RESUMEN
On-flow ReactIR and (1)H NMR reaction monitoring, coupled with in situ intermediate characterization, was used to aid in the mechanistic elucidation of the N-chlorosuccinimide mediated transformation of an α-thioamide. Multiple intermediates in this reaction cascade are identified and characterized, and in particular, spectroscopic evidence for the intermediacy of the chlorosulfonium ion in the chlorination of α-thioamides is provided. Further to this, solvent effects on the outcome of the transformation are discussed. This work also demonstrates the utility of using a combination of ReactIR and flow NMR reaction monitoring (ReactNMR) for characterizing complex multicomponent reaction mixtures.
Asunto(s)
Acrilamidas/síntesis química , Succinimidas/química , Tioamidas/química , Acrilamidas/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Espectrofotometría InfrarrojaRESUMEN
Homologation and cyclization back to the chiral methine of compound 3 yields achiral 4,4-disubstituted piperidine privileged structures (e.g., 8a) useful in the construction of melanocortin 4 receptor (MC4R) ligands. The piperidine nitrogen was replaced with carbon, oxygen, sulfur, and sulfone with minor erosion of binding. The methyl cyclohexane substituent was the most potent while significant affinity was still seen for smaller lipophilic groups such as ethyl.
Asunto(s)
Piperazinas/síntesis química , Piperazinas/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Sitios de Unión , Carbono/química , Ciclohexanos/química , Ligandos , Oxígeno/química , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Relación Estructura-Actividad , Sulfonas/química , Azufre/químicaRESUMEN
A series of benzylic piperazines (e.g., 4 and 5) attached to an 'address element', the dipeptide H-D-Tic-D-p-Cl-Phe-OH, 3 has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure-activity relationship (SAR) studies on the N-terminal residue of the 'address element'. Several novel dipeptides and reduced dipeptides with high MC4R binding affinities and selectivity emerged from this SAR study.
Asunto(s)
Dipéptidos/síntesis química , Dipéptidos/farmacología , Receptor de Melanocortina Tipo 4/efectos de los fármacos , Dipéptidos/química , Ligandos , Estructura Molecular , Piperazinas/química , Unión Proteica , Receptor de Melanocortina Tipo 4/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
This paper describes a convenient protocol for the regioselective sulfonylation of alpha-chelatable alcohols. Typically, the reaction of alpha-heterosubstituted alcohols with 1 equiv of p-TsCl and 1 equiv of Et(3)N in the presence of 2 mol % of Bu(2)SnO leads to rapid, regioselective, and exclusive monotosylation. The pK(a) of the amine was correlated to the reaction rate. A plausible mechanism for this reaction has been proposed on the basis of (119)Sn NMR studies.