Pyrrolizidine diols

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. ... 

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). 

Selective synthesis of diesters of the pyrrolizidine diols has proved more difficult. A number of semisynthetic pyrrolizidine diesters were prepared by CuLVENOR etal. 81) by acylation of heliotridine (79) with various acyl chlorides. Selective acylation at C-9 of heliotridine and retronecine (18) is possible by conversion of the base into its 1-chloromethyl derivative, followed by nucleophilic substitution with the appropriate carboxylate anion. 

Eupatorieae Tribe.—Nine Eupatorium species that are found in the U.S.A. have been screened for pyrrolizidine alkaloids by Herz et al.2i Intermedine (42) (crystalline for the first time) and echinatine were isolated from Conoclidium coelestinum (L.) DC. (syn. Eupatorium coelestinum L.). Intermedine (42) and lycopsamine (41) were present in E. compositifolium Walt. These diastereoisomeric diols were separated as their borate complexes.29 Rinderine and 7-angelyl-heliotridine (43) were isolated from E. altissimum L.28... 

Several applications of this new approach have recently been reported. A series of pyrrolizidine diesters (94) have been synthesized by Anderson and Corey using a range of N-acylproline derivatives. The diesters corresponding to 91 were reduced with lithium aluminum hydride, and the diols were esterified to give 94. Some of these diesters had antileukemic activity. 

This technique has now been extended for use on h.p.l.c., and the alkaloids from comfrey (Symphytum spp.) were separated. Diastereoisomeric pyrrolizidine alkaloid monoesters containing a vicinal diol were previously separated as their borate complexes (cf. Vol. 12, p. 62). Related diastereoisomeric alkaloids have... 

Concomitant loss of the a-methyl-p-methoxybenzyl group of 48 led to the resulting pyrrolizidine 49 as a single diastereomer, after crystallization from the crude reaction mixture. Reduction of the hydroiodide salt 49 led to the diol 50 in 87% yield. Diol oxidative cleavage and deprotection in 51 finally afforded the 7a-epimer of hyacinthacine Ai 52 with a final 10% overall yield (nine steps from 2,3,5-tri-O-benzyl-ribofuranose Scheme 8). 

Geissman-Weiss lactone is an important intermediate in the synthesis of a number of necine bases (pyrrolizidine alkaloids). The palladium-catalyzed car-bonylative cyclization of 3-hydroxy-4-pentenylamine to the Geissman-Weiss lactone was reported in 1991 and later in 1996 (Scheme 10.5) [47 9]. This methodology was also applied in the total synthesis of C19 lipid diols [50]. 

The reductive cyclization of N-(w-iodoalkyl)succinimides induced by samarium(II) iodide was disclosed by Ha et al. as a novel method for making pyrrolizidines and indoUzidines (Scheme 46). " In the apphcation of the method to the synthesis of (+)-lentiginosine (127), reaction of N-(4-iodo-butyl)tartarimide (+)-335 with samarium(II) iodide in the presence of the iron(III)—tris(dibenzoylmethane) complex as catalyst produced the unsaturated indolizidin-3-one (+)-336 in 82% yield. Reduction of the bridgehead alkene was accomplished with triethylsilane and trifluoroacetic acid via an intermediate acyliminium ion, giving (+)-337 as the sole product in 93% yield. Routine hydrolysis of the silyl ethers produced the known diol (+)-177, after which reduction of the lactam with Hthium aluminum hydride then completed this short synthesis of (+)-127. 

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