Pyrrolidine derivatives pyrrolizidine alkaloids from

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... 

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. 

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-... 

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,... 

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-... 

A quite different approach to the pyrrolizidine nucleus starting with pyrrolidine has led to a synthesis of the alkaloids isoretronecanol (19) and trachelanthamidine (20) (Scheme 52). A novel synthesis of A -dehydropyrrolizidinium perchlorate from a-butyrolactone has been reported. The key step is the synthesis of the 2-pyrroline (21) from the butyric acid derivative (Scheme 53). 

Species belonging to the genera Alexa from Amazonia and Castanospermum from Australia contain polyhydroxylated piperidines, pyrrolidines, indolizines and pyrrolizidines. The presence of this related series of alkaloids suggests the original derivation of both genera from a common ancestor thriving on the old South Panagean continent. 

---