Synthesis of Indolizidine

Another Rhn-catalyzed decomposition of a a-diazoester as described by Sabe and coworkers [198] was used for the synthesis of indolizidine alkaloids (Scheme 6/2.8). It can be assumed that, first, an ammonium ylide is formed which then undergoes a 1,2-shift with ring-expansion. Thus, reaction of 6/2-40 with Rh2(OAc)4 led to a 72 28 mixture of 6/2-41 and 6/2-42 in 85 % yield. Cu(acac)2 can also be used with even better yields, but lower selectivity (65 35). 

Reactions where the reduction of a functionalized nitrogen, or the deprotection of an amine group, start a domino process with the sequential formation of the two rings of the indolizidine system, find many examples in the literature. A recent one is provided by the synthesis of (—)-indolizidine 223AB <20040L1493> (Scheme 10). 

An efficient sequential reaction process was developed from y-amino chlorides 42 with propargylate 41 (Scheme 16). In the proposed mechanism, after the alkylation of the nitrogen atom, a subsequent cyclization by the same nucleophilic center induced the formation of intermediate 43, which cyclized to afford the indolizidine 44 <20010L3927, 20050L705>. This synthetic approach found application in the synthesis of indolizidine 223A. 

An oxidative Mannich cyclization methodology allowed the synthesis of indolizidine skeletons. The oxidation of the a-silylamide 140 with ceric ammonium nitrate (CAN) formed in situ an iV-acylaminium cation, which cyclized to afford the bicyclic compound 141 (Scheme 35) <1998JOC841>. 

Several other examples are reported in the literature on the synthesis of indolizidine skeleton through the intramolecular nucleophilic attack of the six-membered ring nitrogen atom onto an electrophilic center such as an alkyl halide <20000L3861, 1997S95>, triflate <20010L711>, and esters <1998TL5693>. 

A new synthesis of indolizidine (—)-223AB was also reported <2006JOC2547>. 

A great number of methods used generally for the synthesis of cyclic compounds have also been used for the synthesis of indolizidines and partially reduced indolizines... 

The easily accessible imides may be attractive starting materials for a synthesis of indolizidines. Thus (208) is formed in 68% yield in a one-pot reaction shown in Scheme 31 (81TL719). 

Smith has employed a related process using the ligand 3 developed by Jiang to obtain a chiral propargyl alcohol. This served as a key building block in an elegant synthesis of (-)-indolizidine 223AB (Eq. 21) [26],... 

The faster halogen-metal exchange and controlled conformation in vinyl and aryl systems meant that aryllithiums and vinyllithiums can be cyclised remarkably efficiently onto cyclic vinylogous amides to give 179 and 180. 180 was used in a synthesis of (+)-indolizidine 209D.87... 

Interestingly, all other diols, tried as a protecting group on the acetal, led to lower diastereoselectivity of the addition. This synthetic strategy was used in the synthesis of indolizidine alkaloids,279 bis(l-arylethyl)amines,280 a protease inhibitor.281 The addition reaction of 1,2-bisimines, easily available from glyoxal and chiral cr-phenylethy-lamine, gives under optimized conditions a diastereomerically pure product, that was converted to a chiral 1,2-diamine. Interestingly, decrease of the temperature below the optimum (50 °C) leads to a sharp drop of the stereoselectivity (Scheme 96).282... 

Another fascinating intramolecular process involves the spirocyclic epoxide 103, which carries a pendant azide group. Under the influence of ethylaluminum chloride, this substrate undergoes Lewis acid assisted cyclization followed by an intramolecular Schmidt reaction and subsequent in situ reduction of the intermediate iminium species 105 upon addition of sodium borohydride. This protocol was used as a key step in a novel synthesis of indolizidine alkaloids of pharmaceutical interest <03OL583>. 

The asymmetric synthesis of indolizidine alkaloids is described utilizing a palladium-catalyzed amination process. Ionization of an allylic carbonate provides a symmetrical rr-allyl palladium complex, subsequent reaction with a protected homoallylamine gave the product in 93% yield and >99.5% ee (eq 5). ... 

This review describes structural diversity, structural identification and biological activity of simple indolizidine and quinolizidine alkaloids, and covers the period from 1994 to 1999. A review of stereoselective methods for the synthesis of indolizidines and quinolizidines will be pubUshed in this series in the near future. 

The synthesis of indolizidine 195B (450) has in general been the fortuitous result of indifferent diastereoselectivity in routes to its diastereomer monomorine I (427). The racemic alkaloid accompanied ( )-monomorine I, and sometimes other diastereomers, in several post-1985 syntheses (393,397,399,400,402,403). Enantioselective syntheses of 450 published during the period 1985-1993, most of them also producing 427, were discussed in Volume 44 of this treatise (2), while post-1993 enantioselective syntheses leading to mixtures of 427 and 450 were detailed in Section V.A of this chapter (404,410,413,415,419). A conference paper describing the synthesis of (+ )-450 and the C-5 epimer (+ )-595 was also highlighted in Volume 44 this work has subsequently been published with full experimental details (468). 

Nine routes to racemic indolizidine 223AB (rac-432), occasionally accompanied by diastereomers, were published between 1985 and 1994 (393,469-476), but subsequent syntheses all appear to have been enantioselective (vide infra). The only recent synthesis of indolizidine 239CD yielded the racemic alkaloid ( )-597 (477). 

The earlier literature pertaining to this small group of indolizidine alkaloids was described in Volume 28 of this treatise (/). More recent coverage may be found in a general survey of indolizidine alkaloids from plant and fungal sources 14), and in a review on the synthesis of indolizidine alkaloids (555). 

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