Asymmetric Radical Addition of TEMPO to Titanium Enolates

Abstract

A mild method for α-hydroxylation of N-acyl oxazolidinones by asymmetric radical addition of the 2,2,6,6-tetramethylpiperidine N-oxy (TEMPO) radical to titanium enolates was developed. The high diastereoselectivity and broad scope of the reaction show synthetic utility for the α-hydroxylation of substrates that are not tolerant to strongly basic conditions.

SuperQuat chiral auxiliaries: design, synthesis, and utility

“…Reaction optimisation showed that L-Phe-Evans 59 gave α-aminooxylated product 61 in 80:20 dr whereas L-Phe-SuperQuat 60 gave αaminooxylated product 62 in 93:7 dr (Scheme 11). Zakarian et al, 23 and later Romea, Urpí, et al, 24 established the generality of this procedure for a range of N-acyl L-Phe-SuperQuat derivatives. Representative examples of cleavage (reduction or methanolysis) to liberate the α-functionalised products were also included in these studies.…”

“…For example, 20 Zakarian et al also developed an α-aminooxylation protocol upon treatment of N-acyl SuperQuats with TiCl4 and Et3N, then TEMPO. 23 It was proposed that the in situ formed titanium enolate undergoes oxidation upon introduction of TEMPO; ensuing radical-radical coupling with TEMPO then gives the α-aminooxylated product. Reaction optimisation showed that L-Phe-Evans 59 gave α-aminooxylated product 61 in 80:20 dr whereas L-Phe-SuperQuat 60 gave αaminooxylated product 62 in 93:7 dr (Scheme 11).…”

“…Representative examples of cleavage (reduction or methanolysis) to liberate the α-functionalised products were also included in these studies. 23,24 The substrates investigated included the diastereoisomeric N-acyl SuperQuats 64 and 65 [derived from coupling enantiopure (R)-dihydrocitronellic acid 63 with both L-Phe-SuperQuat L-24 and D-Phe-SuperQuat D-24]: α-aminooxylation of 64 and 65 proceeded to give adducts 66 and 67 in 97:3 dr and 95:5 dr, respectively, and in 73% isolated yield in both cases, indicating that the stereochemical outcomes of these reactions are dictated predominantly by the stereoinduction of the SuperQuat fragment in both cases, with the relative configuration of the β-stereocentre having little effect 23 Zakarian et al also reported related (i.e., radical mediated) methods for haloalkylation of N-acyl SuperQuat enolates, 25,26 which they deployed in a unified synthesis of sintokamides A 72, B 73 and E 74. 27 Type II: Enolates via Conjugate Addition.…”

Catalyst‐Free α‐Aminoxylation of 1,3‐Dicarbonyl Compounds with TEMPO Using Selectfluor as an Oxidant

“…The existing protocols for Cu‐, Fe‐, or Cu/Fe‐catalyzed α‐aminoxylation of ketones and amides have also been widely disclosed . Furthermore, Zakarian and co‐workers explored titanium tetrachloride‐mediated radical addition of TEMPO to ketones . Subsequently, CAN‐catalyzed rapid α‐aminoxylation of 1,3‐dicarbonyl compounds for alkoxyamine synthesis was successfully realized by Jiao group .…”

“…[8] Furthermore, Zakarian and co-workers explored titanium tetrachloride-mediated radical addition of TEMPO to ketones. [9] Subsequently, CAN-catalyzed rapid αaminoxylation of 1,3-dicarbonyl compounds for alkoxyamine synthesis was successfully realized by Jiao group. [10] Besides, The groups of Koike, Tan and Wu well demonstrated visiblelight-induced photoredox-catalyzed α-aminoxylation reactions of 1,3-dicarbonyl compounds with TEMPO.…”