Indolizidines natural synthesis

A complete review on the synthesis of indolizines has appeared <2000HOU(10)745>. This chapter is an extension of the reviews in CHEC(1984) <1984CHEC-I(4)443> and CHEC-II(1996) <1996CHEC-II(8)237>, mainly focusing on the development of synthetic methods aimed at the synthesis of natural alkaloids and important bioactive compounds containing the indolizidine nucleus. 

Often, in the synthesis of natural products containing the indolizidine substructure, it is necessary to modify a preformed indolizidine ring. This is the case in the synthesis of (+)-myrmicarin 217 191 where the key step is the closure of the third ring through an electrophilic substitution on the pyrrole nucleus (Scheme 45) <2000JOC2824>. 

The dipolar cycloaddition of nitronates has been applied to the synthesis of several natural products in the context of the tandem [4+2] / [3 + 2] nitroalkene cycloaddition process. All of these syntheses have focused on the construction of pyrrolidine, pyrrolizidine, and indolizidine alkaloids. For example, the synthesis of ( )-hastanecine (316), a necine alkaloid, involves the elaboration of a p-benzoy-loxynitroalkene 311 via [4 + 2] cycloaddition with a chiral vinyl ether (312) in the presence of a titanium based Lewis acid, to provide the nitronate 313 with high diastereo- and facial selectivity (Scheme 2.30) (69). The dipolar cycloaddition of... 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

During 1993, Daly and co-workers reviewed the alkaloids found in amphibians [5] and Takahata et al. focused on structural assignments and the synthesis of amphibian and polyhydroxylated indolizidines [6]. Wink reviewed the characterisation, natural distribution and biological activity of lupine alkaloids [7] and systematic updates on indolizidine and quinolizidine alkaloids are annually summarized by Michael [8-14]. 

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-... 

Synthesis of (—)-Laulimalide. Different approaches to the (3-hydroxy sulfone moiety needed for the olefination reaction are frequently used in the synthesis of natural products. For instance, a very common strategy consists of carbonyl reduction of the corresponding a-ketosulfone followed by reductive elimination. This sequence is employed in the synthesis of polyhydroxylated indolizidine alkaloids (Eq. 121),207 (+)-dihydromevinolin,268 pleraplysillin-1,269 amphidino-lide B,270 and the novel antitumor agent (—)-laulimalide (Eq. 158).271... 

Polyhydroxylated indolizidine alkaloids, due to their biological activity, have attracted considerable synthetic interest. The total synthesis of ( —)-l-qp/-swainsonine (250) from the chiral imine 238 (Scheme 58) and the parallel synthesis of (+ )-2,8,8a-tri-qp/-swainsonine (252) from the enantiomeric threose A-benzylimine 251, prepared from natural L-tartaric acid, provide further examples of the utility of tartaric acid in meeting the challenge of complex syntheses. A stereospecific 4 + 4 homologation utilizing 2-(trimethylsiloxy)furan (178) pro-... 

An example of nucleophilic fluorination to prepare an indolizidine derivative is found in the synthesis of a fluorinated analogue of (+ )-castanospermine, a naturally occurring glucosidase inhibitor. The epoxylactam 84 was treated with HF-Et3N. Stereospecific attack at position 6 gave, after acylation, the acetyl-protected... 

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