Enantioselective One‐Pot Conjugate Addition of Grignard Reagents Followed by a Mannich Reaction

Abstract

Asymmetric addition of Grignard reagents to cyclohexenone, catalyzed by ferrocene diphosphanes, afforded chiral magnesium enolates. These enolates reacted in a one‐pot arrangement with N‐benzylidenetoluenesulfonamide to give β‐amino carbonyl compounds with three contiguous stereocenters. Two major diastereoisomers (dr = 60:40) of product with enantioselectivities up to 95 % ee were separated by flash chromatography.

Diastereoselective Mannich Reaction of Chiral Enolates Formed by Enantioselective Conjugate Addition of Grignard Reagents

“…We started our investigation with previously established optimal reaction conditions (Scheme 1). [21] The reaction with ketone 1 and methylmagnesium bromide in tBuOMe followed by the addition of imines in 2-methyltetrahydrofuran (mTHF) afforded a range of products 3b-f. In all instances, only two major diastereoisomers, (R,R,S)-3 and (R,R,R)-3, were isolated.…”

“…[21] The configurations of products 3b-e were assigned by comparison of the H,H coupling constants within the series of compounds 3a-e. Coupling constants between COCH and CHN are consistent within groups of both diastereomers (R,R,S)-3 ( 3 J H,H = 3.0-4.3 Hz) and (R,R,R)-3 ( 3 J H,H = 5.1-5.8 Hz). Because of the opposite sense of diastereoselectivity with imine 2f, the relative configuration of its tandem reaction product, compound 3f, was further ascertained by NOESY NMR experiments.…”

“…The Cu-Taniaphos complex was able to catalyze the highly enantioselective conjugate addition of Grignard reagents to cyclohex-2-enone followed by a one-pot reaction with N-benzylidenetoluenesulfonamide. [21] With this imine, however, diastereoselectivity of the addition was poor. Therefore, we decided to study this transformation with the aim of addressing the problem of low diastereoselectivity.…”

TADDOL‐Based Phosphane–Phosphite Ligands in Enantioselective Cu‐Catalyzed Grignard 1,4‐Additions Followed by Mannich‐Type Alkylations

“…We started our investigation with the addition of MeMgBr to cyclohex‐2‐enone ( 1 , Scheme ), followed by the addition of N ‐benzylidene‐4‐methylbenzenesulfonamide ( 2 ). Applying our previously developed reaction conditions,20a we screened the TADDOL‐based phosphane–phosphite ligands L1 – L7 with use of CuBr · Me 2 S as a copper source. The product of these one‐pot reactions (i.e., the aminoketone 3 ) was isolated as mixtures of two (out of four possible) major diastereoisomers.…”

Multicomponent Mannich‐Like Reactions of Organometallic Species

“…The use of Grignard reagents 121 as nucleophiles was studied by Sebesta and co-workers. [133] Initial studies of the onepot catalyzed conjugate addition/Mannich reaction sequence allowed them to identify Taniaphos as best ligand for enantiocontrol, although only moderate diastereoselectivities were observed. They subsequently circumvented this issue by identifying the crucial importance of the imine protecting group for the fate of the Mannich step (Scheme 54).…”