We developed a strategy to harness alkyl amines as alkylating agents via C–N bond activation. This Suzuki–Miyaura cross coupling of alkyl pyridinium salts, readily formed from primary amines, is the first example of a metal-catalyzed cross coupling via C–N bond activation of an amine with an unactivated alkyl group. This reaction enjoys broad scope and functional group tolerance. Primary and secondary alkyl groups can be installed. Preliminary studies suggest a NiI/NiIII catalytic cycle.

Reliable design of artificial metalloenzymes (ArMs) to access transformations not observed in nature remains a long-standing and important challenge. We report that a monomeric streptavidin (mSav) Rh(III) ArM permits asymmetric synthesis of α,β-unsaturated-δlactams via a tandem C−H activation and [4+2] annulation reaction. These products are readily derivatized to enantioenriched piperidines, the most common Nheterocycle found in FDA approved pharmaceuticals. Desired δ-lactams are achieved in yields as high as 99% and enantiomeric excess of 97% under aqueous conditions at room temperature. Embedding a Rh cyclopentadienyl (Cp*) catalyst in the active site of mSav results in improved stereocontrol and a 7-fold enhancement in reactivity relative to the isolated biotinylated Rh(III) cofactor. In addition, mSav-Rh outperforms its wellestablished tetrameric forms, displaying 11−33 times more reactivity.

A nickel-catalyzed reductive cross-coupling of alkylpyridinium salts and aryl bromides has been developed using Mn as the reductant. Both primary and secondary alkylpyridinium salts can be used, and high functional group and heterocycle tolerance is observed, including for protic groups. Mechanistic studies indicate formation of an alkyl radical, and controlling its fate was key to the success of this reaction.

A Negishi cross-coupling of alkyl pyridinium salts and alkylzinc halides has been developed. This is the first example of alkyl-alkyl bond formation via cross-coupling of an alkyl amine derivative with an unactivated alkyl group, and allows both primary and secondary alkyl pyridinium salts to react with primary alkylzinc halides with high functional group tolerance. When combined with formation of the pyridinium salts from primary amines, this method enables the non-canonical transformation of NH 2 groups into a wide range of alkyl substituents with broad functional group tolerance.

We have developed a stereospecific, nickel-catalyzed cross-coupling of secondary benzylic ammonium salts and diboronate esters to deliver highly enantioenriched benzylic boronates. This reaction utilizes amine-derived electrophiles, which are readily available in high enantiopurity, and simple, inexpensive nickel catalysts. This reaction has broad scope, enabling synthesis of a variety of secondary benzylic boronates in good yields and excellent ee’s.