Pyrrolizidine products, formation

Hudlicky and coworkers also reported a related 2-pyrroline formation from viny-laziridines [81], which are extremely useful for the synthesis of pyrrolizidine alkaloids such as the protected (+)-trihydroxyheliotridane 210 (Scheme 2.51). Since the pyrolysis of either diastereomer of 208 furnished the cyclized product 209 as a... 

Pyrrolizidine amino-alcohols are readily dehydrated for example, hydroxyheliotridane and retronecanol, when treated with sulfuric acid, afford heliotridene (see e.g., refs. 105 to 107). A more complicated dehydration reaction is the transformation of the alkaloid rosmarinine into the alkaloid senecionine.83 Dehydration of 1-hydroxy-l-carbethoxypyrrolizidine53 in the presence of phosphorus oxychloride in pyridine results mainly in the formation of the A1,8-unsaturated ester (see Section II, E). The authors61,62 claimed that the dehydration product of l-carbethoxy-2-hydroxy-3-oxopyrrolizidine contained a A1,2-double bond (159). Later, however, the UV, IR, and NMR spectra67 revealed that the double bond had migrated the... 

Both pyrrolizidine and indolizidine alkaloids can be synthesized by taking advantage of the anodic a-alkoxylation of A -alkoxycarbonylpyrrolidines (e.g., 83 to 84). The method, first developed by Ross, Finkelstein, and Petersen, and later explored by Ban and coworkers [24, 25], has been utilized by Shono s group to synthesize isoretronecanol (87), trachelanthamidine (88), elaeokanine A (89), and elaeokanine C (90) [26] (Scheme 7). Once the or-methoxy group has been installed via electrooxidation and nucleophilic capture of the intermediate by methanol, the product 84 is treated with enol ether 85 and titanium tetrachloride to affect C-C bond formation adjacent to nitrogen and afford 86. The latter served nicely in syntheses of both indolizidine alkaloids elaeokanine A (89) and C (90). 

Russian workers have continued their studies on the production of alkyl-pyrrolizidines from furan derivatives by catalytic dehydration. The original catalyst used was thorium oxide on alumina, but improved yields were obtained with zirconium oxide on alumina [Eq. (5)]. In the formation of... 

The final example in this section is classed as a 1,3-dipolar addition, as this is the key step in the reaction, although actual formation of the pyrrolizidine ring is by an intramolecular alkylation process. Tufariello and Tette showed that A -pyrroline-N-oxide added regioselectively in a 1,3-dipolar fashion to the dipolarophile to give an isoxazolidine (95) in 80% yield [Eq. (27)]. The pyrrolizidine ring was then formed by hydrogenolysis of the methanesulfonate derivative of 95 in 95% yield. The dehydration and reduction steps were not so efficient, and a mixture of reduction products was obtained. Half of this mixture was ( )-supinidine (96) and the remainder consisted of fully reduced isomeric 1-hydroxymethylpyrrolizidines. 

The cascade sequence was also used to synthesize indolizidine, pyrrolizidine, and quinolizidine structures. Thus, heating oximes 52 at 180 °C in a sealed tube provided cycloadducts 53 or 54 in 60-76% yields (equation (1)) (89TL2289). Each of the products were isolated as single diastereomers. When five-membered rings were obtained from the cycloaddition, cis-anti isomers (i.e. 53a,b) were formed, whereas formation of a six-membered ring led only to the cis-syn isomer (i.e. 54a,b). 

Another synthesis of a quaternary salt (8) was developed by Meyer and Sapianchiay for the purpose of studying the steric course of formation of the pyrrolizidine system.9 Photolysis of the N-chloroamine (9) in a Hofmann-Loeffler-Freytag reaction [Eq. (4)], gave an intermediate that yielded the pyrrolizidine salt (8) in an intramolecular N-alkylation. The product was the cis-isomer, reflecting the greater degree of strain in the trans-fusion of two five-membered rings. 

B.ii.e Carbonylation and Acylation. The keto function in pyrrolo[3,2-c]pyridin-4-ones and pyrido[3,4- ]pyrrolizidin-l-ones can be enolized and triflated to yield the substrates 72 and 73, respectively (Scheme 34). Replacement of the triflyloxy group by carbonylation is effected with palladium catalysis. Reaction of the pyrido[3,4-fc]-pyrrolizidin-l-ones 73 was complicated by formation of a by-product, namely, the 2-methoxy adduct 74. In the latter case competitive palladium-assisted elimination of the triflyloxy group leads to an imminium intermediate, which adds a methoxy group as a... 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

As has been stated above, reaction of n-allyl tricarbonyliron lactone complexes with amines in the presence of Lewis acids such as ZnQ2 results in the formation of the corresponding tricarbonyliron lactam complexes via an Sn2 reaction. These complexes (e.g. 46) may be converted by CAN to p-lac-tams such as 44 (Scheme 4.15) in an exactly analogous way to the method described above. Since p-lactams occur in numerous physiologically important natural products this is a valuable reaction sequence which has been applied to the synthesis of nocardicins and thienamydn. Recently a synthesis of pyrrolizidine alkaloids has been developed using this methodology. ... 

The pyrrolizidine natural products can be obtained by exploitation of the Petasis MCR for combining aldehydes, amines, and vinylboronic acids, as shown by Pyne and coworkers in 2008 [35]. Application of aldopentoses yields polyhydroxylated allyl amines, that provides opportunity for further derivatization to, for example, uniflorines. The MCR commences by boronate-assisted imine formation and protonation (111). Subsequent alkenyl transfer from the borate to the protonated imine delivers the secondary allyl amine 116 in excellent diastereoselectivity (Scheme 14.14). 

---