Regioselective Construction and Screening of 1,3-Disubstituted Tetrahydroindazolones in Enantiomerically Pure Pairs

Abstract

In this paper, we describe a regioselective synthetic pathway for enantiopure 1,3-disubstituted tetrahydroindazolone derivatives via the condensation of 2-acylcyclohexane-1,3-dione with various alkyl- and arylhydrazines using the steric effects of a Boc-protected pyrrolidine ring. This synthetic method has a broad scope for substrate generality for various hydrazines with excellent regioselectivity. To maximize the molecular diversity, further diversifications of 1,3-disubstituted tetrahydroindazolones were pursued by systematic N-modification of the secondary amine of the pyrrolidine ring using solution-phase parallel synthesis with polymer-supported reagents. A library containing a total of 272 drug-like tetrahydroindazolones, including 85 enantiomeric pairs, was constructed; the average purity, without further purification, was 95%.

Crystal structure of 3,6,6-trimethyl-4-oxo-1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-indazol-7-aminium chloride and its monohydrate

“…Among other synthetic approaches, the Ritter reaction provides a fast entry into structural modifications and is applicable to obtain a combinatorial library of compounds (Turks et al, 2012). Combinatorial chemistry methodology has been reported for the construction of tetrahydroindazolones in enantiomerically pure pairs (Song et al, 2012). Also, enantiomerically pure 7-amino-tetrahydroindazolones (Strakova et al, 2011) have been obtained.…”

Synthesis and Library Construction of Privileged Tetra-Substituted Δ5-2-Oxopiperazine as β-Turn Structure Mimetics

“…To address this unmet need, the synthetic chemistry community has embraced the diversity-oriented synthesis (DOS) strategy, which aims to provide an efficient generation of complex and diverse compound libraries that contain a large number of structurally diverse molecular frameworks . Our group has been focused on the development of divergent synthetic routes for the systematic construction of libraries of drug-like polyheterocycles embedded with privileged substructures, including benzopyran, benzodiazepine, pyrazole, pyrazolopyridine, and tetrahydroindazolone . We named this approach a privileged-substructure-based diversity-oriented synthesis (pDOS) .…”

Synthesis and Anti-HIV Profile of a Novel Tetrahydroindazolylbenzamide Derivative Obtained by Oxazolone Chemistry

“…have been introduced so far. 14,21,22 In principle, using different amino acids as starting materials for the oxazolone formation, the proposed synthetic methodology might give efficient entry into facile diversification of the side-chain, allowing to maximize the molecular diversity of the final tetrahydroindazolylbenzamide. Moreover, the amino group could be further derivatized to improve the pharmaceutical properties including pharmacokinetic and druggability, i.e., by conjugation with biopolymers.…”

“…To the best of our knowledge, the introduction of a functionalized side-chain at the C3-pyrazole carbon of the tetrahydroindazolylbenzamide scaffold is unprecedented, as only alkyl or aryl substituents (e.g., Me, Et, i -Pr, CF 3 , cyclohexyl, Ph, thienyl, etc.) have been introduced so far. ,, In principle, using different amino acids as starting materials for the oxazolone formation, the proposed synthetic methodology might give efficient entry into facile diversification of the side-chain, allowing to maximize the molecular diversity of the final tetrahydroindazolylbenzamide. Moreover, the amino group could be further derivatized to improve the pharmaceutical properties including pharmacokinetic and druggability, i.e., by conjugation with biopolymers.…”