Regio and Diastereoselective Multicomponent 1,3-dipolar cycloadditions combining cyclic alpha-amino esters-aldehydes-dipolarophiles for the synthesis of pyrrolizidines

JOSÉ M. SANSANO-GIL; JUAN MANCEBO ARACIL; CARMEN NÁJERA

Congreso; 4th Brazil-Spain Workshop on Organic Chemistry; 2014

The diversification and evolution of secondary metabolites such as pyrrolizidine alkaloids constitutes a clear example of the confrontation betweern plants and microoganisms/insects. Natural PAs are frequently hydroxylated, O-alkylated or O-acylated at key positions of the bicyclic heterocycle. The synthesis of all these alkaloids is not so simple. They have been prepared by diastereoselective (4+2) cycloassitions using nitroalkenes and a chiral vinyl ether and by diastereoselective (2+2) dichloroketene-chiral enol ether cycloaddition, respectively. besides, main scaffolds were prepared by double reductive amination or through a biomimetic Mannich-type reaction, or by metathesis.In this work, a general synthesis of highly substituted pyrrolizidines can be performed by a multicmomponent 1,3-dipolar cycloaddition using proline ester hydrochlorides, aldehydes and dipolarophiles, at room temperature without catalyst or in the presence of AgOAc. In the case of (2S,4R)-4-hydroxyproline derivatives it is possible to obtain enantioenriched pyrrolizidines with high control of the regio. and diastereoselctivity affording the adducts 2,4-trans-2,5-trans according to an endo-approach and S-dipole conformation of the in situ generated azomethine ylide. For proline esters a similar regioselectivity and endo-diastereoselctivity are observed when dipole promotes an alfa-attack. However, when ethyl glyoxylate is used as aldehyde component the gamma.attack of the S-dipole takes place preferentially giving rise the opposite regioselectivity for the acrylic dipolarophiles, being crucial the role of silver acetate. In this case, the exo-adducts with a 2,3-cis-2,5-trans relative configuration are diastereoselectivity obtained.