Synthesis and Diversification of 1,2,3-Triazole-Fused 1,4-Benzodiazepine Scaffolds

Abstract

A substituted heterocyclic scaffold comprising a 1,4-benzodiazepine fused with a 1,2,3-triazole ring has been synthesized and diversified via a variety of refunctionalizations. The strategy features the rapid assembly of the scaffold by combining 3-4 reactants in an efficient multicomponent assembly process, followed by an intramolecular Huisgen cycloaddition.Privileged scaffolds are uniquely suited to the preparation of molecular libraries for lead development in medicinal chemistry. 1 Such frameworks are attractive for drug discovery because of the high hit rates and the pharmacological profiles of their derivatives relative to those of other ring systems. By varying substitutents on these privileged scaffolds, one can often identify potent and selective binders for multiple biological targets from a single library. Indeed, a retrospective analysis of all known drugs reveals that nearly 25% can be traced back to a mere 41 substructures that have since been catagorized as privileged. 2

Application of a Sequential Multicomponent Assembly Process/Huisgen Cycloaddition Strategy to the Preparation of Libraries of 1,2,3-Triazole-Fused 1,4-Benzodiazepines

“…15 This approach afforded scaffolds 6 and 7 in high purity after recrystallization and represents a considerably more expedient access to compound 6 than previously reported. 21 …”

Evolution of a strategy for preparing bioactive small molecules by sequential multicomponent assembly processes, cyclizations, and diversification

“…In one version of this approach, cyanide ion was employed as the nucleophilic partner in a MCAP involving propargylamine and a 2-azidobenzaldehyde, such as 29 , to produce the α -aminonitrile 30 (Scheme 4), 35,36 which underwent a Huisgen dipolar cycloaddition when heated in toluene to afford the 1,4-benzodiazepine 31 . It is noteworthy that N -acetylation of the acyclic α -aminonitrile 30 facilitated spontaneous [3+2]-dipolar cycloaddition to give the tricyclic amide 32 in a single step.…”

Diversity oriented synthesis: concise entry to novel derivatives of Yohimbine and Corynanthe alkaloids

“…These adducts can be subjected to various cyclization reactions that are enabled by selective functional group pairing to construct substituted heterocyclic ring systems. 7 We have demonstrated the utility of this general approach to diversity oriented synthesis (DOS) by applying it to preparation of small libraries of substituted benzodiazepines, 8 norbenzomorphans, 9 aryl piperidines, 10 tetrahydroisoquinolines, 11 as well as several conformationally-constrained benzoxazocines and benzazocines. 12 We now report the extension of this useful methodology to the facile preparation of compounds derived from the yohimbine and corynanthe scaffolds.…”