Biocatalytic Friedel–Crafts Alkylation Using a Promiscuous Biosynthetic Enzyme

The Friedel–Crafts alkylation is commonly used in organic synthesis to form aryl–alkyl C?C linkages. However, this reaction lacks the stereospecificity and regiocontrol of enzymatic catalysis. Here, we describe a stereospecific, biocatalytic Friedel–Crafts alkylation of the 2‐position of resorcinol rings using the cylindrocyclophane biosynthetic enzyme CylK. This regioselectivity is distinct from that of the classical Friedel–Crafts reaction. Numerous secondary alkyl halides are accepted by this enzyme, as are resorcinol rings with a variety of substitution patterns. Finally, we have been able to use this transformation to access novel analogues of the clinical drug candidate benvitimod that are challenging to construct with existing synthetic methods. These findings highlight the promise of enzymatic catalysis for enabling mild and selective C?C bond‐forming synthetic methodology.     

Morpholine Ketene Aminal as Amide Enolate Surrogate in Iridium‐Catalyzed Asymmetric Allylic Alkylation

Morpholine ketene aminal is employed in iridium‐catalyzed asymmetric allylic alkylation reactions as a surrogate for amide enolates to prepare γ,δ‐unsaturated β‐substituted morpholine amides. Kinetic resolution or, alternatively, stereospecific substitution affords the corresponding products in high enantiomeric excess. The utility of the products generated by this method has been showcased by their further elaboration into amines, ketones, or acyl silanes. A putative catalytic intermediate (η³‐allyl)iridium(III) with achiral P,Olefin‐ligand was synthetized and characterized for the first time.     

Sulfonamide‐Promoted Palladium(II)‐Catalyzed Alkylation of Unactivated Methylene C(sp3)?H Bonds with Alkyl Iodides

The alkylation of unactivated β‐methylene C(sp³) H bonds of α‐amino acid substrates with a broad range of alkyl iodides using Pd(OAc)₂ as the catalyst is described. The addition of NaOCN and 4‐Cl‐C₆H₄SO₂NH₂ was found to be crucial for the success of this transformation. The reaction is compatible with a diverse array of functional groups and proceeds with high diastereoselectivity. Furthermore, various β,β‐hetero‐dialkyl‐ and β‐alkyl‐β‐aryl‐α‐amino acids were prepared by sequential C(sp³) H functionalization of an alanine‐derived substrate, thus providing a versatile strategy for the stereoselective synthesis of unnatural β‐disubstituted α‐amino acids.