A Practical Catalytic Asymmetric Addition of Alkyl Groups to Ketones

Abstract

Many catalysts will promote the asymmetric addition of alkylzinc reagents to aldehydes. In contrast, there are no reports of additions to ketones that are both general and highly enantioselective. We describe herein a practical catalytic asymmetric addition of ethyl groups to ketones. The catalyst is derived from reaction of camphor sulfonyl chloride and trans-1,2-diaminocyclohexane. The resulting diketone is reduced with NaBH4 to give the C2-symmetric exo diastereomer. Use of this ligand with titanium tetraisopropoxide and dialkylzinc at room temperature results in enantioselective addition of the alkyl group to the ketone. The resulting tertiary alcohols are isolated with high enantiomeric excess (all cases give greater than 87% ee, except one). The reaction has been run with 37 mmol (5 g) 3-methylacetophenone and 2 mol % catalyst to afford 73% yield of the resulting tertiary alcohol with 99% ee.

Catalytic asymmetric addition of diphenylzinc to cyclic α,β-unsaturated ketones

“…We have examined the use of our bis(sulfonamide) diol ligand (1) in the asymmetric addition of phenyl groups to cyclic ␣,␤-unsaturated ketones. Good to excellent enantioselectivities have been obtained with cyclic enones bearing alkyl substituents in the 2 position (71-97% enantiomeric excess).…”

“…1; ref. 1). When cyclic ␣,␤-unsaturated ketones were used as substrates, we found that the asymmetric addition reaction could be coupled with a diastereoselective epoxidation by using molecular oxygen as the oxidant to provide a one-pot synthesis of epoxy alcohols with high enantio-and diastereoselectivity (Eq.…”

“…These studies provide a solution to a long-standing problem in synthetic organic chemistry: the catalytic synthesis of tertiary alcohols from ketones with high enantioselectivity. Unlike related additions of dialkylzinc reagents to aldehyde substrates, which are promoted by hundreds of catalysts (3,4), only a few systems will catalyze alkyl additions to ketones (1,2,(5)(6)(7)(8), and most of them use high catalyst loadings and long reaction times (6)(7)(8).…”

Diethylzinc

“…4 Walsh and co-workers described also the synthesis of tertiary alcohols by the asymmetric addition of ZnEt 2 to ketones catalyzed by a titanium catalyst with a chiral diamine ligand. 5 (B) 1,4-Addition to Cyclic Enones: Alexakis and co-workers reported an asymmetric copper-catalyzed 1,4-addition of diethylzinc to cyclic enones using a phosphoramidite ligand, followed by C-enolate trapping resulting in the synthesis of α,β-disubstituted ketones with a high degree of stereoselectivity. 6 (C) 1,4-Addition to Reactive Acceptors: Carreira and co-workers developed the copper-catalyzed highly stereoselective conjugate addition of diethylzinc to Meldrum's acid derived acceptors with phosphoramidite ligands.…”

Titanium Tetraisopropoxide

“…This reaction was studied by Walsh et al using bis(sulfonamido) or BINOL/ Ti(i-PrO) 4 complexes, applied to aldehydes, 17 ketones 18 and a,b-unsaturated ketones. 19 In the case of 18, the reaction is totally chemoselective, as no conjugate addition compound was detected.…”