Densely substituted unnatural l- and d-prolines as catalysts for highly enantioselective stereodivergent (3 + 2) cycloadditions and aldol reactions

Abstract

Cycloaddition reaction between azomethine ylides and p-deficient alkenes leads to densely substituted L-and D-unnatural prolines. These (3 + 2) cycloadducts in turn catalyse the preparation of an offspring of unnatural endo-and exo-L-proline derivatives. These latter compounds are also efficient catalysts of aldol reactions and yield aldol adducts with the opposite stereochemistry obtained under natural L-Pro organocatalysis.

Asymmetric 1,3-Dipolar Cycloadditons of Stabilized Azomethine Ylides with Nitroalkenes

“…Under these reaction conditions, endo-5a·Cu(MeCN) 4 PF 6 afforded exo-cycloadducts 5 in good yield (83-90%), and both high diastereo-(up to 96:4 dr) and enantioselectivities (95->99% ee) when the reaction was performed at -20 ºC. However, 22·Cu(MeCN) 4 PF 6 chiral complex gave the opposite diastereoisomer endo-5 in good yield (79-85%), and not with so high diastereo-(up to 96:4 dr) and enantioselectivities (92-94% ee) when the reaction was performed at -80 ºC (Scheme 8) [9]. This is a clear example of fine tuning catalyst in order to obtain different stereoisomers maintaining a high efficiency of the processes.…”

“…This allowed the blockage of one of the two prochiral faces of the dipole favoring the mentioned endo-cycloadduct 5. However, this coordination of the nitro group was not available due to the coordination of the nitrogen atom of the pyrrolidine ring furnishing the exo-cycloadduct 5 [9].…”

“…This second step, involving a final metal-catalyzed intramolecular Mannich-type reaction, was completed in almost quantitative yield and excellent diastereoselectivity (>99:1 dr) (Scheme 4) [33]. Both molecules endo-trans-22 and endo-cis-5a were immediately tested as chiral ligands in combination with copper(I) salts in the enantioselective catalytic 1,3-DC of imino esters 6 with various dipolarophiles (including nitroalkenes) yielding cycloadducts in very good yields and good enantioselections (see, Scheme 8) [9].…”

“…Finally, the most simple prolinesexo-5 have been recently used as chiral organocatalysts in aldol reactions obtaining good to excellent diastereoselections and *Address correspondence to this author at the Departamento de Química Orgánica and Instituto de Síntesis Orgánica (ISO). Universidad de Alicante, E-03080-Alicante, Spain; Tel: +34-965903549; Fax: +34-965903549; E-mail: cnajera@ua.es; jmsansano@ua.es high enantiomeric ratios [9]. These applications and properties of the mentioned compounds represent a small part of the enormous interest of prolines and pyrrolidines in many scientific areas [10][11][12].…”

Coinage metal complexes as chiral catalysts for 1,3-dipolar cycloadditions

“…The most simple prolinesexo-46 have been recently used as chiral organocatalysts in aldol reactions [ 79 ]. In particular, for the asymmetric 1,3-DC of nitroalkenes as dipolarophiles chiral copper(I) complexes, formed from ferrocenyl-type phosphanes, have been mainly used as catalysts [80,81,82,83,84,85].Copper(I) complexes 47 [80,82], 48 [81,83], and 49 [79], generally afforded exo-cycloadducts, whereas the corresponding endo-diastereomers have been prepared using complex 50 [79]. On the other hand, when copper(II) triflate and chiral ligand PyBidine [86] were combined the resulting catalyst 51afforded mainly endo-cycloadducts.…”