Indolizidines alkaloids, bicyclic

Table 1 Structure of indolizidine alkaloids (bicyclic gephyrotoxins) synthesized since 1995...

An intramolecular palladium-catalyzed tandem cyclization of dienamides 67 in which the amide nucleophile adds twice has been developed (equation 29)60. This reaction constitutes a formal [4+1] cycloaddition and provides a new route to pyrrolizidine and indolizidine alkaloids. Reaction of dienamides 67 in the presence of catalytic amounts of Pd(OAc)2 and CUCI2/O2 as the oxidant afforded bicyclic compounds 68 in good yields. The pyrrolizidine derivative 68 (R = Me, n = 1) was transformed to the alkaloid ( )-heliotridane. 

Swainsonine is a trihydroxylated bicyclic indolizidine alkaloid with four chiral centres, whose relative stereochemistry was determined by X-ray crystallographic analysis and the absolute configuration was deduced on the basis of biosynthetic and asymmetric induction studies, and then confirmed by an enantiospecific synthesis from D-mannose [2a]. 

The previous review on Nuphar (water-lily) alkaloids in this treatise appeared in Volume 35, and covered the period 1974-1987 (7). It overlapped in part with the treatment of simple bicyclic Nuphar metabolites in Volume 28 (7). Nuphar alkaloids include sesquiterpenoid monomeric (C15) piperidine and quinolizidine alkaloids as well as more complex dimeric (C30) sulfur-containing metabolites. Related metabolites isolated from the scent glands of the Canadian beaver, Castor fiber, also include a unique indolizidine alkaloid 944 606). Only the indolizidine and simple quinolizidine alkaloids are relevant to the present review. Compounds mentioned in the ensuing discussion are illustrated in Fig. 18. 

Removing the Me3Si and Boc groups and redrawing the structure reveals the amino acid 96 that cyclises in acid solution to bicyclic 97 having the skeleton of the indolizidine alkaloids. Further steps lead to (-)-petasinecine 98. This sequence looks involved but in fact only three intermediates are isolated 92, 96, and one between 97 and 98. 

This year has seen continued interest in synthesis of indolizidine alkaloids and related compounds from sugars. o-Arabinose derivative 256 was homologated by Wittig reaction, Mitsunobu-type azidation affording 257. Subsequent epoxida-tion, and bicycle construction via double alkylation through epoxide opening and JV-alkylation, followed by full debenzylation afforded diastereomers 258 and 259. 2... 

The epoxide-initiated Schmidt reaction proceeds in a similar fashion to the mercury-promoted version. Treatment of epoxyazide 40 with a Lewis acid brings about cyclization to give the aminodiazonium intermediate 42, regioslective ring expansion results in the bicyclic iminium ion 43, and in situ reduction of 43 affords 5-hydroxymethyl azabicyclic compound 44. This alcohol has been converted to indolizidine alkaloids 167B and 209D. 

The intramolecular oxidation using nitrogen nucleophiles was developed further by using an amide with the ability to undergo a twofold attack on the diene (Scheme 12). This leads to a bicyclic system and constitutes a useful [4 + 1] intramolecular cycloaddition, which gives access to pyrrolizidine and indolizidine alkaloids. " ... 

Following the pioneering work on the synthesis of [x.3.0] bicychc systems by RRM from norbornene derivatives [35], Aube et al. applied this strategy to synthesize indolizidine alkaloid 251F, where enone 76 was obtained from the rearrangement of norbornene 75 (Scheme 11.20) (36). Early attempts afforded the desired product in only poor yield (30%) mainly because of olefin oligomerization. Under an atmosphere of ethylene, it was possible to optimize the metathesis cascade and the bicyclic compound 76 was isolated in 93% yield with the use of catalyst [Ru]-I (5 mol%). 

Bicyclic alkaloids. Nagao et al. have developed a general synthesis of chiral bicyclic alkaloids with a nitrogen atom at the ring juncture, such as pyrrolizidines [5.5], quinolizidines [6.6], and indolizidines [6.5], based on a highly diastereose-lective alkylation of 3-a>-chloroacyl-(4S)-isopropyl-l,3-thiazolidine-2-thiones (1, m = 1,2) with 5-acetoxy-2-pyrrolidinone (2, n = 1) or 6-acetoxy-2-piperidinone (2, n = 2). Thus the tin enolate of 1 (m = 1), prepared with Sn(OTf) and N-... 

The amphibian alkaloids considered to be 3,5-disubstituted indolizidines are tabulated below. Two other bicyclic alkaloids, proposed as monosub-stituted indolizidines in an earlier review, are included. These are 167B, which was considered likely to be a 5-n-propylindolizidine, based on its mass spectrum and biosynthetic considerations, and 209D, which was considered likely to be a 5-n-hexylindolizidine. These two indolizidines have been synthesized (130,131), but efforts to compare the synthetic indolizidines to natural 167B and 209D were thwarted when the natural trace alkaloids could no longer be detected in extracts. Structures of relatively well-characterized 3,5-disubstituted indolizidines from amphibians are shown in Fig. 11. 

The monocyclic 2,6-disubstituted piperidines have been considered as possible precursors for dendrobatid alkaloids containing piperidine rings, such as the histrionicotoxins, decahydroquinolines, and gephyrotoxins (see Ref. J). Similarly, the monocyclic 2,5-disubstituted pyrrolidines have been considered as possible precursors for dendrobatid alkaloids containing pyrrolidine rings, such as the pumiliotoxins, the indolizidines, and now the pyrrolizidines (see Ref. 5). It should be noted that 2,6-disubstituted piperidines and 2,5-disubstituted pyrrolidines occur only rarely in dendrobatid frogs, while in ants they appear as major venom constituents, along with pyrrolizidines and indolizidines. It has been proposed that the monocyclic piperidines and pyrrolidines may serve as biosynthetic precursors of the bicyclic alkaloids in ants 125,134). 

A new convenient procedure for the chiral alkylation of 5-acetoxy-2-pyrrolidinone (91) and 6-acetoxy-2-piperidinone (92) has been developed. This procedure should be useful for an extremely short chiral synthesis of the bicyclic alkaloids involving pyrrolizidine, indolizidine, and quinolizidine skeletons (88JA289). 

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). 

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