Pyrrolizidine alkaloids from pyrrolidines

The heteroatom version of the vinylcyclopropane rearrangement serves to facilitate alkaloid construction. Scheme 13 outlines a strategy for the pyrrolizidine alkaloid isoretronecanol 211 90). Use of a carboxaldehyde (i.e. 213) as a synthon for the primary alcohol provides an ability to adjust stereochemistry. It also sets up formation of the pyrrolidine ring bearing the aldehyde by an aldol-type condensation of an enol of the aldehyde onto an imine derived from 214. Because of the lability of such systems, introduction of X=PhS imparts stability. The resultant azacyclopentene translates to an imine 215 using the iminocyclopropane rearrangement methodology. Simple condensation of the primary amine 216 with aldehyde 37a then initiates this... 

Ornithine is a metabolically quite active amino acid, and the important precursor of pyrrolidine nucleus, which is found in pyrrolizidine alkaloids. Ornithine itself is a non-protein amino acid formed mainly from L-glumate in plants, and synthesized from the urea cycle in animals as a result of the reaction catalyzed by enzymes in arginine. 

The bioactive secondary metabolites reported from Broussonetia kazinoki can be classified into major two groups, alkaloids and flavonoids (Table 1), Fig. (1). The Kusano group at Osaka University of Pharmaceutical Sciences in Japan reported over 20 pyrrolidine alkaloids, broussonetines A-H, K-M, O-T, V-X, and Mi, and broussonetinines A and B, four pyrrolidinyl piperidine alkaloids, broussonetines I, J, Ji, and J2, two pyrroline alkaloids, broussonetines U and U, and one pyrrolizidine alkaloid, broussonetine N, from hot water extracts of B. kazinoki [16-24]. As shown in Table 1, some of these alkaloids exhibited strong... 

Glycosidase-inhibiting alkaloids from plants are classified into five structural classes polyhydroxylated pyrrolidines, piperidines, indolizidines, pyrrolizidines, and nortropanes. Furthermore, they also occur as the glycosides. This review describes recent studies on isolation, characterization, glycosidase inhibitory activity, and therapeutic application of the sugar-mimicking alkaloids from plants. 

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 enantioselective synthesis of monoprotected fra 5-2,5-pyrrolidine dialcohol 1119, a potentially useful intermediate for the construction of pyrrolizidine alkaloids, uses ( S)-malic acid as the chiral source and radical cyclization to fabricate the heterocycle (Scheme 164) [236]. The crucial intermediate 1112 is prepared from acetonide 454b by a Mitsunobu reaction of 1110 with oxazolidine-2,4-dione, resulting in inversion of configuration at the hydroxyl-bearing carbon. Reduction of the 4-carbonyl group of heterocycle 1111 with sodium borohydride followed by dehydration of the resulting alcohol furnishes 1112. 

Since 2001, Izquierdo et al. reported a series of syntheses of natural and uimatural polyhydroxylated pyrrolizidine alkaloids and their analogues, including some hyacinthacines. The starting compounds were various protected polyhydroxylated pyrrolidines which were prepared from carbohydrates. A general synthetic pathway using the o-fructose-derived 2,5-dideoxy-2,... 

In order to clarify its absolute stereochemistiy, both enantiomers of the naturally-occurring sialidase inhibitor siastatin B were prepared from the enantiomers of ribose in multistep sequences, and the natural product was shown to have structure (48), the carbons of the precursor L-ribose being indicated.Compounds (49, R=H and OBn) have been prepared from D-glucose (carbons indicated) as potential precursors for the pyrrolizidine alkaloids retroneclne and crotanecine respectlvely. S Some other references to the synthesis of hydroxylated pyrrolidines and piperidines appear in Chapter 18. 

Several species pertaining to the sub-family Myrmicinae (e.g., Solenopsis spp., Monomorium spp.) are characterized by a venom rich in dialkylated saturated nitrogen heterocycles (e.g., piperidine, pyrrolidine, indolizidine, pyrrolizidine). Exhaustive lists of these alkaloids have already been published [114-116]. Since then, only a few more of these alkaloids have been reported from a few further species. 

A variety of alkaloid skeletons can be prepared from 5-exo cyclizations of aminium cation radicals derived from PTOC carbamates, and some are listed in Table VI (90T2329). Perhydroindoles (entry 1), 1-, 2-, and 3-substituted pyrrolizidines (entry 2-4), tropanes (entry 5), and other pyrrolidine containing ring systems were obtained in 50-96% yields. Direct com-... 

Alkaloids that contain pyrrolidine and pyrrolizidine ring systems are derived from the nonprotein amino acid, L-ornithine. Cocaine (Nl) and (—)-hyoscyamine, the two important pyrrolidine alkaloids that contain a tropane ring system, have been found to occur in coca (Erythroxylon coca, Erythroxylaceae) leaves and the whole plant of the deadly nightshade (Atropa belladonna, Solanaceae). The hepatotoxic alkaloid senecionine (N2) contains a bicyclic pyrrolizidine skeleton derived from two molecules of L-ornithine. 

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