RESUMEN
1-Aryltetrahydroisoquinolines (1-arylTHIQs) are important structural motifs in many alkaloids and biologically active compounds. Ligand 2a promotes the enantioselective addition of arylzinc reagents to 3,4-dihydroisoquinoline N-oxide to yield (S)-1-arylTHIQs in 97-99% ee. Pinacol arylboronic esters are the optimal precursors for the arylzinc reagents. This method is applied to the enantioselective synthesis of Solifenacin.
Asunto(s)
Tetrahidroisoquinolinas/síntesis química , Catálisis , Técnicas Químicas Combinatorias , Ésteres , Estructura Molecular , Estereoisomerismo , Tetrahidroisoquinolinas/químicaRESUMEN
[structure: see text] A series of squaric acid-peptide conjugates were synthesized and evaluated as inhibitors of MMP-1. The cyclobut-3-enedione core was substituted at the 3-position with several functional groups, such as -N(alkyl)OH, -NHOH, and -OH, that are designed to bind to the zinc atom in the active site of the metalloprotease. The 4-position of the cyclobut-3-enedione was derivatized with mono- or dipeptides that are designed to bind in the S1' and S2' subsites of the enzyme, and position the metal chelating group appropriately in the active site for binding to zinc. Positional scanning revealed that -N(Me)OH provided the highest level of inhibition among the chelating groups that were tested, and Leu-Tle-NHMe was the preferred amino acid sequence. A combination of these groups yielded an inhibitor with an IC50 value of 95 microM. For one inhibitor, conversion of one of the carbonyl groups on the cyclobut-3-enedione core to a thiocarbonyl group resulted in a 18-fold increase in potency, and yielded a compound with an IC50 value of 15 microM.
Asunto(s)
Ciclobutanos/química , Inhibidores de la Metaloproteinasa de la Matriz , Péptidos/farmacología , Inhibidores de Proteasas/farmacología , Péptidos/química , Inhibidores de Proteasas/químicaRESUMEN
This report describes a high-throughput method for measuring the enantiomeric excess of allylic acetates. Such methods are useful tools for screening libraries of potential catalysts for enantioselective reactions. This technique, which is called EMDee for an enzymatic method for determining enantiomeric excess, uses the lipase from Pseudomonas cepacia to hydrolyze the (R) enantiomer of an allylic acetate, while the (S) enantiomer does not react. The rate of the reaction is monitored by measuring the acetic acid that is produced during the hydrolysis reaction with a pH indicator. Using the Michaelis-Menten equation, the rate of the reaction can be correlated with the concentration of the (R) enantiomer. This method can process 88 samples in less that 30 min.