A General Approach to Indoles: Practical Applications for the Synthesis of Highly Functionalized Pharmacophores

The development of a long-term manufacturing route to a potent and selective KDR kinase inhibitor has led to the discovery of several novel methodologies for the general synthesis of indoles. The key transformations involved addition of a trimethylsilylnitro benzene to an aromatic aldehyde which afforded the key nitroalcohol intermediate. Oxidation of the nitroalcohol intermediate led to a nitroketone; whereas, elimination afforded exclusively a trans-nitrostyrene. Reductive cyclization gave the target compounds in excellent overall yield from readily available bulk chemicals. Application of this methodology has led to the synthesis of highly functionalized pharmacophores including other KDR kinase inhibitors, biindoles and tjipanazole natural products, indolo[2,3-a]pyrrolo [3,4-c]carbazoles, indole-4-carboxylic amides, N-hydroxyindoles, and 2,3-dihydrobenzofurans

Chemoselective Reduction of α‑Cyano Carbonyl Compounds: Application to the Preparation of Heterocycles

β-Aminoacrylates are reactive intermediates that are useful building blocks in synthesis. General methods for their preparation typically afford α and β disubstitution patterns or β only. Molecules with only α-substituents (β-hydrogen) are much less well-known. A chemoselective reductive tautomerization of α-cyanoacetates, using DIBAL-H, has been developed to access these valuable synthons. α,β-Unsaturated cyanoacetates and α-cyanoketones can, also, be selectively reduced via this methodology. A series of heterocycles were prepared using these β-enamino carbonyl compounds

Photoredox-Catalyzed Giese Reactions: Decarboxylative Additions to Cyclic Vinylogous Amides and Esters

An effective strategy has been developed for the photoredox-catalyzed decarboxylative addition of cyclic amino acids to both vinylogous amides and esters leading to uniquely substituted heterocycles. The additions take place exclusively trans to the substituent present on the dihydropyridone ring affording stereochemical control about the new carbon-carbon bond. These reactions are operationally simplistic and afford the desired products in good to excellent isolated yields