Organocatalytic [4+2] Benzannulation Between 1,4-Dithiane-Based Enal and Nitroolefins to Access 2-Nitrobiaryls.

A simple method for constructing unsymmetrical 2-nitrobiaryls has been developed between substituted 1,4-dithiine-2-carbaldehyde and nitroolefins under metal-free conditions. To gain the advantage of the HOMO-raising effect of temporary substitutions on in situ generated dienamine intermediate, the present protocol established [4+2] benzannulation of 1,4-dithiane-tethered enals with nitroolefin. Further, easy unmasking of 1,4-dithiine units results in a benzannulation product like that of unsubstituted enals, which are difficult to access.

Enantioselective synthesis of α-(3-pyrrolyl)methanamines with an aza-tetrasubstituted center under metal-free conditions.

Construction of a chiral methanamine unit at the C3 position of pyrrole is highly desirable; nevertheless, it remains challenging due to its intrinsic electronic properties. Herein, we present an operationally straightforward and direct asymmetric approach for accessing α-(3-pyrrolyl)methanamines under benign organocatalytic conditions for the first time. The one-pot transformation proceeds smoothly through an amine-catalyzed direct Mannich reaction of succinaldehyde with various -cyclic imines, followed by a Paal-Knorr cyclization with a primary amine.

Electrochemical Synthesis of 2-Aryl-3-(2-aminoaryl)quinoxalines via Oxidative Dearomatization/Ring-Opening/Cyclization Cascade Sequence of 2-Arylindoles with 1,2-Diaminoarenes.

A straightforward method has been developed to synthesize 2-aryl-3-(2-aminoaryl) quinoxalines from 2-arylindoles and 1,2-diaminoarenes under mild electrochemical conditions. The reaction proceeds through in situ generations of 2-arylindole-3-ones under electrochemical oxidative dearomatization of 2-arylindoles, followed by a ring opening-cyclization sequence with 1,2-diaminoarenes. A series of 2-aryl-3-(2-aminoaryl) quinoxalines have been prepared with moderate to good yields (up to 75%).

Electrochemical Oxidative Addition of Nucleophiles on 2-Arylindoles: Synthesis of C2-Heteroquaternary Indolin-3-ones.

An electrochemical method has been developed to synthesize 2,2-disubstituted indolin-3-ones under mild conditions. A series of nucleophiles have been added to the 2-arylindole-3-ones, generated in situ under metal-free electrochemical oxidative dearomatization of 2-arylindoles, to afford 2,2-disubstituted 3-carbonyl indoles with heteroquaternary centers in 57-79% yields.

Enantioselective Direct Synthesis of C3-Hydroxyalkylated Pyrrole via an Amine-Catalyzed Aldol/Paal-Knorr Reaction Sequence.

Creating functionality with chirality at position C3 of pyrrole is challenging. An operationally simple organocatalytic method has been developed to generate functionality with a chiral tertiary/quaternary stereocenter at position C3 of pyrrole. The process proceeds through an amine-catalyzed direct aldol reaction of succinaldehyde with various acceptor carbonyls, followed by a Paal-Knorr reaction with a primary amine in the same pot.

Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy.

Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2'3'- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes).

Electrochemical Oxidative Coupling Between Benzylic C(sp)-H and N-H of Secondary Amines: Rapid Synthesis of α-Amino α-Aryl Esters.

An intermolecular electrochemical coupling between the benzylic C(sp)-H bond and various secondary amines is reported. The electronic behavior of two electronically rich units viz the α-position of α-aryl acetates and amines was engineered electrochemically, thus facilitating their reactivity for the direct access of α-amino esters. A series of acyclic/cyclic secondary amines and α-aryl acetates were tested to furnish the corresponding α-amino esters with high yields (up to 92%) under mild conditions.

Identification and structure-activity relationship studies of small molecule inhibitors of the human cathepsin D.

Cathepsin D, an aspartyl protease, is an attractive therapeutic target for various diseases, primarily cancer and osteoarthritis. However, despite several small molecule cathepsin D inhibitors being developed, that are highly potent, most of them show poor microsomal stability, which in turn limits their clinical translation. Herein, we describe the design, optimization and evaluation of a series of novel non-peptidic acylguanidine based small molecule inhibitors of cathepsin D.

Direct Amine-Catalyzed Enantioselective Synthesis of Pentacyclic Dibenzo[,][1,4]oxazepine/Thiazepine-Fused Isoquinuclidines along with DFT Calculations.

A direct protocol for the asymmetric synthesis of dibenzoxazepine/thiazepine-fused [2.2.2] isoquinuclidines is developed.