3a-Tropine

From a pharmaceutical point of view, three natural-occurring compounds are widely used as chemotherapeutic agents viz. (-)-hyoscyamine, (-)-scopolamine (hyoscine) and atropine (Fig. 2). The latter compound is formed by the racemization of (-)-hyoscyamine during isolation and purification and is thus ( )-hyoscyamine. All three compounds are esters of 3a-tropine with tropic acid. 

Tropinone is reduced stereospecifically to either tropine or pseudotropine (Fig. 4). This reduction is brought about by two independent tropinone reductases, often referred to as TR-I and TR-II [30], TR-I catalyzes the NADPH-dependent formation of tropine, whereas TR-II reduces tropinone to pseudotropine. The TR-I reaction is reversible but the TR-II reaction is essentially irreversible, the reduction of the ketone being highly favoured over the oxidation of the alcohol pseudotropine [31]. Results of feeding indicate that 3a-tropine and 3(3-tropine do not isomerize and that only the former is incorporated into hyoscyamine [32]. 

Along with 3a-tropine derivatives, characteristic for the plants of the family Erythroxylaceae are the esters of 3jS-tropine (pseudotropine) and ecgonine with benzoic, phenylacetic, 3,4,5-trimethoxybenzoic, 3,4,5-trimethoxycinnamic acids, etc. Dimeric esters of methylecgonine (tmxillines) and tropine (mooniines) have been also reported [15]. 

Tropinone is stereospecifically reduced to yield both tropine (3a-hydroxytropine), which led to the formation of tropane alkaloids, and pseudotropine (3p-hydroxytropine), the precursor of calystegines. These stereospecific reductions are catalyzed by two different tropinone reductases, tropinone reductase I and II (TRI and TRII). Both enzymes have been isolated from many Solanaceous species. Thus, TR I and TR II were isolated from D. innoxia roots and the crude extract favoured the production of pseudotropine over tropine [151]. Also, from transformed root cultures of D. stramonium two different tropinone reductases were obtained. In this species, TRI showed about 5-fold larger activity than TRII, and TRI displayed a pronounced pH-dependency, while TRII was more tolerant to different pH values [152]. Moreover, two tropinone reductases were also isolated from H. niger root cultures. TRI-reduction was reversible, whereas TRII-reduction was essentially irreversible [153]. In subsequent studies it was found that the accumulation of both TRs was the highest in the lateral roots of H. niger throughout development, with different cell-specific patterns [154]. 

A convention for the nomenclature has been suggested (3) based upon the. AT -methyl bridge as a reference group in the tropanes. Syn-plaoed groups will hence be denoted by /3, awii-placed groups by a. Therefore, tropine will be 3a-tropanol and i/>-tropine will be 3j8-tropanol. This convention will be used throughout this chapter. 

A number of 3a and 3/3 aminotropanes have been obtained by reductive amination of tropinone under various conditions, and they have been checked for physiological activity (126). Some new esters of tropine and their quaternary salts have been prepared recently (128). 

The exact correlation of the configuration of the C3-OH group in valeroidine and in scopolamine with that of tropine could be realized by converting scopolamine and valeroidine into tropine (65). Dehydration of ( ) 3a,6j8-dihydroxytropane (XLII) led to ( ) tropene oxide, ... 

Atropine. endo-( )-a-< Hydroxy methyl )benzene-acetic acid 8-methyl-8-azabicyclo[3.2.1 oct 3 yl ester, laH,-SaH-tropan 3a-ol (+)-tropate dj-hyoscyamine tropic acid ester with tropine di-tropyl tropate tropine tropate. C17-HjjNOj mo] wt 289.38, C 70.56%, H 8.01%, N 4.84%. O 16.59%. Parasympatholytic alkaloid isolated from Atropa belladonna L, Datura stramonium L, and other Solanaceae. 

Tropacine. endo-a-Phenylbenzeneacetic acid ( methyt-8-azabicyclo[3.2,l]oct-3-yl ester laH.SaH-tropon-3a-ol diphenylacetate diphen ylacet ic acid 3c<-tropanyl ester 3a-tr0panyl diphenylacetate tropine diphenylacetate. C22-Hjjn02 mol wt 335.43. C 78.77%. H 7.51%, N 4.18%, O 9.54%. Prepd from tropine and diphenyiacetyl chloride Swiss pat. 202,181 (1939 to Ciba), C.A. 33, 8922 (1939) Friess et af., Toxicol. AppL PharmacoL 2, 574 (I960). 

Tropine Benzylate. endo- -Hytlroxv-O -phenyiben-zeneacetlc acid 8-methyi-8-azahicyeio[3. 2. lfoet-3-yI ester IaH,5aH-tropan-3a -ol benzilate benzitic acid 3o -tropanyl ester glykin BAT BTE BETE. CjjHjjNOj mol wt 351.43. C 75.18%. H 7.17%. N 3.99%. O 13.66%. Prepn Hromatka et al. Monatsh. 83, ]321 (1952). 

Plants in the Solanaceae family produce a variety of alkaloids, some of them having a considerable therapeutic importance. One such group of alkaloids possesses a tropane nucleus. Tropane alkaloids are structurally related natural products having in common the azabicyclo[3.2.1]octane structure and therefore the systematic name for tropane is 8-methyl-8 azabicyclo[3.2.1]octane (Fig. 1). The majority of these alkaloids are esters between organic acids and hydroxytropanes. 3a-Hydroxytropane, called tropine, is the amino alcohol most frequently encountered. In addition, its 3 (3-isomer (pseudotropine), the di- (3,6- 3,7- or 6,7-) and trihydroxylated... 

Withania somnifera, a inemDer of the Solanaceae, has been shown to contain choline, tropine, pseudotropine, 3a-tigloyloxytropane,... 

Comprehensive reviews have recently appeared on the tropane alkaloids of the Solanaceae and on the biosynthesis and metabolism of the same type of alkaloids. The stereospecific hydroxylation of tropine to 6/3-hydroxytropine and the conversion of its tropic acid ester into 6,7-dehydrohyoscyamine and further into scopolamine have been conclusively proven. Hence, the total synthesis of scopolamine from 6-tropen-3a-yl esters is indeed a biomimetic synthesis. 

Structure occurrence The T. a. occur principally in plants of the Solanaceae, Convolvulaceae, Eryth-roxylaceae, Proteaceae, and Rhizophoraceae families as well as in isolated species of the Euphorbiaceae and Brassicaceae. The most important of the ca. 140 known T. a. are either esters of 3a-tropanol (tropine) or, less commonly, of 3/S-tropanol (pseudotropine). Prominent examples are the T. a. of the Solanaceae hyoscya-mine [racemate ( )-hyoscyamine= atropine], scopolamine, and the T. a. of the Erythroxylaceae (Coca... 

A key branch point in tropane alkaloid biosynthesis is the conversion of tropinone into either tropine or pseudotropine (or i/ -tropine), which possess opposite stereochemistry at the 3-hydroxyl position. Two different NADPH-dependent enzymes catalyze the stereospecilic reduction of tropinone the 3-carbonyl of tropinone is reduced to the 3a-hydroxy group of tropine by tropinone reductase I (TR-I) and to the 3jS-hydroxy group of pseudotropine by tropinone reductase II (TR-II). Genes encoding both TR-I and TR-II have been identified in the tropinone... 

Through the incorporation studies using D. innoxia, it was found that a P-ketothioester was the intermediate in the biosynthesis of (-)-hyoscyamine and (-)-scopolamine [3-7].Tropinone is formed from the P-ketothioester, and is stereoselectively reduced by a NADPH-dependent oxidoreductase TR-1 to give tropine.Then littorine is formed by adding a phenyllactic acid moiety derived from phenylalanine via phenylpyruvic acid. Regarding the incorporation of phenyllactic acid into tropine and its transformation, it was found that [1,3A C2](—)-hyoscyamine was obtained when [1,3- C2] phenyllactic acid was incorporated into D. innoxia [8]. A transformation therefore occurred on littorine to form (—)-hyoscyamine, and scopolamine was biosynthesized from 6P-hydroxyhyoscyamine by oxidation as described below. 

The reduction of tropinone (18) to tropine (1) has been subject to several studies in cell-free systems derived from intact plants and from root culture systems. In early studies of this step an enzyme was detected which reduced (18) to an alcohol with 3a-stereochemistry, namely (1) [56]. Subsequently, in Hyoscyamus niger, a plant which predominantly forms alkaloids with 3a-stereochemistry, an enzyme was found which reduces (18) to i -tropine (34) with 3/1-stereochem-istry [57] (Scheme 17). Other workers observed varying ratios of (1) and (34)... 

The next step from the biosynthetic pathway is a branch point of the tropane alkaloid pathway [1,2]. Tropinone 24 is the first intermediate with a tropane ring, and it is converted into intermediates that lead to hyoscyamine 1 or calystegines production depending on the stereochemistry of the reduction [37], Two stereospecific tropinone reductases (TR EC 1.1.1.236) - tropinone reductase I (TR-I) reduces the 3-carbonyl group of tropinone 24 to the 3a-hydroxy group of tropine 27 and tropinone reductase II (TR-II) to the 3p-hydroxy group of pseudotropine 25. TR-I leads to hyoscyamine 1 and scopolamine 6 formation via tropine 27, whereas pseudotropine 25 produced by TR-II is converted into calystegines and other nortropane alkaloids [1, 7, 36]. 

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