Bifunctional squaramide and thiosquaramide organocatalysts were assessed in a stereoselective Michael addition of aldehydes to nitroalkenes. Organocatalysts feature pyrrolidine unit for enamine activation of aldehydes and hydrogen bond donating fragment for nitroalkene activation. The corresponding Michael adducts were obtained in good yields and good to high enantiomeric purities. Solvent‐free conditions were also tested but did not provide any significant improvement. Michael adducts were transformed into chiral pyrrolidines via reductive cyclization.
Azlactones, a potent building block for the synthesis of complex molecules, have been explored in an organocatalytic Mannich reaction with protected imines. In this study, azlactones containing a propargyl substituent were employed for the first time in organocatalysis so far. The catalytically active species responsible for high enantioselectivity with substrate containing such a small linear substituent is assembled in situ from a bifunctional thiourea, prone to dimerization, and an organic acid, as evidenced by DOSY NMR. The resulting α,β‐diamino acid derivatives were subjected to further derivatization: as an example, gold‐catalyzed intramolecular hydroamination of alkynes gave chiral spirocyclic dihydropyrrole. Alternatively, related squaramide catalyst enabled a Mannich reaction of azlactones with N‐aryl or alkyl glyoxylate imines. Reduction of these adducts gave access to 2,3‐diaminobutyrolactones or 2,3‐diamino‐1,4‐diol with a tertiary and a quaternary stereocenter.
Enantioselective organocatalytic Michael additions serve as the key step in syntheses of chiral drugs based on γ-aminobutyric acid. The applicability of various squaramide catalysts for these Michael-type reactions has been assessed. Very good results in terms both activity and enantioselectivity were obtained in the Michael addition of dimethyl malonate to β-nitrostyrenes. On the other hand, a complementary approach, the addition of nitromethane to cinnamaldehydes, worked well with a squaramide catalyst possessing an adjacent pyrrolidine moiety. The corresponding Michael adducts obtained in the best conditions are suitable chiral intermediates for the synthesis of therapeutically useful GABA derivatives. Polymer-immobilized squaramides afforded the Michael adduct in high enantiomeric purity, but yield deterioration was observed between runs. Two different formal total syntheses of baclofen have also been accomplished.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.