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.

Primary vs. secondary alkylpyridinium salts: a comparison under electrochemical and chemical reduction conditions.

This report details a systematic comparison of the scope of aryl bromides in nickel-catalyzed, reductive cross-electrophile couplings of primary vs. secondary alkylpyridinium salts using both electrochemical and chemical reductants. Facilitated by the use of high-throughput experimentation (HTE) techniques, 37 aryl bromides, including 13 complex, drug-like examples, were investigated. By using primary and secondary substrates differing only by one methylene, we observed that the trends in ArBr scope are similar between the primary and secondary alkylpyridinium salts, although distinctions were observed in isolated cases. In addition, the electrochemical conditions compared favorably to those using chemical reductants, especially among the more complex, drug-like aryl halides.

2,6-Bis(pyrazol-1-yl)pyridine (1-bpp) as a General Ligand for the Negishi Alkylation of Alkylpyridinium Salts.

A Ni/1-bpp catalyst was demonstrated to be effective in the Negishi alkylation with multiple classes of alkylpyridinium salts, including α-primary and α-secondary. These conditions are also effective for benzylic pyridinium salts, demonstrating the successful Negishi alkylation of benzylic pyridinium salts for the first time. Further, 14 derivatives of 1-bpp were prepared with a variety of steric and electronic properties to study how these changes impact the success of the Negishi alkylation.

Overcoming the Naphthyl Requirement in Stereospecific Cross-Couplings to Form Quaternary Stereocenters.

The use of a simple stilbene ligand has enabled a stereospecific Suzuki-Miyaura cross-coupling of tertiary benzylic carboxylates, including those lacking naphthyl substituents. This method installs challenging all-carbon diaryl quaternary stereocenters in good yield and ee and represents an important breakthrough in the "naphthyl requirement" that pervades stereospecific cross-couplings involving enantioenriched electrophiles.

Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids.

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.

Harnessing Alkylpyridinium Salts as Electrophiles in Deaminative Alkyl-Alkyl Cross-Couplings.

A Negishi cross-coupling of alkylpyridinium 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 alkylpyridinium 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 noncanonical transformation of NH2 groups into a wide range of alkyl substituents with broad functional group tolerance.

Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross Couplings via C-N Bond Activation.

We developed a strategy to harness alkyl amines as alkylating agents via C-N bond activation. This Suzuki-Miyaura cross coupling of alkylpyridinium 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.

Stereospecific Cross Couplings To Set Benzylic, All-Carbon Quaternary Stereocenters in High Enantiopurity.

Asymmetric preparation of all-carbon quaternary stereocenters is an important goal. Despite advances in formation of highly enantioenriched products with quaternary stereocenters proximal to a functional group, methods to install quaternary stereocenters isolated from functional groups are limited. Transition metal catalysis offers a potential solution, but prior cross couplings are limited to allylic substrates or deliver little to no enantiomeric enrichment. We report a stereospecific, nickel-catalyzed Suzuki-Miyaura arylation of tertiary benzylic acetates to deliver products with diaryl and triaryl quaternary stereocenters in high yields and ee's. This reaction employs an inexpensive, air-stable Ni(II) salt and commercially available phosphine ligand to transform tertiary alcohol derivatives, which are easily available in exceptional ee, into valuable products with stereoretention.

Accessing Both Retention and Inversion Pathways in Stereospecific, Nickel-Catalyzed Miyaura Borylations of Allylic Pivalates.

We have developed a stereospecific, nickel-catalyzed Miyaura borylation of allylic pivalates, which delivers highly enantioenriched α-stereogenic γ-aryl allylboronates with good yields and regioselectivities. Our complementary sets of conditions enable access to either enantiomer of allylboronate product from a single enantiomer of readily prepared allylic pivalate substrate. Excellent functional group tolerance, yields, regioselectivities, and stereochemical fidelities are observed. The stereochemical switch from stereoretention to stereoinversion largely depends upon solvent and can be explained by competitive pathways for the oxidative addition step. Our mechanistic investigations support a stereoretentive pathway stemming from a directed oxidative addition and a stereoinvertive pathway that is dominant when MeCN blocks coordination of the directing group by binding the nickel catalyst.

Enantioselective copper-catalyzed alkynylation of benzopyranyl oxocarbenium ions.

We have developed highly enantioselective, copper-catalyzed alkynylations of benzopyranyl acetals. By using a copper(I) catalyst equipped with a chiral bis(oxazoline) ligand, high yields and enantioselectivities are achieved in the alkynylation of widely available, racemic isochroman and chromene acetals to deliver α-chiral oxygen heterocycles. This method demonstrates that chiral organometallic nucleophiles can be successfully used in enantioselective additions to oxocarbenium ions.

Enantioselective Copper(I)-Catalyzed Alkynylation of Oxocarbenium Ions to Set Diaryl Tetrasubstituted Stereocenters.

An enantioselective, copper(I)-catalyzed addition of terminal alkynes to isochroman ketals to set diaryl, tetrasubstituted stereocenters has been developed. The success of this reaction relies on identification of a Cu/PyBox catalyst capable of distinguishing the faces of the diaryl-substituted oxocarbenium ion. This challenging transformation enables efficient conversion of readily available, racemic ketals into high-value enantioenriched isochroman products with fully substituted stereogenic centers. High yields and enantiomeric excesses are observed for various isochroman ketals and an array of alkynes.

Enantioselective additions of copper acetylides to cyclic iminium and oxocarbenium ions.

The development of enantioselective, copper-catalyzed alkynylations of cyclic iminium and oxocarbenium ions is reviewed. The use of chiral copper-based catalysts has enabled high yields and enantioselectivites in the formation of nitrogen- and oxygen-containing heterocycles with α-stereogenic centers. This review highlights both the accomplishments and the future work needed in this important area.

A General, Simple Catalyst for Enantiospecific Cross Couplings of Benzylic Ammonium Triflates and Boronic Acids: No Phosphine Ligand Required.

Highly improved conditions for the enantiospecific cross coupling of benzylic ammonium triflates with boronic acids are reported. This method relies on the use of Ni(cod)2 without ancillary phosphine or N-heterocyclic carbene ligands as catalyst. These conditions enable the coupling of new classes of boronic acids and benzylic ammonium triflates. In particular, both heteroaromatic and vinyl boronic acids are well tolerated as coupling partners. In addition, these conditions enable the use of ammonium triflates with a variety of substituents at the benzylic stereocenter. Further, naphthyl-substitution is not required on the benzylic ammonium triflate; ammonium triflates with simple aromatic substituents also undergo this coupling. Good to high yields and levels of stereochemical fidelity are observed. This new catalyst system greatly expands the utility of enantiospecific cross couplings of these amine-derived substrates for the preparation of highly enantioenriched products.

Nickel-catalyzed cross-couplings of benzylic pivalates with arylboroxines: stereospecific formation of diarylalkanes and triarylmethanes.

We have developed a stereospecific nickel-catalyzed cross-coupling of benzylic pivalates with arylboroxines. The success of this reaction relies on the use of Ni(cod)2 as the catalyst and NaOMe as a uniquely effective base. This reaction has broad scope with respect to the arylboroxine and benzylic pivalate, enabling the synthesis of a variety of diarylalkanes and triarylmethanes in good to excellent yields and ee's.

Nickel-catalyzed cross couplings of benzylic ammonium salts and boronic acids: stereospecific formation of diarylethanes via C-N bond activation.

We have developed a nickel-catalyzed cross coupling of benzylic ammonium triflates with aryl boronic acids to afford diarylmethanes and diarylethanes. This reaction proceeds under mild reaction conditions and with exceptional functional group tolerance. Further, it transforms branched benzylic ammonium salts to diarylethanes with excellent chirality transfer, offering a new strategy for the synthesis of highly enantioenriched diarylethanes from readily available chiral benzylic amines.

Nickel-Catalyzed Electroreductive Coupling of Alkylpyridinium Salts and Aryl Halides.

An electrochemical, nickel-catalyzed reductive coupling of alkylpyridinium salts and aryl halides is reported. High-throughput experimentation (HTE) was employed for rapid reaction optimization and evaluation of a broad scope of pharmaceutically relevant structurally diverse aryl halides, including complex drug-like substrates. In addition, the transformation is compatible with both primary and secondary alkylpyridinium salts with distinct conditions. Mechanistic insights were critical to enhance the efficiency of coupling using secondary alkylpyridinium salts. Systematic comparisons of the electrochemical and non-electrochemical methods revealed the complementary scope and efficiency of the two approaches.

Copper-catalyzed enantioselective additions to oxocarbenium ions: alkynylation of isochroman acetals.

We have developed an enantioselective, copper(I)-catalyzed addition of terminal alkynes to racemic isochroman acetals. This method is one of the first transition-metal-catalyzed approaches to enantioselective additions to prochiral oxocarbenium ions. In this reaction, TMSOTf is used to form the oxocarbenium ion in situ under conditions compatible with simultaneous formation of the chiral copper acetylide. By using a bis(oxazoline) ligand, good yields and enantioselectivities are observed for a variety of enantioenriched 1-alkynyl isochromans.

Nickel-Catalyzed Deaminative Cyanation: Nitriles and One-Carbon Homologation from Alkyl Amines.

A nickel-catalyzed deaminative cyanation of Katritzky pyridinium salts has been developed. When it is coupled with formation of the pyridinium salt from primary amines, this method enables alkyl amines to be converted to alkyl nitriles. A less toxic cyanide reagent, Zn(CN)2, is utilized, and diverse functional groups and heterocycles are tolerated. The method also enables a one-carbon homologation of alkyl amines via reduction of the nitrile products, in addition to many other potential transformations of the versatile nitrile group.