Recent developments in asymmetric Heck type cyclization reactions for constructions of complex molecules.

Intramolecular carbometallation-initiated asymmetric transformations are a general and powerful approach for the construction of carbo- and heterocyclic systems with one and more stereocenters. In addition, the newly developed multiple cascade reactions are an attractive strategy for increasing the molecular complexity in one step. In recent years, great progress has been made in this area with the use of various palladium and nickel complexes with P- and N-donor chiral ligands. This review highlights recent developments in intramolecular asymmetric Heck reactions, reductive Heck reactions and various types of cascade transformations (intramolecular Heck/Heck, Heck/nucleophilic trapping, Heck/Tsuji-Trost, Heck/Suzuki-Miyaura, Heck/Sonogashira, and Heck/carbonylation) in the synthesis of complex molecules over the past 5 years. A number of examples from before 2016 are included as background information. Particular attention is paid to the use of inexpensive nickel complexes as highly efficient catalysts for a number of asymmetric reactions considered here. A perspective on current challenges and potential future developments in the field of asymmetric Heck type cyclizations is also provided.

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction.

A new synthetic strategy toward nonracemic phosphoryl-substituted pyrrolidines and tetrahydropyranes with three and five contiguous stereocenters is presented. Readily available ß-keto phosphonates react with conjugated nitroolefins in the presence of a chiral Ni(II) complex to give nitro keto phosphonates with two stereocenters with excellent enantioselectivity and moderate to high diastereoselectivity. These products were used for a reductive cyclization leading to pyrrolidin-3-ylphosphonic acid and for reactions with aldehydes yielding tetrahydropyranylphosphonates as individual stereoisomers. These nonracemic heterocycles containing phosphoryl moieties are useful for designing new pharmacologically active compounds.

Synthesis of non-racemic 4-nitro-2-sulfonylbutan-1-ones via Ni(II)-catalyzed asymmetric Michael reaction of ß-ketosulfones.

Functionally substituted sulfones with stereogenic centers are valuable reagents in organic synthesis and key motifs in some bioactive compounds. The asymmetric Michael addition of ß-ketosulfones to conjugated nitroalkenes in the presence of Ni(II) complexes with various chiral vicinal diamines was studied. This reaction provides convenient access to non-racemic 4-nitro-2-sulfonylbutan-1-ones with two stereocenters with high yield and excellent enantioselectivity (up to 99%). It has been established that the catalytic Michael reaction itself was carried out with high diastereoselectivity, but the Michael adducts may epimerize at the C-2 position at a significant rate. Conditions for the preparation of individual diastereomers were found.

Molecular design, synthesis and biological evaluation of cage compound-based inhibitors of hepatitis C virus p7 ion channels.

The hepatitis C caused by the hepatitis C virus (HCV) is an acute and/or chronic liver disease ranging in severity from a mild brief ailment to a serious lifelong illness that affects up to 3% of the world population and imposes significant and increasing social, economic, and humanistic burden. Over the past decade, its treatment was revolutionized by the development and introduction into clinical practice of the direct acting antiviral (DAA) agents targeting the non-structural viral proteins NS3/4A, NS5A, and NS5B. However, the current treatment options still have important limitations, thus, the development of new classes of DAAs acting on different viral targets and having better pharmacological profile is highly desirable. The hepatitis C virus p7 viroporin is a relatively small hydrophobic oligomeric viral ion channel that plays a critical role during virus assembly and maturation, making it an attractive and validated target for the development of the cage compound-based inhibitors. Using the homology modeling, molecular dynamics, and molecular docking techniques, we have built a representative set of models of the hepatitis C virus p7 ion channels (Gt1a, Gt1b, Gt1b_L20F, Gt2a, and Gt2b), analyzed the inhibitor binding sites, and identified a number of potential broad-spectrum inhibitor structures targeting them. For one promising compound, the binding to these targets was additionally confirmed and the binding modes and probable mechanisms of action were clarified by the molecular dynamics simulations. A number of compounds were synthesized, and the tests of their antiviral activity (using the BVDV model) and cytotoxicity demonstrate their potential therapeutic usefulness and encourage further more detailed studies. The proposed approach is also suitable for the design of broad-spectrum ligands interacting with other multiple labile targets including various viroporins.