Pyrrolizidine alkaloids total synthesis

Morphinan and related compounds, synthesis of 88YGK626. Macrocyclic pyrrolizidine alkaloids, total synthesis of 88YGK693. Pyrrolizidine alkaloids, syntheses of 87YGK873 89CSR375,89YZ345, 89YZ685 90H(30)1231, 90MI58. 

Nitroalkenes are shown to be effective Michael acceptor B units in three sequential reactions (A + B + C coupling) in one reaction vessel. The sequence is initiated by enolate nucleophiles (A) and is terminated by aldehydes or acrylate electrophiles (C). The utility of this protocol is for rapid assembly of complex structures from simple and readily available components. A short total synthesis of a pyrrolizidine alkaloid is presented in Scheme 10.16.114... 

An intermediate 5-hydroxy-5,6-dihydro-2/7-pyrrolo[l,2- ][l,2]oxazin-7(4a//)-one 142 has been described in the total synthesis of (—)-loline, a pyrrolizidine alkaloid extracted from rye grass Lolium cuneatum. The key step of the synthesis was an intramolecular cycloaddition of acylnitrosodienes (obtained by in situ oxidation of the corresponding hydroxamic acids 143). This reaction generated predominantly the rro/o-stereoisomer that was further cleaved at the N-O bond with Na(Hg) and further elaborated in several steps to reach the target compound (Scheme 19) <2001J(P 1)1831 >. 

Scheme 11.14 The synthesis of building block 44 in the total synthesis of (+)-heliotridine, a necine base present in a large diversity of pyrrolizidine alkaloids [69], a)78 22 mixture of diastereomers.

A related oxime 304 was prepared for the total synthesis of 305, an unusual pyrrolizidine alkaloid isolated from the venom of a variety of thief ant... 

Hudlicky et al. (65) reported a formal stereoselective total synthesis of the oxygenated pyrrolizidine alkaloids platynecine (336), dihydroxyheliotridane (337), hastanecine (341), and tumeforcidine (342), involving an intramolecular azide-diene cycloadditions (Scheme 9.65). Intramolecular 1,3-dipolar cycloaddition of... 

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 %). 

The Lewis acid-promoted tandem inter[4 + 2]/intra[3 + 2]-cycloaddition of the (fumaroyloxy)nitroalkene (124) with the chiral /i-silylvinyl ether (125) is the key step in the total synthesis of (+)-crotanecine (126), the necine base of a number of pyrrolizidine alkaloids (Scheme 46).237 The tandem inter[4 + 2]/intra[3 + 2]-cycload-ditions of nitroalkenes (127) with dipolarophiles attached to the /f-carbon of a vinyl ether (128) provides a method of asymmetric synthesis of highly functionalized aminocyclopentanes (129) (Scheme 47).238 trans-2-( 1 -Methyl-phenylethyl)cyclohex-anol has been developed as a new auxiliary in tandem 4 + 2/3 + 2-cycloadditions of nitroalkenes.239 The scope and limitations of the bridged mode tandem inter-[4 + 2]/intra[3 + 2]-cycloadditions involving simple penta-1,4-dienes are described in detail.240 A tandem intermolecular/intramolecular Diels-Alder cycloaddition was successfiilly used to synthesize a B/C cA-fused taxane nucleus (130) in 50% overall... 

In addition to the syntheses of these classes mentioned in previous sections, RCM was applied to the total synthesis of the pyrrolizidine alkaloid (-)-croalbinecine and the indolizidine alkaloid (-)-coniceine <01TA2621, 00CC1027> (Scheme 69). 

DCP-hased Chiral Auxiliaries in Total Synthesis. DCP-based chiral auxiliaries have proven amenable to asymmetric total synthesis, including Denmark s syntheses of of the pyrrolizidine alkaloid (-)-rosmarinecine and the pentahydroxy pyrrolizidine alkaloid (+ )-casuarine. Denmark s synthesis of (+)-casuarine involves [4 + 2] cycloaddition of dienophile 15 with nitrobenzoate followed by [3 + 2] cycloaddition of the resulting nitronate 17 with a vinyl silane 18 (eq 10). During formation of the [4 + 2] cycloadduct, the relative configuration between C4 and C5 is a direct consequence of the vinyl ether geometry, while the stereochemistry at C6 is determined by the ability of the chiral auxiliary to differentiate the diastereotopic n faces (Re of Si) of the vinyl ether (termed internal diastereoselection). Thus, this tandem sequence... 

There have been numerous papers related to the total synthesis of bicyclic alkaloids, such as pyrrolizidines, indolizidines, and quinolizidines, because of their interesting biological activities (e.g., anticancer activity). 

As mentioned previously, acyliminium ions are electrophilic enough to react intramolecularly even with nonactivated alkenic ir-systems. These cyclization reactions have been recognized and elaborated as valuable tools in the stereoselective total synthesis of quinolizidine, indolizidine and pyrrolizidine alkaloids. A typical example from Speckamp s laboratory is the highly stereospecific acid-catalyzed cyclization of (81) to (83 Scheme 40), presumably via the corresponding acyliminium ion (82). Analogously, other more complex natural products, such as the antiulcerogenically active alkaloid ma-trine (85), can be built up with high stereocontrol (Scheme 41), with an enol ether function as a more electron-rich nucleophile for the intermediate iminium ion (84). ... 

Pyrrolizidines compounds have been produced in connection with syntheses of other types of natural products. For example, Gensler and Hu prepared the dioxopyrrolizidine ester (46) as an intermediate in the synthesis of ( + )-slaframine, an indolizidine alkaloid obtained from cultures of Rhizoctonia leguminicola. The pyrrolidone ester (47), prepared from l-glutamic acid [Eq. (14)], was optically active, but the cyclized product, formed in quantitative yield from 47, was completely racemized. The synthesis of 2-acetyl-1,3-dioxopyrrolizidine (48) was carried out by Kruger and Arndt to assist with their investigations on model compounds aimed toward the total synthesis of a-cyclopiazonic acid, the main toxic principle of Penicillium cyclopium The spectra of the product (48) obtained in 30% overall yield was typical of an intramolecularly H-bonded enolized )S-... 

The total synthesis of (+ )-dehydroheliotridine (4), a toxic metabolite of the pyrrolizidine alkaloids (e.g. lasiocarpine and heliotrine), has also been described.2 The pyrrole ring was obtained by reaction of l,6-dihydroxy-2,5-dicyanohexa-l,3,5-triene-l,6-dicarboxylic ester (5) with j3-alanine, which afforded the N-substituted pyrrole ester (6), together with the appropriate amide of oxalic acid. Careful hydrolysis of (6) with dilute alkali afforded the related tricarboxylic acid, which was converted, by Dieckmann cyclization, hydrolysis and decarboxylation, into the keto-acid (7). Esterification of (7) with diazomethane, followed by reduction with lithium aluminium hydride, finally afforded ( )-dehydroheliotridine (4), identical, except in optical rotation, with dehydroheliotridine obtained earlier by Culvenor et al.3... 

Gramain J-C, Remuson R, Vallee-Goyet D, Guilhem J, Lavaud C (1991) Total synthesis and determination of structure of the pyrrolizidine alkaloid curassanecine. J Nat Prod 54 1062-1067... 

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]. 

Moreover, recently the boronic acid Mannich reaction, mostly referred to as Petasis reaction [163,164], has evolved as a powerful entry to polyhydroxylated pyrrolizidine, indol-izidine, and tropane alkaloids, among others [165, 166]. For example, Pyne and coworkers disclosed a short total synthesis of calystegine (270) starting from (-)-o-lyxose in 4.7% overall yield (Scheme 11.55), which involved, besides a ring-closing metathesis, the Petasis reaction as key step [167]. In a similar fashion, castanospermine (86) was prepared in 14 steps from (-)-L-xylose in 1.5% overall yield (Scheme 11.55) [168]. 

The total synthesis of (—)-hastanecine (240) is illustrative (Scheme 16.54) [149]. (—)-Hastanecine is a pyrrolizidine alkaloid that can be prepared from nitroso acetal 241. The N—C(6) bond can be formed through a reductive alkylation upon hydrogenolysis, and N—C(l) bond can be formed through lactamization. The rales compiled in Figure 16.8 guide the retrosynthetic analysis for nitroso acetal 241. Because C(2) is not a stereogenic center in 240, dipolarophile 242 of any configuration can be used for the [3 + 2]... 

Couty et al. the reported on the total synthesis of a pyr-rolizidine alkaloid, (—)-absouline 294, which was isolated from new Caledonian plants and shows modest antiviral activity. Starting from 2-cyanoazetidine 290, they synthesized A-Boc-protected aminopyirohdine 291 after three steps with high yield and stereoselectivity. Then, C N alkylative cyclization was performed on 291 in the presence of triphenylphosphine to afford A-Boc-protected pyrrolizidine 292, which after deprotection followed by AA -dicyclohexylcarbodiimide (DCC) coupling with ( )-/ -methoxy cinnamic acid 293 afforded the alkaloid (—)-absouline 294 with good overall yield (Scheme 40.65). 

Kiyooka, S., T. Hase, and J. D. Edwards Pyrrolizidine Alkaloids. The Total Synthesis of Retusaminic Acid. Chem. Lett. 1973, 963. 

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). 

The most outstanding achievement of synthetic pyrrolizidine chemistry is the recently published69 total stereospecific synthesis of (+ )-retronecine, a constituent of many alkaloids (see Scheme 7). 

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