Nortropane ring

A common procedure used to forge carbocyclic systems is represented by the ring-closing metathesis reactions exploiting various Grubbs-type carbene catalysts. Based on this cyclization technology, Skaanderup and Madsen [71], on the way to polyhydroxy-nortropane calystegines, reported the asymmetric synthesis of aminated 6a-carbahexoseptanose derivatives 311. 

Ferrier carbocyclization can form only cyclohexanones. Nevertheless, chemical manipulations of the latter can provide us with seven-membered rings. This is illustrated by the synthesis of (—)-calystegine B2 by Boyer and Lallemand [305]. These natural polyhydroxylated nortropane compounds are growth stimulators of nitrogen fixing bacteria. 

Both alkaloids have (+) and (-) forms but only the (-) hyoscyamine and (-) scopolamine are active. The biosynthetic pathway of tropane alkaloids, Fig. (1) is not totally understood, especially at the enzymatic level. Edward Leete has pioneered the biosynthetic studies of tropane alkaloid since 1950"s using whole plants and isotope labels [85-86]. The tropane alkaloid hyoscyamine is bioconverted by the enzyme H6H (hyoscyamine 6p-hydroxylase, EC 1.14.11.11) to scopolamine via 6p-hydroxyhyoscyamine. Hyoscyamine is the ester of tropine and (S)-tropic acid. The (S)-tropic acid moiety derives from the amino acid L-phenylalanine, while the bicyclic tropane ring derives from L-omithine primarily or L-arginine via tropinone. Tropinone is stereospecifically reduced to form either, tropine which is incorporated into hyoscyamine, or on the other hand into pseudotropine which proceeds to calystegines, a group of nortropane derivates that were first found in the Convolvulaceae family [87]. 

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]. 

Tropane alkaloids (TAs), a class of specialized metabolites with a bicyclic tropane ring in their structures, include clinically important hyoscyamine and scopolamine, the stimulant and narcotic cocaine, and the nortropane alkaloids calystegines. Plants producing TAs are distributed, sometime sporadically, across separate angiosperm families (e.g., Proteaceae, Convolvulaceae, Brassicaceae, Euphorbiaceae, Rhizophoraceae, Solanaceae, and Erythroxylaceae) (Griffin and Lin 2000). Studies of TA biosynthesis have been performed predominantly in Solanaceae plants, and thus little is known regarding TA pathways in other families. 

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