Pyrrolidine alkaloids biological activities

The chemical diversity of pyrrolidine alkaloids indicates a broad spectrum of biological activities, which, however, does not allow, at the present time, structure-activity relationship studies. The available data are inhomogeneous, ranging from investigations of pure compounds to reports of use in folk medecine. 

Denmark and Marcin showed that 2,2-disubstituted 1-nitroalkenes undergo facile MAD-promoted [4 -r 2] cycloaddition with n-butyl vinyl ether in toluene at 0 °C to give cyclic nitronates as anomeric mixtures in good yield [173]. This method is a promising route to the stereoselective synthesis of disubstituted pyrrolidines and can thus be applied to the synthesis of the biologically active pyrrolidine alkaloid, mesembrine (Sch. 134). 

Pyrrolizidine alkaloids ( )-trachelanthamidine (240) and ( )-supinidine (244) were synthesized, based on the Michael addition of an aziridine to an a,/J-unsaturated ester and subsequent ring opening of an aziridinium intermediate. Interest in these alkaloids stems from their biological activities. Treatment of ethyl 6-chloro-2-hexenoate (236) with excess aziridine at 0°C gave the pyrrolidine derivative 238 in one step, probably via the aziridinium salt 237 in 73% yield. The intramolecular cyclization of 238 with lithium diisopropylamide in tetrahydrofuran provided the thermodynamically more stable ester 239 as the sole product, (86%), which was then converted to ( )-trachelanthamidine (240) by reduction with lithium aluminum hydride. Since necine bases must contain a 1,2-didehydro system in their molecule to exhibit physiological activity, the following reactions were carried out to introduce a 1,2-didehydro system. Treatment of 238 with 2.4 equiv of lith-... 

The pyrrolidine ring is found abundantly in both naturally occurring and synthetic biologically active compounds. The alkaloid nicotine, an agonist for the nicotinic acetylcholine receptor, is a notorious example of the former. Pyrrolidine itself is found in carrot and tobacco leaves. The prevalence of pyrrolidines in bioactive compounds has led to much interest in the development of flouropyrrolidine building blocks. The... 

Because they exhibit various fascinating biological activities [1], polyhydroxylated alkaloids that mimic sugar structure arouse a growing interest in the last few years. Naturally occurring iminosugars are classified in five structural families polyhydroxylated pyrrolidines, piperidines, indolizidines, nor-tropanes, and pyrrolizidines (fused pyrrolidines with N at the bridgehead) alkaloids [2]. The pyrrolizidine skeleton with a hydroxyl substituent at C-3 is relatively rare in Nature and appears to be restricted to specific families, while piperidine and pyrrolidine skeleton are conunon in many species. 

The asymmetric hydrogenation of pyrroles is a useful method to optically active pyrrolidines that are building blocks of pyrroline based alkaloids and otlier biolog ically active compounds. It was not until very recently that the catalytic asymmetric hydrogenation of pyrroles has become the truth. 

Hyoscyamine.—Hyoscyamine (103) is a member of a large family of alkaloids in which a pyrrolidine ring is derived from ornithine. The biosynthetic pathway to hyoscyamine shown in Scheme 22 is supported by a wealth of evidence from past work.68 It is noteworthy that the route from ornithine to (102) parallels exactly the corresponding sequence (path b, Scheme 16) by which lysine is converted to A -piperideine in the currently favoured route to sedamine. Further support69 for this sequence has come from the administration of ATa-methyl-ornithine (101) to Datura stramonium plants. The precursor was multiply labelled with 14C as indicated and the activity was incorporated specifically into the corresponding positions of the alkaloid, without change in isotopic ratio. In contrast, the JV -methyl isomer of ornithine was biologically inert. 

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