Formation of Quaternary Stereogenic Centers by Copper‐Catalyzed Asymmetric Conjugate Addition Reactions of Alkenylaluminums to Trisubstituted Enones

Abstract

Alkenylaluminums undergo asymmetric copper-catalyzed conjugate addition (ACA) to β-substituted enones allowing the formation of stereogenic all-carbon quaternary centers. Phosphinamine-copper complexes proved to be particularly active and selective compared with phosphoramidite ligands. After extensive optimization, high enantioselectivities (up to 96% ee) were obtained for the addition of alkenylalanes to β-substituted enones. Two strategies for the generation of the requisite alkenylaluminums were explored allowing for the introduction of aryl- and alkyl-substituted alkenyl nucleophiles. Moreover, alkyl-substituted phosphinamine (SimplePhos) ligands were identified for the first time as highly efficient ligands for the Cu-catalyzed ACA.

Catalytic enantioselective synthesis of quaternary carbon stereocentres

“…6 for conjugate additions to 3-methyl-2-cyclohexen-1-one ( 54 ). Copper-catalyzed additions of various alkyl-, 39 alkenyl-, 40 and arylaluminum 41 compounds to cyclic enones in the presence of phosphoramidite ligands such as 58 have been described by Alexakis and co-workers (e.g., 54→55 , Fig. 6a).…”

“…The upper segment of the Figure depicts several Cu-catalyzed conjugate additions to 3-methyl-2-cyclohexen-1-one ( 54 ) that form new quaternary stereocenters: a , The addition of an arylaluminum compound to 54 to form cyclohexanone 55 . 40 CuTC, copper(I) thiophene-2-carboxylate; Ph, phenyl; Et, ethyl. b , The addition of a trialkylaluminum compound to 54 to form cyclohexanone 56 .…”

Copper(II) Trifluoromethanesulfonate

“…Alkenylaluminum species undergo asymmetric Cu(OTf) 2catalyzed conjugate addition to β-substituted enones. 56 Optimal enantioselectivities were usually obtained with copper(I) thiophene-2-carboxylate, Cu(OTf) 2 affording inferior enantioselectivities (up to 64% ee). Sugar-based phosphoramidite ligand was also studied in the asymmetric Cu-catalyzed conjugate addition reactions of trimethylaluminum to β-substituted enones, for which Cu(OTf) 2 afforded a low enantioselectivity (12% ee).…”

Formation of Quaternary Stereocentres by Copper-Catalysed Enantioselective Conjugate Addition Reaction

“…Copper catalysed ECA of organoaluminium reagents to -aryl cyclohexenones by Alexakis [47,48].Regarding the challenging -substituted cyclopenten-2-one substrates, phosphinamine ligands give moderate, comparable enantioselectivities to phosphoramidites, as shown in Scheme 15.Scheme 15. Copper-phosphinamine catalysed ECA of organoaluminium reagents to -substituted cyclopentenones by Alexakis [47,48].The tandem hydroalumination-ECA process to β-substituted cyclic enones with phosphinamine ligands also works very efficiently (Scheme 16) [49,50]. The best copper source for this catalytic system is copper (II) naphthenate, which is cheaper than the CuTC used in previous methodologies and can be used as a stock solution.…”

“…The tandem hydroalumination-ECA process to β-substituted cyclic enones with phosphinamine ligands also works very efficiently (Scheme 16) [49,50]. The best copper source for this catalytic system is copper (II) naphthenate, which is cheaper than the CuTC used in previous methodologies and can be used as a stock solution.…”