Palladium‐Catalyzed Highly Enantioselective Arylation of Cyclic N‐Sulfonyl α‐Ketimino Esters towards the Synthesis of α‐Quaternary Chiral Amino Acid Derivatives

Abstract

We have developed a highly effective palladium/PHOX catalyst system for efficient asymmetric 1,2‐addition of arylboronic acids to six‐membered 1,2,6‐thiadiazine‐1,1‐dioxide type cyclic N‐sulfonyl α‐iminoesters. The protocol allows convenient synthesis of a variety of nearly optically pure α‐quaternary amino acid derivatives under mild reaction conditions. The synthetic utility of the reaction is demonstrated by simple product transformations. It allows the convenient construction of α,γ‐substituted chiral γ‐lactams having two carbon stereogenic centres, including one quaternary centre, in a highly enantiomerically pure form. This chemistry may be used to generate analogous molecules of BMS‐561392 for bioactivity screening and drug discovery.

Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes

“…Therefore, synthetic access to this type of compound can be regarded as significant and a challenging task for organic chemists. Indeed, creation of quaternary stereocenters is elusive mainly due to the steric hindrance between the carbon substituents, and consequently, considerable efforts have been dedicated to implement chemical methodologies for this purpose. ,, These encompass long-established approaches such as Claisen rearrangement and Diels–Alder reaction up to the most recent ones based on transition metal catalysis ,,, and organocatalytic reactions. , However, innovative procedures expanding the range of structurally diverse products with improved efficacy, simplicity, and stereoselectivity are key for advancing the field of chemical synthesis. , …”

Accessing unnatural α-amino acids with tetrasubstituted stereogenic centersviacatalytic enantioselective reactions of ketimine-type α-iminoesters/α-iminoamides

“…In 2020, Xu and co-workers reported the use of six-membered 1,2,6-thiadiazine-1,1-dioxide-type cyclic sulfonyl α-iminoesters 154 as electrophiles in palladium-catalyzed enantioselective arylation chemistry (Scheme 62). 98 This reaction proceeds efficiently in the presence of chiral phosphinooxazoline-ligated palladium complex 156 to afford chiral ATAAs 155 with high enantioselectivities. Furthermore, ATAA 155 is easily converted into chiral γ-lactam 157 bearing α-tetrasubstituted α-amino acid moiety, which is analogs of a TNF-α convertase enzyme (TACE) inhibitor and an anti -inflammatory agent, without loss of enantiopurity.…”

Palladium/N,N′-Disulfonyl Bisimidazoline-Catalyzed Enantioselective Addition of Arylboronic Acids to Cyclic N-Sulfonyl Ketimines

“…In this context, transition metal-catalyzed asymmetric arylation of imines offer an efficient protocol for producing chiral quaternary stereocenters with the amino functionality. − In particular, palladium- and rhodium-catalyzed asymmetric addition of cyclic ketimines has inspired considerable attention by virtue of their general high reactivity and effective control of high enantioselectivity in the arylation reactions (Scheme , path a). − Since the pioneering work of palladium-catalyzed asymmetric addition reaction of arylboronic acids to cyclic ketimines by Zhang’s group, chiral palladium catalysts coordinated with a phosphinooxazoline, a pyridinohydrazone, a ferrocene-derived palladacycle, and a phosphine-imine were independently developed to achieve the asymmetric arylation of cyclic N -sulfonyl imines. Moreover, Xu’s group designed a type of elegant chiral sulfur-based olefin ligands and successfully realized their applications in Rh-catalyzed asymmetric reactions of arylboronic acids to cyclic ketimines . Despite these advances gained in this area, achieving stereocontrol with new catalytic systems together with a broad substrate scope still represents a quite challenging task.…”