The synthesis and functionalization of amines are fundamentally important in a vast range of chemical contexts. We present an amine synthesis that repurposes two simple feedstock building blocks: olefins and nitro(hetero)arenes. Using readily available reactants in an operationally simple procedure, the protocol smoothly yields secondary amines in a formal olefin hydroamination. Because of the presumed radical nature of the process, hindered amines can easily be accessed in a highly chemoselective transformation. A screen of more than 100 substrate combinations showcases tolerance of numerous unprotected functional groups such as alcohols, amines, and even boronic acids. This process is orthogonal to other aryl amine syntheses, such as the Buchwald-Hartwig, Ullmann, and classical amine-carbonyl reductive aminations, as it tolerates aryl halides and carbonyl compounds.

A new transformation is presented that enables chemists to couple simple alkyl carboxylic acids with aryl zinc reagents under Ni-catalysis. The success of this reaction hinges on the unique use of redox-active esters that allow one to employ such derivatives as alkyl halides surrogates. The chemistry exhibits broad substrate scope and features a high degree of practicality. The simple procedure and extremely inexpensive nature of both the substrates and pre-catalyst (NiCl2·6H2O, ca. $9.5/mol) bode well for the immediate widespread adoption of this method.

This Article details the development of the iron-catalyzed conversion of olefins to radicals and their subsequent use in the construction of C–C bonds. Optimization of a reductive diene cyclization led to the development of an intermolecular cross-coupling of electronically-differentiated donor and acceptor olefins. Although the substitution on the donor olefins was initially limited to alkyl and aryl groups, additional efforts culminated in the expansion of the scope of the substitution to various heteroatom-based functionalities, providing a unified olefin reactivity. A vinyl sulfone acceptor olefin was developed, which allowed for the efficient synthesis of sulfone adducts that could be used as branch points for further diversification. Moreover, this reactivity was extended into an olefin-based Minisci reaction to functionalize heterocyclic scaffolds. Finally, mechanistic studies resulted in a more thorough understanding of the reaction, giving rise to the development of a more efficient second-generation set of olefin cross-coupling conditions.

We outline the synthesis of six novel derivatives that are based on a recently discovered HDAC inhibitor FR235222. Our work is the first report utilizing a novel binding element, guanidine, as metal coordinators in HDAC inhibitors. Further, we demonstrate that these compounds show cytotoxicity that parallels their ability to inhibit deacetylase activity, and that the most potent compounds maintain an L-Phe at position 1, and a D-Pro at position 4. Both inhibition of HDAC activity and cytotoxicity against the pancreatic cancer cell line BxPC3 are exhibited by these compounds, establishing that a guanidine unit can be utilized successfully to inhibit HDAC activity. There are already numerous HDAC inhibitors in clinical trials. 3,4 However, treating pancreatic cancers has been unsuccessful with any drug currently on the market. Given that HDACs are inappropriately up-regulated in pancreatic cancers, 5,6 HDAC inhibitors (HDACIs) have tremendous potential for treating these drug-resistant cancers. Pancreatic cancer is the fifth most deadly cancer in U.S. Only 10% of patients are eligible for surgery, 7 and less than 20% of pancreatic cancers respond to the drug of choice (Gemzar) or other drugs on the market. 8, 9The 5-year survival rate for patients with pancreatic cancers is less than 5%. 10 With such a low response rate to current chemotherapeutic treatments, there is an immediate need for new drugs that provide additional chemotherapeutic options to pancreatic cancer patients.To date, HDACIs can be divided into five chemical families: hydroxamic acid derivatives, short chain fatty acids, benzamides, electrophilic ketones, and cyclic tetrapeptides. 1,11 These five families all inhibit the activity of metal-dependent HDAC classes I and II. The There is extensive literature on derivatives containing the three moieties found in natural product metal-binding units. In addition to work exploring their potency, other non-traditional metal binding units have been published including, sulfur, 15 N-formyl hydroxylamine, 16 and phosphorous-containing compounds. 17 However, no work has been published to date on guanidines as metal-binding units in HDACIs. Guanidines represent a very important class of compounds both biologically and chemically. Their hydrophilic nature provides stabilization of protein conformations via hydrogen bonding and mediates solubility of natural products. 18 With a high pK a value of 12.5, arginine residues containing a guanidinium side chain may not be considered optimal metal-binding ligands. However, the highly acidic nature of a metal cation found in the HDAC pocket can potentially lower the pK a value of the guanidinium side chain, allowing for coordination with the metal. In fact, several recent reports document the stability of guanidine-metal interactions, 19,20 although additional studies are needed. Despite their likely metal binding capabilities, guanidines have gone unexplored in the realm of HDACI as potential metal-binding units.Here we describe the design and synthesis of HDAC...