Synthesis of indolizidine alkaloid

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). 

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). ... 

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). 

The synthesis of indolizidine alkaloids, including tylophorine and 6-coniceine as well as Elaeocarpus alkaloids, by the intramolecular imino Diels-Alder method (cf. vol.12, p.71) has been pub-... 

B.I. The Claisen Condensation. A classical reaction is the condensation of an ester enolate with an ester, illustrated by the self-condensation of ethyl butanoate in the presence of sodium ethoxide to give 3-keto-ester 167. Initial reaction with the base, under thermodynamic control in this case, generates the enolate anion (165). This anion attacks the carbonyl of a second molecule of ethyl butanoate to give 166. Displacement of ethoxide generates ketone 167. As shown here, this reaction is known as the Claisen condensation. A synthetic example is taken from Lubell s synthesis of indolizidine alkaloids, in which diester 168 was treated with LiN(SiMe3)2 in THF at -78°C to give the self-condensation product 169, in 52% yield. 

In addition to the ahove-quoted methods, tertiary 3-lactams have heen reduced to the corresponding cyclic amines hy dropwise addition of MeOH to the refluxing mixture of NaBHa and substrate in t-BuOH, or hy using trifluoroethanol as solvent. This reaction was applied during a synthesis of indolizidine alkaloid swainso-nine for the reduction of lactam (1) to amine (2) (eq 5). ... 

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... 

A versatile intermediate for the synthesis of indolizidine alkaloids is the compound shown in Scheme 2.65. 

Yoda, H., Katoh, H., Ujihara, Y. and Takabe, K. (2001) SmI2-mediated hetero-coupUng reaction of lactams with aldehydes synthesis of indolizidine alkaloids, (—)-D-coniceine, (-l-)-5-epiindolizidine 167B and (-l-)-lentiginosine. Tetrahedron Lett., 42, 2509-12. 

Scheme 4.31 Smith Ill s synthesis of indolizidine alkaloids 223AB and 205B.

The second set of examples involves the use of thionium ions as electrophiles in inter- and intramolecular processes to obtain a-substituted sulfides (see 24 25, Scheme 20.7T which is the most common type of Pummerer reaction. Applications of this classical Pummerer rearrangement are exemplified in the synthesis of trans-solamin, the synthesis of indolizidine alkaloids, and the synthesis of the CDE ring of erinacine E. The first exanple fScheme 20.10 uses Pummerer chemistry in the generation of a thionium ion, which reacts in an intermolecular tin-mediated ene reaction the second one fScheme 20.11 uses Pummerer chemistry to introduce a nitrogen-containing heterocycle by intramolecular addition to form the coniceine core and the third example fScheme 20.12 is an intramolecular silicon-induced Pummerer reaction with oxygenated nucleophiles applied to the synthesis of a precursor of erinacine. Details of these Pummerer-based strategies are discussed below. 

In contrast to the previous examples, the preferred formation of linear aldehydes was the main target in some syntheses to construct a cyclic derivative with an appropriate ring size in the next step or for simply elongating a carbon chain. The linear aldehydes are the proper intermediates for the synthesis of indolizidine alkaloids [11], the tricyclic marine alkaloid lepadiformine [12], ACE inhibitors such as MDL 27210 and its analogues [13,14], and bryostatin, a remarkably potent anticancer agent [15]. Rhodium complexes of bisphosphite ligands provide one of the best known classes of linear-selective hydroformylation catalysts for simple ot-olefins. Except for the lepadiformine intermediate, where hydroformylation was carried out in the presence of the Rh(acac)(CO)2/P(OPh)3 catalyst system, in other... 

SCHEME 24.33. RRM-based synthesis of indolizidine alkaloid 25IF. 

An alternative intramolecular cyclization protocol, Ni(COD)2/PBu3/Et3SiH, was developed for the consideration of avoiding the 1,2-addition of EtjZn to the aldehyde when a complexed substrate was used. The synthesis of indolizidine alkaloid, (-i-)-allopumiliotoxin 267A, was accomplished using this protocol [197]. 

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