Synthesis of Acyclic Aliphatic Amides with Contiguous Stereogenic Centers via Palladium‐Catalyzed Enantio‐, Chemo‐ and Diastereoselective Methylene C(sp3)−H arylation

The enantioselective desymmetrizing C−H activation of α‐gem‐dialkyl acyclic amides remains challenging because the availability of four chemically identical unbiased methylene C(sp3)−H bonds and increased rotational freedoms of the acyclic systems add tremendous difficulties for chemo‐ and stereocontrol. We have developed a method for the synthesis of acyclic aliphatic amides with α,β‐contiguous stereogenic centers via PdII‐catalyzed asymmetric arylation of unbiased methylene C(sp3)−H, in good yields and with high levels of enantio‐, chemo‐ and diastereoselectivity (up to >99 % ee and >20:1 d.r.). Successive application of this method enables the sequential arylation of the gem‐dialkyl groups with two different aryl iodides, giving a range of β‐Ar1‐β′‐Ar2‐aliphatic acyclic amides containing three contiguous stereogenic centers with excellent diastereoselectivity. The enantioselective synthesis of acyclic aliphatic amides with contiguous stereogenic centers is reported using PdII‐catalyzed asymmetric methylene C(sp3)−H arylation. Good yields and high levels of enantio‐, chemo‐ and diastereoselectivity were obtained. The readily available 3,3′‐F2‐BINOL ligand plays a crucial role in distinguishing four chemically identical β‐methylene C(sp3)−H groups and in enhancing monoselectivity.