RESUMEN
RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed.
Asunto(s)
Amidas/química , Hidrocarburos Cíclicos/química , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Sulfonas/química , Amidas/síntesis química , Amidas/metabolismo , Animales , Ciclización , Agonismo Inverso de Drogas , Humanos , Hidrocarburos Cíclicos/síntesis química , Hidrocarburos Cíclicos/metabolismo , Ratones , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/metabolismoRESUMEN
The use of the weak base Cs2CO3 in Pd-catalyzed carboamination reactions of N-protected gamma-aminoalkenes with aryl bromides leads to greatly increased tolerance of functional groups and alkene substitution. Substrates derived from (E)- or (Z)-hex-4-enylamines are stereospecifically converted to 2,1'-disubstituted pyrrolidine products that result from suprafacial addition of the nitrogen atom and the aryl group across the alkene. Transformations of 4-substituted pent-4-enylamine derivatives proceed in high yield to afford 2,2-disubstituted products, and cis-2,5- or trans-2,3-disubstituted pyrrolidines are generated in good yield with excellent diastereoselectivity from N-protected pent-4-enylamines bearing substituents at C1 or C3. The reactions tolerate a broad array of functional groups, including esters, nitro groups, and enolizable ketones. The scope and limitations of these transformations are described in detail, along with models that account for the observed product stereochemistry. In addition, deuterium labeling experiments, which indicate these reactions proceed via syn-aminopalladation of intermediate palladium(aryl)(amido)complexes regardless of degree of alkene substitution or reaction conditions, are also discussed.
Asunto(s)
Aminas/química , Nitrógeno/química , Paladio/química , Pirrolidinas/química , Alquenos/química , Aminación , Catálisis , Deuterio/química , Isoquinolinas/química , Coloración y EtiquetadoRESUMEN
A new Pd-catalyzed reaction for the stereoselective synthesis of cyclopentane-fused benzocyclobutenes is described. These transformations likely proceed via carbamate-directed carbopalladation followed by intramolecular C-H activation of an alkylpalladium intermediate. The mechanistic relationship between these transformations and Pd-catalyzed reactions of gamma-(n-Boc-amino)alkenes with aryl bromides that afford pyrrolidines is discussed. Differences in reactivity between Pd-amino and Pd-amido complexes appear to play a key role in the outcome of these transformations.
Asunto(s)
Ciclopentanos/síntesis química , Paladio/química , Compuestos Policíclicos/síntesis química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
[reaction: see text] The palladium-catalyzed carboamination of N-protected gamma-aminoalkenes with aryl bromides and triflates has been achieved under new, mild reaction conditions using the weak base Cs(2)CO(3) in dioxane solvent. These reactions tolerate a wide variety of functional groups, including enolizable ketones, nitro groups, methyl esters, and acetates, which are not compatible with previously described conditions.
Asunto(s)
Carbonatos/química , Paladio/química , Pirrolidinas/síntesis química , Acetatos/química , Alquenos/química , Aminación , Catálisis , Cesio/química , Dioxanos/química , Ésteres/química , Hidrocarburos Bromados/química , Cetonas/química , Mesilatos/química , Modelos Químicos , Nitrocompuestos/química , Solventes/químicaRESUMEN
A new tandem Wittig Rearrangement/aldol reaction of O-benzyl or O-allyl glycolate esters is described. This reaction generates two carbon-carbon bonds and two contiguous stereocenters in a single step from simple starting materials. The [1,2]-Wittig rearrangement proceeds under very mild reaction conditions that do not require the use of a strong base, and the 1,2-diol products are obtained in good yield with excellent diastereoselectivity (>20:1).
Asunto(s)
Aldehídos/síntesis química , Glicolatos/químicaRESUMEN
[reaction: see text] A new stereoselective synthesis of the antifungal and antitumor agents Preussin and 3-epi-Preussin via a Pd-catalyzed carboamination of a protected amino alcohol is described. The key transformation leads to simultaneous formation of the N-C2 bond and the C1'-aryl bond, and allows installation of the aryl group one step from the end of the sequence. This strategy permits the facile construction of a variety of preussin analogues bearing different aromatic groups.