Diversifying Amino Acids and Peptides via Deaminative Reductive Cross-Couplings Leveraging High-Throughput Experimentation.

A deaminative reductive coupling of amino acid pyridinium salts with aryl bromides has been developed to enable efficient synthesis of noncanonical amino acids and diversification of peptides. This method transforms natural, commercially available lysine, ornithine, diaminobutanoic acid, and diaminopropanoic acid to aryl alanines and homologated derivatives with varying chain lengths. Attractive features include ability to transverse scales, tolerance of pharma-relevant (hetero)aryls and biorthogonal functional groups, and the applicability beyond monomeric amino acids to short and macrocyclic peptide substrates. The success of this work relied on high-throughput experimentation to identify complementary reaction conditions that proved critical for achieving the coupling of a broad scope of aryl bromides with a range of amino acid and peptide substrates including macrocyclic peptides.

Homogeneous Organic Electron Donors in Nickel-Catalyzed Reductive Transformations.

Many contemporary organic transformations, such as Ni-catalyzed cross-electrophile coupling (XEC), require a reductant. Typically, heterogeneous reductants, such as Zn0 or Mn0, are used as the electron source in these reactions. Although heterogeneous reductants are highly practical for preparative-scale batch reactions, they can lead to complications in performing reactions on process scale and are not easily compatible with modern applications, such as flow chemistry. In principle, homogeneous organic reductants can address some of the challenges associated with heterogeneous reductants and also provide greater control of the reductant strength, which can lead to new reactivity. Nevertheless, homogeneous organic reductants have rarely been used in XEC. In this Perspective, we summarize recent progress in the use of homogeneous organic electron donors in Ni-catalyzed XEC and related reactions, discuss potential synthetic and mechanistic benefits, describe the limitations that inhibit their implementation, and outline challenges that need to be solved in order for homogeneous organic reductants to be widely utilized in synthetic chemistry. Although our focus is on XEC, our discussion of the strengths and weaknesses of different methods for introducing electrons is general to other reductive transformations.

Palladium-Catalyzed Aerobic Acetoxylation of Benzene using NOx-Based Redox Mediators.

Palladium-catalyzed methods for C-H oxygenation with O2 as the stoichiometric oxidant are limited. Here, we describe the use of nitrite and nitrate sources as NOx-based redox mediators in the acetoxylation of benzene. The conditions completely avoid formation of biphenyl as a side product, and strongly favor formation of phenyl acetate over nitrobenzene (PhOAc:PhNO2 ratios up to 40:1). Under the optimized reaction conditions, with 0.1 mol% Pd(OAc)2, 136 turnovers of Pd are achieved with only 1 atm of O2 pressure.

Nickel-catalyzed carbon-carbon bond-forming reactions of unactivated tertiary alkyl halides: Suzuki arylations.

The first Suzuki cross-couplings of unactivated tertiary alkyl electrophiles are described. The method employs a readily accessible catalyst (NiBr(2)·diglyme/4,4'-di-tert-butyl-2,2'-bipyridine, both commercially available) and represents the initial example of the use of a group 10 catalyst to cross-couple unactivated tertiary electrophiles to form C-C bonds. This approach to the synthesis of all-carbon quaternary carbon centers does not suffer from isomerization of the alkyl group, in contrast with the umpolung strategy for this bond construction (cross-coupling of a tertiary alkylmetal with an aryl electrophile). Preliminary mechanistic studies are consistent with the generation of a radical intermediate along the reaction pathway.

Triazoloamides as potent γ-secretase modulators with reduced hERG liability.

Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Aß42 IC(50) in cell-based assays and reduced affinity for the hERG channel.