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.

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low‐abundance starting materials. In contrast, amide formation is the most‐used bond‐construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N‐alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2‐pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.

A Suzuki−Miyaura cross-coupling of α-pyridinium esters and arylboroxines has been developed. Combined with formation of the pyridinium salts from amino acid derivatives, this method enables amino acid derivatives to be efficiently transformed into α-aryl esters and amides. Under the mild conditions, broad functional group tolerance on both the amino acid derivatives and the arylboroxine are observed, including protic functional groups. Mechanistic studies support an alkyl radical intermediate, similar to other cross-couplings of alkylpyridinium salts.

Recognizing the importance of all-carbon, quaternary stereocenters in complex molecule synthesis, a stereospecific, nickel-catalyzed cross-coupling of allylic pivalates with arylboroxines to deliver products equipped with quaternary stereocenters and internal alkenes was developed. The enantioenriched allylic pivalate starting materials are readily prepared, and a variety of functional groups can be incorporated on both the allylic pivalate and the arylboroxine. Additional advantages include the use of a commercially available and air-stable Ni(II) salt and BISBI ligand, mild reaction conditions, and high yields and ee’s. The observed stereoinversion of this reaction is consistent with an open transition state in the oxidative addition step.

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low‐abundance starting materials. In contrast, amide formation is the most‐used bond‐construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N‐alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2‐pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.

A new pyrrole building block is described, which allows for the regiospecific synthesis of 2,3,5-trisubstituted pyrroles and 2,3,4,5- tetrasubstituted pyrroles. Optimization studies are presented for the preparation of the pyrrole building block along with the evaluation of various cross-coupling conditions and cross-coupling agents. A short, formal synthesis of the natural products Polycitone A, Polycitone B and Polycitrin A from the pyrrole building block is also described.

Primary alkyl amines are well appreciated as building blocks for the synthesis of nitrogen‐containing molecules. However, their use as alkylating agents via cleavage of the carbon–nitrogen (C–N) bond is largely undeveloped. Recognizing this opportunity to expand the utility of alkyl amines in synthesis, the M. Watson group is developing strategies to convert primary alkyl amines into alkyl arenes via nickel‐ catalyzed cross‐couplings of Katrizky pyridinium salt intermediates. We are now developing this chemistry to enable cross‐couplings of alpha‐amino acids and peptides via cleavage of the alpha‐C–N bond. Pyridinium salts were formed from the N‐termini of a number of α‐amino acids and a tripeptide, prepared via solid phase peptide synthesis. Once formed, the pyridinium salts were allowed to undergo nickel‐catalyzed cross‐coupling. Our preliminary scope, as well as future work, will be presented.Support or Funding InformationThe National Institutes of Health (R01 GM111820) University of Delaware David A. Plastino FellowshipThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Formation of quaternary stereocenters is an essential goal for organic chemistry due to these centers' presence in numerous drugs and their importance in biological activity. Transition metal catalysis offers a unique approach to this challenge, but previous attempts have been limited in either scope or enantiomeric enrichment. We are introducing a stereospecific Suzuki cross coupling of enantioenriched benzyl alcohol derivatives via C‐O bond activation that yields quaternary stereocenters with both aryl and vinyl substituents. Using benzylic carboxylates available in high enantiopurity, an air‐stable, inexpensive nickel source, and pinacol boronates, the reaction yields products in high yield and enantioenrichment and can tolerate a wide range of functional groups, including heteroaromatics. The optimization and scope of these reactions will be presented.Support or Funding InformationThe National Institutes of Health (R01 GM111820) is gratefully acknowledged.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.