Formation of α-chiral centers by asymmetric β-C(sp ³ )–H arylation, alkenylation, and alkynylation

Abstract

The enzymatic β-C–H hydroxylation of the feedstock chemical isobutytic acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transitionmetal catalyzed enantioselective β-C–H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline (MPAO) ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp3)-H bonds of one of the prochiral methyl groups. We detail the enantioselective β-arylation, -alkenylation and -alkynylation of isobutyric acid/2-amino-isobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.

PdII‐Catalyzed Enantioselective C(sp3)−H Activation/Cross‐Coupling Reactions of Free Carboxylic Acids

“…The combination of monodentate coordinating substrates with chiral bidentate mono‐N‐protected amino acid ligand (MPAA) has led to the development of a wide range of Pd II ‐catalyzed enantioselective intermolecular C−H activation reactions . Recently, chiral bidentate quinoline ligands and oxazoline ligands were developed to realize the enantioselective functionalization of methylene C−H bonds and methyl C−H bonds in carboxylic acid derivatives, respectively ,. However, substrates in these reactions require preinstalled directing groups that need to be removed after C−H functionalization .…”

Katalytische Desymmetrisierung durch C‐H‐Funktionalisierung: eine Lösung für das Problem der stereogenen Methylgruppe

“…Vor diesem Hintergrund entwickelten Jin‐Quan Yu und Mitarbeiter kürzlich einen biomimetisch inspirierten Ansatz zur Palladium‐katalysierten β‐C‐H‐Aktivierung (Abbildung ), womit die katalytische Desymmetrisierung der prochiralen α‐Isopropylgruppe eines Isobutyrats gelang. Um dies zu erreichen, musste ein neuer Katalysator entwickelt werden, der in der Lage ist, zwischen den enantiotopen Methylgruppen zu differenzieren.…”

Scalable Synthesis of N‐Acetylated α‐Amino Acid‐Derived Oxazoline Ligands

“…Remarkable enantioselectivity achieved may stimulate further applications of this type of chiral molecules, including industrially relevant transformations . Bearing in mind an emerging interest to the С─H activation chemistry and prospects of α‐amino acid‐derived oxazolines , we focused on the developing their cost‐effective and scalable synthesis.…”