from antiemesis to resuscitation, as an alkamine part, and may be esterified in position
and also serves as a raw material in synthesis of the C-3 with a variety of acids as, for example benzoic,
next generation drugs. The use of compound 14 as an cinnamic, tiglic, truxillic, isovaleric, methylbutyric,
interrogative aid (or “truth serum”) is poorly docu- and others. They did not became drugs, with a notable
mented, for obvious reasons. Minor tropane alkaloids exception of anisodamine (3-tropoyl-6-hydroxytropi-
contain tropine, nortropine or hydroxylated tropines ne, 13) [70].
The mind-altering properties of extracts from tro- ulcer, colic, cystitis and pancreatitis. All main three
pane alkaloid-containing plants (e.g. hallucinogenic) alkaloids mentioned above (considering, according to
are known since antiquity but the main application of the medical tradition, hyoscyamine and its racemate –
these substances in modern medicine is different [10, atropine as separate entities), are known to cause the
28, 45]. Their antispasmodic action is useful in treat- pupil dilatation (mydriasis), which is accompanied by
ment of bladder spasms, irritable bowel disease, peptic impairment of the lens accommodation (cycloplegia).
tion. Obviously, MR antagonists can produce a vari- thus it is applied as an antidote. It was also the first ef-
ety of physiological responses, which are of great in- fective drug in therapy of Parkinson’s disease [27, 28].
terest in physiology, and some of them are exploited Scopolamine has a very similar mechanism of ac-
in clinical practice. Since dysfunction of muscarinic tion to atropine and its profile of medical use is
cholinergic system have been implicated in depres- largely overlapping. However, its action on the CNS
sion, epilepsy, Parkinson’s disease and Alzheimer’s is much more pronounced, with sedation at low doses
disease, MR antagonists remain of great interest as and possibility of disorientation and hallucinations
potential CNS drugs [3, 15, 27, 33]. observed after higher doses. Since scopolamine is
Tropane alkaloids are absorbed rapidly from the the most effective compound in prevention of motion
gastrointestinal tract. Drugs, in the form of injectable sickness, transdermal therapeutic system has been de-
solution, are usually administered intramuscularly. signed for this indication, releasing 0.5 mg of the drug
Atropine is capable of binding to MR at neuroeffector over a period of 3 days from 1.5 mg reservoir. Another
principal clinical application of scopolamine is pre-
sites of muscles and gland cells, peripheral ganglia
medication before anesthesia by parentheral applica-
and in the central nervous system. Both, atropine and
tion (iv infusion; sc or im injection). Although this
scopolamine have a characteristic, dose dependent ac-
substance has a very long story of medicinal applica-
tion on the cardiovascular system, which is clinically
tion, reliable pharmacokinetic data derived from
useful for resuscitation. They inhibit secretion in the
analyses of biological matrices with the help of liquid
respiratory tract and also reduce gastric secretion. At- chromatography with tandem mass spectrometry de-
ropine has prolonged inhibitory effect on the gastroin- tection (LC-MS/MS) equipment, were obtained only
testinal motor activity. The action of tropane alkaloids recently, showing considerable dependence on the dos-
on the spincter muscle of the iris and the ciliary mus- age form. Maximum drug concentration in plasma oc-
cle of the lens, after topical application, leads to pupil curs after ca 0.5 h and the biological half-life is short.
dilatation and to temporary paralysis of accommoda- Scopolamine is metabolized mainly by glucuronida-
tion. Full recovery may take as long as 7 to 12 days tion and by ester function hydrolysis [8, 10, 28, 71].
[10, 19, 28]. Atropine is also effective in counterbal- There is a growing body of evidence that tropane
ancing high systemic concentrations of ACh, which alkaloids and their synthetic analogs can interact ef-
may result from poisoning with organophosphorous fectively with receptors other than acetylcholinergic
insecticides or nerve gases used as chemical weapons, MR. The synthetic tropeine: 1-H-indole-3-carboxylic
Scheme 5. Pervilleine A
be conveniently split by the action of phosgene or intermediate in synthesis of 3-phenyl analogs of co-
chloroformates, with formation of the corresponding caine (e.g. 33), is presented in Scheme 8 [80].
carbamates. Utility of this transformation was first
demonstrated on chloroethyl chloroformate, but tri-
chloroethyl ester is more frequently used recently
[43]. Suitably protected nortropine derivatives can
More distant synthetic relatives of
also be obtained in a variety of reactions, in which
atropine and cocaine
N-carboxyalkyl derivatives of pyrrole (e.g. 28) or pyr-
rolidine, (e.g. 47) are applied as C4 synthon in cyclo-
condensation reactions. An example of such ap- Perhaps the most significant continuation of the early
proach, leading through a protected nortropine 30 to work on semi-synthetic tropane derivatives came from
anhydroecgonine derivative 31, which is a principal J. von Braun (an eminent and very prolific chemist,
born and educated in Poland, also professor in [then] furt (1921–1935), who carried out systematic investi-
Breslau 1909–1918 and Rector of Technical Univer- gation on the effects of transposing functional groups
sity in Warsaw 1915–1917), at the University of Frank- within a drug molecule. He has managed to place tro-
pate ester moiety in different positions around the tro- Search for a cocaine antagonist was initially fuelled
pane ring, without losing the mydriatic activity. Fur- by belief that the alkaloid is a competitive inhibitor of
ther, he demonstrated that intact tropine ring was not dopamine (DA) uptake. A number of DAT blockers
essential for activity and could be substituted by a ter- (including tropane derivatives: benztropine 61 and
tiary amine function situated a couple of carbon atoms a group of 3-phenyl analogs of ecgonine, Scheme 9)
away from tropate moiety. In parallel investigation have been developed, but they found no clinical use in
concerning minimal pharmacophore of cocaine, con- cocaine addiction treatment. More recent evidence
ducted by A. Einhorn and G. Merling, it has been suggests that dopamine and cocaine have separate
found that 2-carbomethoxy substituent of pseudotro- binding sites on DAT. This finding renders some
pine is not essential for anesthetic activity. This dis- credibility to continuous effort dedicated to synthesis
covery started an avalanche of synthetic compounds of cocaine analogs [80]. Other targets, like 5-HT re-
expected to outperform atropine and cocaine in clini- ceptors are also actively pursued [49]. The main line
cal practice. Eventually, it led to development of a group of cocaine structural analog production was based on
of synthetic local anesthetics and antispasmodics [81], anhydromethylecgonine 31 as the key intermediate
which bear little resemblance to the alkaloid progeni- capable of stereoselective C-C bond formation at C-3.
tors, thus validating fundamental concepts of struc- Addition of phenylmagnesium bromide to 31 gave
ture-based drug design and pharmacophore optimiza- 2b-carbomethoxy-3b-phenyl tropane 32 with 75%
tion. The ethyl ester of p-aminobenzoic acid, known yield. By application of the standard aromatic chemis-
as benzocaine, first introduced in 1903 and still in use try, the compound was transformed into a library of
today, was the first in a long series, with well known derivatives, in which compound 33, obtained by di-
drugs: procaine and amylocaine to follow [45]. rect iodination or a sequence of: nitration, reduction
and diazotization, proved particularly useful as an ex-
perimental cocaine antagonist, molecular probe, and
also as a starting material for modern aromatic cou-
pling reactions [80] (Scheme 9). Compound 34 known
Prospects of cocaine abuse treatment as IPT, or iptakalim, turned out to be a human nico-
tinic acetylcholine receptor antagonist and adenosine
triphosphate (ATP)-dependent potassium channel
Cocaine abuse has already attained a level of alarming opener. IPT inhibits cocaine-induced release of dopa-
epidemic in the United States and the threat to the rest mine and glutamate, which suggests its possible ap-
of the world is obvious. Our understanding of addic- plication in drug addiction [35].
tion as a physiological and pharmacological phe- Much attention has been devoted to development
nomenon is certainly not complete, but scientific of protein-based therapies of cocaine addiction, like
framework already exists, upon which various lines of anti-cocaine antibodies [12, 82, 89]. Vaccination of
research seeking effective means for cocaine abuse rodents with such construct appeared to reduce self-
treatment, can be based. Among tools, extensively administration of the drug. Another biotech approach
used by pharmacologists, are a variety of behavioral idea is based on enzyme technology. It is known that
animal models (drug self-administration etc.) and nu- butyrylcholinesterase (BChE), which splits off ben-
merous sophisticated neurochemical assays [2, 4, 5, zoic acid from cocaine molecule leaving behind
30, 47, 62]. A considerable evidence has been accu- harmless methylecgonine, is a principal cocaine me-
mulated indicating that the dopamine transporter tabolizing enzyme in mammals. The enzyme was ap-
(DAT) constitutes the main target, responsible for the plied to experimental animals as such, or in the form
reinforcing effect of the drug [44, 86]. On the other of an antibody, with moderate success in cocaine de-
hand, dopamine transporter gene deletion studies indi- toxification. Interestingly, another efficient protein
cated that this pathway was not the only one. More re- catalyst for cocaine hydrolysis has been found in bac-
cently, involvement of another monoamine transport- teria. Rhodococcus sp. strain MB1, which uses cocaine
ers [serotonin (SERT), norepinephrine (NET)] have as the sole source of carbon and nitrogen, is equipped
been suggested [2, 49, 74]. Besides, cocaine also with cocaine esterase (CocE), which shows hydrolytic
modulates endogenous opioid system (through m and rate constant 1000-fold higher than that of BChE [42].
k receptors) and preprodynorphin release. It seems that both lines of research, synthetic and bio-
technological, offer reasonable chance for a new lated from natural sources should be followed by its
molecule (either small ligand or biomacromolecular synthesis, providing the unambiguous proof of struc-
construct), which will bring a breakthrough in cocaine ture. Although today structural analysis is based
abuse therapy. mainly on application of advanced spectral tech-
niques, the art of total synthesis of natural products
flourishes, and long, complicated sequences of reac-
tions utilizing most sophisticated molecular transfor-
mations, still set academic standards of excellence
Chemical syntheses of tropinone and its
and serve as teaching aids to education of organic
derivatives
chemists [60]. Although detailed synthetic delibera-
tions are outside of the scope of this review, we will
We owe a great deal of spectacular successes of only touch upon some most important topics con-
chemistry as an art of creating new materials, to the nected with chemical synthesis of tropane analogs:
tradition established in 19th century, which demanded construction of the bicyclic tropane skeleton, dessy-
that elucidation of structure of a new compound iso- metrization of the meso-structure of tropinone (or its
precursors), and stereochemistry of nitrogen atom efficient, but they served the purpose of proving the
quaternization, because understanding of their stereo- structure and additionally provided some pure materi-
chemical features is essential for successful attempts als for investigation of biological activity. R. Robin-
at new drug design in this category. Correct structures son’s synthesis of tropinone, accomplished in 1917,
of atropine and cocaine were determined by R. Will- was based on ingenious idea of a three-component
stätter in 1898 but stereochemical details of tropane biomimetic condensation between succinaldehyde 35,
derivatives were not completely clarified until 90 methylamine 36 and acetonedicarboxylic acid 37,
years later, and X-ray structures of scopolamine com- providing a breakthrough in availability of tropane
pounds were determined in 2000 [24]. It may, there- derivatives [73, 77]. The preparation, depicted in
fore, appear shocking that some syntheses of tropine, Scheme 10 was modified and improved many times,
atropine and cocaine were successfully completed al- and eventually made it into the golden collection of
ready in years 1879–1903 (A. Ladenburg; R. Willstät- the greatest achievements in the total synthesis of
ter), when methodology of organic chemistry was still natural products [6, 60, 77].
in its infancy. Total syntheses of alkamine part, start- It should be pointed out here that tropanone and
ing from cycloheptanone, were rather tedious and in- tropines are symmetric (chirality of bridgehead car-
trimethoxytetrahydrofuran) as a C3 component, and cult and a mixture of all possible diastereoisomers (R-
subsequent dehydration of 6-hydroxytropinone. An al- and S- 17–20) is obtained. Similarly, carboxylation of
ternative transformation for chemical functionaliza- tropinone with methyl carbonate and metallic sodium
tion of the tropane C-6 position, which involves intra- gives a mixture of endo- and exo-products and each of
molecular reaction of N-carbethoxy nortropine 3-a- them gives in turn two carbinols upon reduction of the
benzenesulfenate, has also been proposed [67]. This carbonyl group. For ecgonine derivatives, there are
approach, based on generation of O – 3 free radical, four pairs of diasteroisomers (R-enantiomers depicted
followed by 1,5-hydrogen shift with formation of C-6 in Scheme 4) and all their members have been iso-
radical, leads to a 6-phenylthio nortropine derivative, lated from natural sources, but (–)-cocaine, the main
from which the desired 6,7-dehydrotropine can be alkaloid of Erythroxylon coca exhibits quite unusual
easily obtained by oxidation/elimination sequence. pharmacological properties, not matched by other iso-
Unlike tropeines, ecgonine derivatives contain mers [46, 80].
a chirality center at C-2 in the alkamine part, which The problem of stereoselectivity of such transfor-
makes their synthesis more demanding, requiring chi- mation, as required in ecgonine (and cocaine) synthe-
ral auxiliaries or enantioselective methods. The use of sis, was addressed by Canadian chemists, who man-
acetonedicarboxylic acid (or its esters) as the C3 com- aged to generate enantiomeric anionic intermediates
ponent of the condensation can easily give rise to C-2 from tropinone by application of lithium derivatives
carboxylic derivatives, particularly ecgonine 15 and of secondary amines containing chiral substituents [53].
its ester cocaine 17 (Scheme 11). However, control of Recently, dissymmetrization of the pyrrolidine in-
stereochemistry of the two new centers of chirality in termediate 47 was achieved in a proline catalyzed in-
classical version of Robinson’s reactions is very diffi- tramolecular aldol condensation, which gave rise after
additional transformations of aldehyde 49, to (+)-co- erature positions [80]. The purpose of these efforts
caine 51, the enatiomer of natural product [55] can be summarized as the search for better cocaine
(Scheme 12). Obviously, at present, chemical synthe- (that is, devoid of addictive properties) and search for
sis of ecgonine and its esters, which are much sought cocaine antagonists, which could block efficiently its
in illicit markets, is no match for isolation of natural interaction with monoamine transporters (particularly
product, because it would have to resort to optical iso- DAT). Although these programs have not been par-
mers resolution through diastereoisomeric salts [6, ticularly successful in terms of pharmacological goal,
85], which is seldom efficient. they served well as an advancement of ecgonine type
Syntheses of cocaine analogs have spanned over alkaloid chemistry. For example, phenyltropane chem-
many decades and recent, comprehensive review of istry was particularly well developed, based on conju-
this activity totals 100 printed pages, and lists 400 lit- gate additions of aromatic Grignard reagents to anhy-
droecgonine esters, e.g. 31). A number of new cocaine realization of this idea proved not entirely satisfac-
analogs (e.g. compounds 33 and 34 presented in tory, because of difficulties in obtaining the amine ac-
Scheme 9) have found application as molecular pro- ceptor. Fortunately, easily available and stable precur-
bes for testing interactions with functional biomacro- sor of cycloheptadien-2,6-one: 8,8-dimethyl-3-oxo-
molecules, for example these engaged in dopamine 8-azoniabicyclo[3.2.1]octane iodide (52) was identi-
turnover [47, 87]. fied, which easily undergoes alkylamine exchange un-
Tropanes are tertiary amines whose conformational der mild conditions, securing availability of a wide
flexibility of the nitrogen atom is somehow restricted range of N-substituted nortropine derivatives with
by the bicyclic structure. Positional preference of the yields up to 80% [92].
N-alkyl group has been studied in some detail by
spectroscopic methods, 1H and 13C nuclear magnetic
resonance (NMR) in particular. It has been concluded
that most derivatives of tropine are in equilibrium
Tropane-derived drugs in contemporary
with preponderance for the axial position of the N-
pharmaceutical industry
methyl (alkyl) group, which, therefore, is depicted as
facing piperidine ring. Both: steric and polar effects
can affect the equilibrium and solvent effects can ad- Among active pharmaceutical ingredients (API),
ditionally complicate the issue [18, 21, 24, 34]. This which contain tropane moiety in their structure, the
situation is of particular importance when bridge ni- most significant in terms of production volume and
trogen in a tropane derivative is further alkylated with value are natural products: atropine, hyoscyamine and
a substituent other than methyl group and it becomes scopolamine, and a group of their semisythetic de-
a center of chirality. Let’s consider a case of ipratro- rivatives obtained by a single chemical step – N-al-
pium bromide (N-isopropylnortropine methylbro- kylation, which results in formation of quaternary am-
mide; 8-R; 55), an important broncholitic medicine, as monium salts [10, 28, 51]. Pharmaceutical products
an example of such situation. Compound 55 can be based on tropane alkaloids developed at the beginning
obtained via different routes, but not by direct quater- of the 20th century in Europe, evolved from ethno-
nization of atropine with isopropyl halides! As dis- pharmaceutical tradition and relied on supply of raw
covered by Fodor [18, 28], configuration of tropane materials from wild plant collection. As soon as me-
quaternary ammonium salts is determined by order in dicinal application of pure chemical entities started to
which N-alkylations are performed. The last substitu- depart from herbal preparations, the need for efficient,
ent introduced becomes situated equatorially over the well standardized sources of tropane alkaloids be-
pyrrolidine ring [78]. Original synthesis of 55 in- came obvious and cultivation replaced collection of
volved Robinson’s C4 + C3 units condensation in the the plants from wild habitates. European plants of
presence of isopropylamine. The resulting N-isopro- Atropa and Datura species contain on average 0.2–0.8%
pylnortropinone was reduced to the corresponding of total alkaloids and proportion of the most valuable
tropine and synthesis was completed by transesterifi- constituent: scopolamine (hyoscine) is fairly low,
cation with formylphenylacetate moiety acting as which hardly justifies industrial isolation based on
a precursor of racemic tropic acid [84]. Alternatively, solvent extraction. In the beginning of the 19th cen-
a sequence of reactions involving N-demethylation of tury, phytochemical investigations revealed that Aus-
atropine, followed by N-isopropylation and N-me- tralian plants, classified as Duboisia, are a much
thylation can be applied. On the other hand, direct richer source of tropine derivatives [88]. Presently,
quaternization of atropine with isopropyl bromide Duboisia myoporoides obtained by hybridization of
leads to the isomeric quaternary salt, (in which iso- local variations, is cultivated on large scale in Queens-
propyl group occupies equatorial position), instead of land, Australia, providing 10–15 tons of fresh leaves
55 [78] (Scheme 13). per hectare upon harvest, which can be made 3 times
Recently, some radical progress in synthesis of tro- a year. The plant is known to contain 2–4% of total al-
panes with various N-alkyl substituents has been kaloids with ca. 60% hyoscine and constitutes the ba-
achieved. Although retrosynthetic analysis points out sis for supply of the global pharmaceutical industry
to cycloheptadien-2,6-one as the synthon for one-pot [11, 88]. Experimental plantations of Duboisia have
double Michael addition of primary amines, practical already been started in India and other Asian coun-
structive pulmonary disease. The drug is relatively and also in mixtures of alike compounds, attained
long-acting, which allows for patient friendly therapy, high level of sophistication. Various chromatographic
based on once daily application of 18 mg dose from separation techniques, coupled with multiple mass
a dry powder inhaler. This therapeutic regimen com- spectroscopic detection can assure quick sample com-
pares very favorably with ipratropium, which is ap- position determination, needed for police investiga-
plied four times daily. Market data indicate that tiotro- tion in suspected drug trafficking, trace analysis for
pium makes globally 1.2 bln $ out of 12 kg of the ac- forensic purposes, metabolite identification and quan-
tive substance produced annually [1, 93]. Synthesis of tification for pharmacokinetics, or impurity profiling
58, using a thiophene analog of benzylic acid as the for pharmaceutical studies [8, 11, 40, 58, 59].
tropine esterifying moiety [39, 63], is presented in Although the shade of illicit cocaine industry con-
Scheme 15. stitutes a serious problem for global healthcare and
As quality management system became an integral economy, there is no reason why closely structurally
part of pharmaceutical management, analytical meth- related derivatives of tropine and ecgonine should not
ods for tropane alkaloids, both as single constituents be discussed jointly, in terms of pharmacological and
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