Pyrrolizidine bases

Allenes have also been used as substrates in free radical cyclizations. Dener and Hart demonstrated that such entries are valuable in constructing pyrrolizidine and indolizidine ring systems [71]. In a total synthesis of pyrrolizidine base (+)-heliotri-dine (340), compound 338 possessing an allene functionality was used as a key intermediate (Scheme 19.62). Tri-n-butyltin radical-mediated carbon-selenium bond homolysis of 338 followed by the addition of the free radical to the allene moiety... 

Stereoselective addition of hydrogen to a C=C double bond of an (S)-proline derivation was applied in the total synthesis of gephyrotoxin, a biologically active alkaloid 87). Optically active pyrrolizidine bases have been synthesized by Robins and Sakdarat88) from chiral hydroxyproline derivatives by hydrogenation (ds > 60 %). 

As already mentioned, this route has been especially important for the preparation of naturally occurring pyrrolizidine bases. Recently, it afforded synthetic 1-hydroxymethylpyrrolizidine, 1-hydroxy-methyl-7-hydroxypyrrolizidine,andl-hydroxymethyl-7-hydroxy-l,2-dehydropyrrolizidine (retronecine). 

Rapid advances in the synthesis of naturally occurring pyrrolizidine bases can be expected, and the most promising method for this purpose is the Dieckmann cyclization of pyrrolidine derivatives. 

The absolute configurations of pyrrolizidine bases were established only very recently. Leonard84 attempted to solve the problem by comparing the shifts of molecular rotation of isoretronecanol derivatives with analogous shifts in the lupinine series. However, it was demonstrated later that this approach led to incorrect conclusions. 

The absolute configuration was also established unequivocally for C-8 of naturally occurring pyrrolizidine bases.88 It was demonstrated in the course of the structural analysis of isoheliotridene (146), obtained by degradation of the alkaloid monocrotaline, that ozonolysis of this compound affords 2-acetylpyrrolidine-l-acetic acid (147).66 The (— )-methyl ester of this acid was condensed with methylmagnesium iodide to give (— )-l-(2-hydroxy-2-methylpropyl)-2-(l-hydroxy-l-methylethyl)pyrrolidine (148). The same glycol (148) was obtained... 

The absolute configurations of the alkaloid 1-methylenepyrrolizi-dine and related naturally occurring pyrrolizidine bases were also established by stereospecific synthesis.89... 

Pyrrolizidine bases readily form A-oxides. Many pyrrolizidine alkaloids occur in plants in the form both of the bases and the A-oxides transformation of the tertiary amine into the A-oxide is closely related to the vegetation period.97-99 The oxidation, as well as the reverse reaction, can be readily accomplished by chemical methods. For example, the alkaloid trachelanthamine, when treated with hydrogen peroxide, affords the alkaloid trachelanthine (trachelanthamine A-oxide), the latter reverting to trachelanthamine when reduced with sulfur dioxide.100... 

Biogenetic pathways leading to naturally occurring pyrrolizidine bases were proposed by Robinson, Schopf, and Lukefi (see, e.g., refs. 119-121) in their publications concerned with the biogenesis of alkaloids. The most probable precursors of the pyrrolizidine system are commonly accepted to be ornithine (176), hydroxyomithine (177), and their biogenetic equivalents. It is noteworthy that ( + )- -hydroxy-jV-methylnorvaline (178) (structurally related to ornithine) was isolated... 

Pyrrolizidine alkaloids have a wide distribution, but are characteristic of certain genera of the Boraginaceae (e.g. Heliotropium, Cynoglossum, and Symphytum), the Compositae/Asteraceae (e.g. Senecio) and the Leguminosae/Fabaceae (e.g. Crotalaria). The pyrrolizidine bases rarely occur in the free form, but are generally found as esters with rare mono- or di-basic acids, the necic acids. Thus, senecionine (Figure 6.18) from Senecio species is a diester of retronecine with senecic acid. Inspection of the ten-carbon skeleton... 

The Baylis-Hillman reaction is rendered enantioselective in the presence of a chiral pyrrolizidine base 51. ... 

There are only two known, naturally occurring trihydric saturated pyrrolizidine bases. The relative stereochemistry of rosmarinecine (123) was determined by Warren and co-workers. For the other base, croalbinecine... 

Culvenor and co-workers have completed a major study of the H-NMR spectra of natural pyrrolizidine bases in the free and esterified states. A detailed analysis was made of the spectra of retronecine (127) and its C-7 epimer, heliotridine (109). From consideration of the coupling constants in these two bases, it was concluded that retronecine and its derivatives have an exo-buckled conformation, whereas heliotridine and its derivatives are usually a mixture of rapidly interconverting exo- and endo-buckled con-formers of approximately equal populations. This same situation was shown to exist by Pachler et al. in their study of heliotridene (133). Furthermore, it was demonstrated that the proportion of endo-buckled form increased to about 75% on acidification. 

The mass spectra of saturated heterocyclic N-oxides generally show the presence of the ions M-16, M-17, and M-18. Abdullaev et al. have demonstrated that this holds true for pyrrolizidine bases also. Peaks corresponding to the free bases were also present, together with ions formed by dehydration, dehydrogenation, and isomerization of the nucleus. 

Many esters, both naturally occurring and semisynthetic, have been prepared by esterification of hydroxy-substituted pyrrolizidine bases. Mattocks synthesized a range of retronecine diesters by heating retronecine (127) hydrochloride with acid chlorides.Mattocks also converted retronecine into the corresponding amine, retronamine, from which amide analogs of pyrrolizidine esters were prepared [Eq. (35)]. 

Robinson s original suggestion that the natural pyrrolizidine bases are derived in vivo from two molecules of ornithine (149) has been supported by studies using C-labeled compounds. Ornithine has been shown to be a specific precursor for the pyrrolizidine nucleus present in a variety of alkaloids. The feeding experiments carried out to date are listed in Table I. Three groups of workers have obtained labeled alkaloids after feeding C-labeled ornithines.Hydrolysis of the alkaloid to yield the free base, retronecine (127), has established that almost all the radioactivity is in the base portion. It is likely that ornithine is incorporated into retronecine after decarboxylation to putrescine (150) [Eq. (40)] since labeled putrescine is also specifically incorporated into retronecine (Table I). 

There are only two known, naturally occurring trihydric saturated pyrrolizidine bases. The relative stereochemistry of rosmarinecine (123) was determined by Warren and co-workers.78 For the other base, croalbinecine (124), the chirality at C-l, C-7, and C-8 was defined by Sawhney et al.19 by correlation with turneforcidine (113) as shown in Eq. (33). The location of the third hydroxy group at C-2, indicated by NMR spectroscopy, was confirmed by decoupling experiments. It was further suggested by these workers79 that the configuration at C-2 is /i-hydroxy, on the basis of the... 

The only example of this type of base is crotanecine (126), and its structure and stereochemistry were deduced by comparison of its NMR and mass spectra with those of the most widespread pyrrolizidine base, retronecine (127).84 The magnitude of the vicinal coupling constants of the protons on C-5 of crotanecine (126), 75 6 = 9.5 Hz and 75a 6 = 6.5 Hz, are consistent with the 6/ -hydroxy group and an exo-buckled ring. The other vicinal coupling constants, J6x l = J18 = 3.5 Hz are indicative of a 7/ -hydroxy group, as in retronecine (127). 

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