Biogenesis and Biogenetic Interconversion of the Tropanes

An extensive use of radioactive tracer technique permits a deeper insight into the formation of the tropane skeleton in vivo. Hyoscyamine-(methyl-i C) (76), atropine- C, tropic acid-i C (77), and succindi-aldehyde-2,3-i4C (78) were synthesized. The last was not incorporated at all by D. stramonium seedlings (78), while the former feeding experiments with ornithine-a-i4C proved its incorporation into hyoscyamine (79) hjD. stramonium (see Volume VI, pp. 172-173). More recently two independent teams (80, 81) reported that this incorporation takes place asymmetrically. 

Hyoscyamine-i C (XXVIIIb) (from ornithine) was degraded following 

Willstatter s method (Volume I, pp. 278 285-286) to a-methyltropidine, i.e. (+ )-5-dimethylamino-l,3-cycloheptadiene (LXXXIV). Resolution of the latter with dibenzoyltartaric acid followed by (a) isomerization of each antimer into )3-methyltropidines (LXXXV), (b) hydrolysis, (c) partial hydrogenation of the cycloheptenone, and (d) Grignard reaction with the cycloheptanones (LXXXVI) gave the phenyl-, and p-chlorophenyl-l-cycloheptenes (LXXXVII). The product of oxidation, arising from (+ )-LXXXI V, contained the whole radioactivity, while the benzoic and p-chlorobenzoic acids from the levorotatory form were radioinactive. This proved that the whole label from ornithine-a-i C was either in C-1 or in C-5 in hyoscyamine (80, 81). 

A correlation of configuration of (-t- )-a-methyltropidine (LXXXIV) therefore gave a clue to the absolute configuration of labeled hyoscyamine. This was achieved by converting it (82) into the V-dimethyl-glutaminol antimer XCa, via the tetraol LXXXVIII and with periodate. The reduction of A,A-dimethyl-L-(-f )-glutamic acid afforded its antimer XCb. Consequently, C-1 was radioactive in hyoscyamine, but, C-5 was not. This ultimate information concerning the biosynthesis of the tropane skeleton had not been anticipated. 

The origin of C-2 and C-4 has also been proved by the tracer technique as coming from acetate methyl, while for C-3 the carboxyl of acetic acid is the precursor (83), probably via acetoacetyl coenzyme A. The question still open is how ornithine reacts with that compoimd to account for the 

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