Pyrrolizidines absolute configuration

If a molecule contains several asymmetric C atoms, then the diastereomers show diastereotopic shifts. Clionasterol (28a) and sitosterol (28b) for example, are two steroids that differ only in the absolute configuration at one carbon atom, C-24 Differing shifts of C nuclei close to this asymmetric C atom in 28a and b identify the two diastereomers including the absolute configuration of C-24 in both. The absolute configurations of carboxylic acids in pyrrolizidine ester alkaloids are also reflected in diastereotopic H and C shifts which is used in solving problem 54. 

Pyrrolizidine derivatives with at least one substituent, and particularly the pyrrolizidine alkaloid components, have one or more asymmetric carbon atoms. The stereochemistry of pyrrolizidine was clarified for the most part in the course of investigation of the naturally occurring pyrrolizidine alcohols. Here, the problems of relative and absolute configuration and of stereoisomeric transformations will be considered. 

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... 

Fig. 10. Structures of 3,5-disubstituted pyrrolizidines from dendrobatid and ranid frogs andbufonid toads (31,73,81, and J. W. Daly, H. M. Garraffo, andT. F. Spande, unpublished). Absolute configurations are unknown. It is assumed, based on analogy to other amphibian alkaloids, that n-alkyl side chains are present. The configurational nomenclature for these pyrrolizidines follows the system devised by Sonnet el at. (122) for 3,5-disubstituted indolizi-dines where the H-S and H-8 configurations are related to that at H-3 and are either cis (Z) or trans (E).

The tandem inter-[4+2]/intra-[3+2] cycloaddition process involving dienylsilyloxy nitroalkene 540 and chiral vinyl ether 541 in the presence of methylaluminium bis(2,6-diphenylphenoxide) (MAPh) as Lewis acid afforded the single cycloadduct 542 in 66% yield. On a preparative scale, a lower yield (49%) of the purified product was obtained (Scheme 126) <2001JOC4276>. The two-atom linker between the nitronate and the dipolarophile moieties in 540 and the configuration of the chiral auxiliary phenylcyclohexanol could be chosen to obtain the adduct 542 with the relative and absolute configuration at the newly formed stereocenters, as required in the pyrrolizidine alkaloid (-l-)-l-epiaustraline. 

There are four known, naturally occurring fully saturated pyrrolizidine diols. The relative stereochemistry of platynecine (43) is known from chemical interconversions of the bases, and the absolute configuration was defined by degradation of heliotridane (7) to S-(-i-)-3-methylheptane. ... 

The absolute configuration of (—)-supinidine (96) was established following the degradation of heliotridane (7) to S-(-f-)-3-methylheptane mentioned earlier (Section III,A). More recently, the enantiomeric (-1-)-supinidine has been isolated by Culvenor and Smith. This represents the first occurrence of an allylic amino alcohol derived from 8) -pyrrolizidine. 

The absolute configuration of monocrotalic acid (44), the necic acid component of monocrotaline (45), has been elucidated aside from the acid derived from retusamine, whose structure has been defined by X-ray crystallography, this is the first necic acid component of a pyrrolizidine diester alkaloid containing an eleven-membered ring to have its stereochemistry unambiguously established. 

Optically active fixed the double bond at the 1,2-position (138). Moreover, supinidine was thereby shown to be in the same stereochemical series as isoretronecanol (CXV) and (—)-heliotridane (CXXVIII) with the absolute configuration at Cg in isoretronecanol fixed as a (166), the complete representation of supinidine becomes CXXXI, 1-hydroxy-methyl-A -dehydro-(8a)-pyrrolizidine. The hydrogenations of supinine... 

Moreover, these workers were able to establish the relative configurations at the four asymmetric centers in the necine. Absolute configurations may now be assigned (166), so that rosmarinecine is fully described as 2a,7/3-dihydroxy-l -hydroxymethyl-(8a)-pyrrolizidine (CLV). 

With a knowledge of the structures of the necines and necic acids and with the location of ester linkages ascertained, it is possible to write structural formulas to represent the pyrrolizidine alkaloids. Configurations (absolute and relative) at asymmetric carbons and double bonds are indicated when the author feels that these have been established with a reasonable degree of certainty. Structures have not been provided where the information is deemed insufficient, so that not all of the alkaloids listed in Table 1 will be given representations. The alkaloids are divided into three main categories monoesters, diesters (two different necic acids), and cyclic diesters. The amine iV -oxides are not given since their structures are obvious from the amines. 

A number of closely related naturally occurring pyrrolizidine cyclic ethers have been identified.74 Four of these, loline (=festucine75) (119), norloline (120), lolinine (121), and decorticasine (122), have had their structures and relative configurations established by chemical methods. In addition, the relative stereochemistry of loline has been defined by an X-ray crystal structure determination of its dihydrochloride.76 The absolute configurations for all these alkaloid bases have now been established by the X-ray technique of anomalous dispersion using the same dihydrochloride of loline (119).7 7... 

There has been no report so far of a synthesis of (+)-hyacinthacines Ci, C4, and C5 bearing substituents at each carlxMi of the pyrrolizidine skeleton. Therefore, their absolute configurations have yet to be determined. Yu and colleagues described recently the total synthesis of the proposed structure of ( )-hyacinthacine C5 [21] based on an original nucleophilic addition of a dithiane onto the xylose-derived nitrone 62 followed by a Cope-House cycli-zation (Scheme 13). 

Contents E. HASLAM The Metabolism of Gallic Acid and Hexahydroxydi-phenic Acid in Higher Plants. — D. G. ROUX and D. FERREIRA The Direct Biomimetic Synthesis, Structure and Absolute Configuration of Angular and Linear Condensed Tannins. — ST. J. GOULD and ST. M. WEINREB Streptonigrin. — D. J. ROBINS The Pyrrolizidine Alkaloids. — J. W. DALY Alkaloids of Neotropical Poison Frogs (Dendrobatidae). 

Fig. 3.30 Unique platynedne-based pyrrolizidine alkaloids occurring in species of the intrageneric Ipomoea taxon subgenus Quamoclit, section Mina (Convolvulaceae) necine base residues = absolute configuration, aliphatic necic acid residues = relative configuration...

The imine 16 possesses all the carbon and nitrogen atoms of the pyrrolizidine fragment of amphorogynine C as well as the correct absolute configuration at C-3 and C-6 of the natural product. Although the transformation of 16 into amphorogynine C seems quite straightforward, the last steps of the synthesis required considerable experimentation. 

Macronecine (8) is a stereoisomer of petasinecine and has been isolated from only one alkaloid, macrophylline (Table 31). Aasen and Culvenor (2) synthesised macronecine from the same ester (3) used in the route to petasinecine (Scheme 2). Reduction of (3) with zinc and acetic acid gave (7) as the major product, from which the racemic pyrrolizidine diol was formed on reduction. Resolution gave the ( + )-isomer which was identical with natural ( + )-macronecine. The absolute configuration of macronecine follows from the work of Danilova and Utkin 94) who degraded macronecine to laburnine (9). 

Bates, R. B., and S. R. Morehead Absolute Configurations of Pyrrolizidine Alkaloids of the Loline Group. Tetrahedron Lett. 1972, 1629. 

Crout, D. H. G., and D. Whitehouse Absolute Configuration of 2,3-Dihydroxy-3-methylpentanoic Acid an Intermediate in the Biosynthesis of Isoleucine, and its Identity with the Esterifying Acid of the Pyrrolizidine Alkaloid Strigosine. J. Chem. Soc., Perkin Trans. I 1977, 544. 

Kochetkov, N. K., A. M. Likhosherstov, and V. N. Kulakov The Total Synthesis of Some Pyrrolizidine Alkaloids and Their Absolute Configuration. Tetrahedron 25,2313 (1969). 

Pyrrolizidine Alkaloids. The Absolute Configuration of Latifolic Acid and its... 

Matsumoto, T., M. Takahashi, and Y. Kashihara Pyrrolizidine Alkaloids. The Synthesis and Absolute Configuration of All Stereoisomers of Monocrotalic Acid. Bull. Chem. Soc. Japan 52, 3329 (1979). 

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