Enantioselective Synthesis of α-Quaternary Isochromanes by Oxidative Aminocatalysis and Gold Catalysis.

A novel strategy that combines oxidative aminocatalysis and gold catalysis allows the preparation of chiral α-quaternary isochromanes, a motif that is prevalent in natural products and synthetic bioactive compounds. In the first step, α-branched aldehydes and propargylic alcohols are transformed into α-quaternary ethers with excellent optical purities (>90% ee) via oxidative umpolung with DDQ and an amino acid-derived primary amine catalyst. Subsequent gold(I)-catalyzed intramolecular hydroarylation affords the isochromane products with retention of the quaternary stereocenter. A second approach explores the use of allylic alcohols as reaction partners for the oxidative coupling to furnish α-quaternary ethers with generally lower enantiopurities. Stereoretentive cyclization to isochromane products is achieved via intramolecular Friedel-Crafts type alkylation with allylic acetates as a reactive handle. A number of synthetic elaborations and a biological study on these α-quaternary isochromanes highlight the potential applicability of the presented method.

Access to Spiropyrazolone-butenolides through NHC-Catalyzed [3 + 2]-Asymmetric Annulation of 3-Bromoenals and 1H-Pyrazol-4,5-diones.

The stereoselective synthesis of spirocyclic pyrazolin-5-ones by N-heterocyclic carbene (NHC) organocatalysis has been less studied so far. For this reason and considering the interest of this class of compounds, here, we present the NHC-catalyzed [3 + 2]-asymmetric annulation of ß-bromoenals and 1H-pyrazol-4,5-diones that achieves to produce chiral spiropyrazolone-butenolides. The synthesis is general for aryl and heteroaryl ß-bromo-α,ß-unsaturated aldehydes and 1,3-disubstituted pyrazolones. The spirobutenolides have been obtained in good yields (up to 88%) and enantioselectivities (up to 97:3 er). This constitutes the first described example using pyrazoldiones as the starting materials for this class of spiro compounds.

Organocatalytic asymmetric synthesis of oxazolidino spiropyrazolinones via N,O-acetalization/aza Michael addition domino reaction between N-Boc pyrazolinone ketimines and γ-hydroxyenones.

A squaramide-catalyzed asymmetric N,O-acetalization/aza Michael addition domino reaction between N-Boc ketimines derived from pyrazolin-5-ones and γ-hydroxyenones has been developed for the construction of pyrazolinone embedded spirooxazolidines. A hydroquinine derived bifunctional squaramide catalyst was found to be the most effective for this cascade spiroannulation. This new protocol allows the generation of two stereocenters and the desired products are obtained in good yields with moderate to good diastereoselectivities (up to 3.3 : 1 dr) and high enantioselectivities (up to >99% ee) from a range of substituted N-Boc pyrazolinone ketimines and γ-hydroxyenones. The developed protocol is amenable for a scale-up reaction.

Squaramide-Catalyzed Asymmetric Mannich Reaction between 1,3-Dicarbonyl Compounds and Pyrazolinone Ketimines: A Pathway to Enantioenriched 4-Pyrazolyl- and 4-Isoxazolyl-4-aminopyrazolone Derivatives.

A series of N-Boc ketimines derived from pyrazolin-5-ones have been used as electrophiles in enantioselective Mannich reactions with different 1,3-dicarbonyl compounds. This method provides a direct pathway to access the 4-amino-5-pyrazolone derivatives bearing a quaternary substituted stereocenter and containing two privileged structure motifs, the ß-diketone and pyrazolinone substructures. The adducts were obtained in excellent yields (up to 90%) and enantioselectivities (up to 94:6 er) by employing a very low loading of 2 mol% of a quinine-derived bifunctional squaramide as an organocatalyst for a wide range of substrates. In addition, the utility of the obtained products was demonstrated through one step transformations to enantioenriched diheterocyclic systems (4-pyrazolyl-pyrazolone and 4-isoxazolyl-pyrazolone), potentially promising candidates for drug discovery.