Synthesis Of Acyclic Aliphatic Amides With Contiguous Stereogenic Centers Via Palladium-Catalyzed Enantio-, Chemo- And Diastereoselective Methylene C(Sp(3))-H Arylation

The enantioselective desymmetrizing C-H activation of alpha-gem-dialkyl acyclic amides remains challenging because the availability of four chemically identical unbiased methylene C(sp(3))-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 alpha,beta-contiguous stereogenic centers via Pd-II-catalyzed asymmetric arylation of unbiased methylene C(sp(3))-H, in good yields and with high levels of enantio-, chemo- and diastereoselectivity (up to >99 %eeand >20:1 d.r.). Successive application of this method enables the sequential arylation of thegem-dialkyl groups with two different aryl iodides, giving a range of beta-Ar-1-beta '-Ar-2-aliphatic acyclic amides containing three contiguous stereogenic centers with excellent diastereoselectivity.