Enantioselective One-Pot Conjugate Addition of Grignard Reagents to Cyclic Enones Followed by Amidomethylation

Abstract

Enantioselective conjugate addition of Grignard reagents to enones, catalyzed by Cu-Taniaphos or Josiphos complex, affords chiral enolates. Ensuing one-pot Mannich reaction with TiCl(4)-generated imine leads to aminocarbonyl compounds with benzyloxycarbonyl-protected nitrogen. Both diastereomers of these compounds are isolated in moderate yields but high enantiomeric purities (up to er 97.5:2.5).

Asymmetric Transition-Metal Catalysis in the Formation and Functionalization of Metal Enolates

“…In situ formed Mg enolates 36b were trapped with TiCl 4 -generated imine, leading to Cbz-protected aminocarbonyl compounds 63 in moderate yields but with high enantiomeric purities (up to 92% ee). 69 We have also examined ferrocenyl phosphane carbene ligands in Cu-catalyzed 1,4-addition to different types of Michael acceptors. 70 The Mg enolates 36 were then trapped with imine or benzaldehyde, leading to the formation of products in moderate yields and with high diastereoselectivities.…”

Domino Reactions Initiated by Enantioselective Cu‐Catalyzed Conjugate Addition

“…[40] Magnesium enolates generated by Cu-Taniaphos-or Cu-Josiphos-catalyzed conjugate additions of Grignard reagents to enones indeed reacted with an amidomethylating reagent to produce βamino ketones 56 (Scheme 23) with high enantiomeric purities (ee ranging from 60-95 %) but only medium diastereoselectivities (typically trans/cis 2:1). [41] Titanium tetrachloride is necessary for activation of the amidomethylating reagent. The presumed imine species were not observed; NMR experiments confirmed only oxygen complexation to titanium.…”

“…The study was inspired by the work of Evans and Seebach, who used reagents of the CbzNHCH 2 OR type for introduction of aminomethyl moieties 40. Magnesium enolates generated by Cu‐Taniaphos‐ or Cu‐Josiphos‐catalyzed conjugate additions of Grignard reagents to enones indeed reacted with an amidomethylating reagent to produce β‐amino ketones 56 (Scheme ) with high enantiomeric purities ( ee ranging from 60–95 %) but only medium diastereoselectivities (typically trans / cis 2:1) 41. Titanium tetrachloride is necessary for activation of the amidomethylating reagent.…”

Asymmetric One‐Pot Conjugate Addition of Grignard Reagents to α,β‐Unsaturated Compounds Followed by Reaction with Carbenium Ions

“…On the other hand, magnesium enolates, formed by the addition of Grignard reagents are less developed. Magnesium enolates participated in reactions with appropriate electrophiles, such as aldehydes,12 imines,13 or imine equivalents,14 or serve as substrates for cyclopropanations 15. Other metal enolates, such as those of aluminium,6d,16 or boron were also used 17…”