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

Abstract

Cu–Taniaphos‐catalyzed enantioselective addition of Grignard reagents to cyclic enones leads to chiral magnesium enolates. These enolates add to N‐protected imines directly, or through in situ transformation to silyl enol ethers. Diastereoselectivity of the addition depends on the nitrogen protecting group of the imine. Diastereoisomers of the resulting β‐amino carbonyl compounds can be separated and are obtained in acceptable yields and in high enantiomeric purities (up to 99:1 er).

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

“…Calculated structures of TS of enolate addition to imines explain that for the sterically less congested imines (protected with Ts, Ms, Boc, and Bz) Si face attack is preferred and leads to the formation of ( R , R , S )- 61 as the major diastereomer (Scheme , TS1 vs TS2). On the other hand, with POPh 2 47b dr 1:4 was observed, and imine is attacked from the Re face, leading to ( R , R , R )- 62 as the major diastereomer (Scheme , TS3 vs TS4) …”

“…On the other hand, with POPh 2 47b dr 1:4 was observed, and imine is attacked from the Re face, leading to (R,R,R)-62 as the major diastereomer (Scheme 18, TS3 vs TS4). 67 Schmalz's phosphane phosphite ligand L13 brought about another improvement to the protocol mentioned above. This ligand allowed a broader scope of the tandem CA−Mannich reaction (Scheme 19a).…”

Recent Advances in Metal-Catalyzed Asymmetric Mannich Reactions

“…Sebesta and Galeštaková reported a novel copper-Taniaphos-catalyzed enantioselective conjugate addition of Grignard reagents to cyclic enones, followed by diastereoselective Mannich reaction of the in situ generated magnesium enolate to N-protected imines. 78 In this study, the authors demonstrated the interesting influence of the imine protecting group on the diastereoselectivity of enolate addition. The reaction with cyclohexenone and meth-ylmagnesium bromide in tert-butyl methyl ether followed by addition of the imine in 2-methyltetrahydrofuran (mTHF) afforded a range of enantioenriched products syn-197 and anti-197 with moderate to good stereoselectivities.…”

Stereoselective Coupling of N-tert-Butanesulfinyl Aldimines and β-Keto Acids: Access to β-Amino Ketones

“…The stereoselective Mannich reactions are also performed with stoichiometric amounts of chiral reagents. In these reactions, the stereochemical information could be provided by a chiral imine, in which most commonly a chiral auxiliary is a substituent of the iminic nitrogen, or by a chiral nucleophile derived from aldehydes, ketones, esters, or enol ethers . Among chiral imines, those derived from tert -butanesulfinamide have been extensively used as electrophiles over the past decade in many synthetic transformations, due mainly to the ready availability of both enantiomers of tert -butanesulfinamide at reasonable prices, the easy deprotection of the resulting amine under mild acidic conditions and the possibility of recycling the chiral auxiliary .…”