Indolizidine alkaloids total synthesis

Smith, A. B. Ill, Kim, D.-K. (2006). A general, convergent strategy for the construction of indolizidine alkaloids total synthesis of (—)-indolizidine 223AB and alkaloid (—)-205B. The Journal of Organic Chemistry, 71, 2547-2557. 

The intramolecular cycloaddition reaction of enamides has been exploited in alkaloid synthesis (81JOC3763). One successful application is provided by the total synthesis of the fused indolizidine 5 from 4 as a 1 1 mixture of epimers in 43% total yield 5 is a key intermediate in aspidosperma alkaloid synthesis (79JA3294). 

Novel synthetic procedures for indolizidine alkaloids were developed via a samarium diiodide-promoted carbon-nitrogen bond cleavage as a key step. Application of the procedure led to the total synthesis of (+)-(8R, 8aR)-perhydro-8-indolizidinol <2006H193>. 

In our group the diastereoselective 1,2-addition of organometallic reagents to aldehyde SAMP hydrazones was employed in the synthesis of several alkaloids and we have now extended our method to the efficient asymmetric synthesis of the poison-dart-frog indolizidine alkaloids 2091 and 223J and their enantiomers via a common late-stage intermediate amino nitrile (5R,8R,8aS)-63 [45]. This amino nitrile chemistry had previously been used by Polniaszek and Belmont in the first enantioselective total syntheses of 5,8-disubstituted indolizidine alkaloids [46]. They were able to prepare the indolizidines 205A (65) from 64 in one or two steps (Scheme 1.2.15). 

Perhydropyrido[l,2-fr][l,2]oxazine 10 was applied in the total synthesis of (-)-monomorine I, an indolizidine alkaloid, to control the stereoselectivity (09S655). 

The alio series of the pumiliotoxin A class have an additional hydroxyl group that has been placed at C-7 on the indolizidine ring, without assignment of configuration. Three members of the alio series have been assigned the tentative structures (7), (8), and (9).3 Pumiliotoxins A and B are relatively toxic, and comparable in potency to strychnine. Pumiliotoxin B has a potent cardiotonic and myotonic activity.3 An enantioselective total synthesis of pumiliotoxin A alkaloids from L-proline has already been announced.4... 

The seco-phenanthroindolizidine alkaloid septicine has been synthesized by a nitrone route. A cycloaddition of 1-pyrroline 1-oxide with 2,3-bis-(3,4-dimethoxyphenyl)butadiene gives two stereoisomeric isoxazolidines, one of which is converted into ( ) septicine.10 ( )-Tylophorine and 5-coniceine have been prepared by a new route that makes use of an intramolecular imino-Diels-Alder reaction.11 A stereoselective synthesis of 3,5-dialkyl-indolizidines has been applied to the synthesis of a stereoisomer of the trail pheromone of the Pharaoh ant and to a stereoisomer of gephyrotoxin 223.12 A stereoselective total synthesis of ( )-perhydrogephyrotoxin (21)13 and a simple synthesis of ( )-gephyran14 have been reported. 

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). 

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). ... 

Both reaction partners, i.e. the diene and the dienophile, may simultaneously be set free in situ, as illustrated in the total synthesis of the indolizidine alkaloid elaeokanine A (139 Scheme 64).Flash pyrolysis of (136) yields (138), presumably via the nonisolable dieneacylimine (137). 

The concise enantioselective total synthesis of (+)-monomorine I, a 3,5-dialkyl-substituted indolizidine alkaloid, was completed by S. Blechert et al. using a sequential cross-metathesis double reductive cyclization strategy. The enedione substrate was prepared in two steps. The Stetter reaction between the masked equivalent of acrolein and butyl vinyl ketone was followed by a retro Diels-Alder reaction under flash vacuum pyrolysis (FVP) conditions. 

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 same research group also utilized the Corey-Kim reaction to prepare aldehyde 30 from alcohol 29 in the total synthesis of polyhydroxylated indolizidine alkaloid castanospermine (31) and its C-6 epimer.7... 

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-... 

The indolizidine alkaloid (+ )-monomorine I (373), isolated from Pharaoh s ant Mono-morium pharaonis, is the first example of an indolizidine alkaloid found in the animal kingdom. One enantioselective total synthesis of 373 exploits an asymmetric cycloaddition of nitrone 370 to the chiral allylic ether 369, which is prepared from 349. The conversion of 349 to a tosylate followed by treatment with -propylmagnesium bromide in the presence of... 

Novel routes to p5UToles, indoles, and carbazoles - Applications in total synthesis of alkaloids including fused indolizidines, yohimbanes, Amarylhdaceae alkaloids, and carbazoles 05COC1601. 

Synthesis and absolute configuration of (+)-lentiginosine, indolizidine alkaloid, a potent and selective inhibitor of amyloglucosidase 07EJO1551. Total synthesis of antitumor pyrroloiminoquinone alkaloids discorhab-dins and makaluvamines 05COC1567. 

A similar approach is used for the synthesis of silaketal 6 as a key intermediate in a total synthesis of (+)-castanospennine and related indolizidine and pyrroUzidine alkaloids (eq 4). First, the triflate moiety in 1 is replaced by reaction with lithium buta-dienolate generated in situ from the reaction of 2,5-dihydrofuran and n-BuLi. Treatment of the monosubstituted intermediate with potassium nitroacetaldehyde in a chloroform-acetonitrile mixture yields the desired sila-tethered compound 6, which is then submitted to a Lewis acid-assisted tandem [4 -F 2]/[3 + 2]-cycloaddition. 

A total synthesis of pseudotabersonine (119) by Grieco et al. [39] utilizes both the aminoethylation (cf. Scheme 2.17) and tandem retro Diels-Alder/intramolecular aza Diels-Alder (cf. Scheme 2.18) protocols to construct spirofused indolizidine oxindoles, 122 and 123, which serve as precursors to dehydrosecodine 125 (Scheme 2.19). The pentacyclic backbone of the Aspidosperma alkaloid, pseudotabersonine, is postulated to be biogeni-cally [40] derived from a dehydrosecodine. 

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