RESUMEN
The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89 %, 99 : 1â er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di- and spirocyclic substitution at C(5) and C(6), as well as benzannulation (>35â examples in total). The DKR process is amenable to scale-up on a 1â g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N-C=Oâ â â isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.
RESUMEN
The concept of bioisostere replacement is of paramount importance in medicinal chemistry, as it can be employed as a rational to expand bioactive chemical space to tackle lead optimization issues like lack of potency, efficacy, and selectivity or pharmacokinetic/dynamic issues. One of the most important building blocks (in the sense of participating in a vast area of chemical space of biological importance) in medicinal chemistry is the 2-phenethyl moiety, a key component of diverse drug-like entities. Although the core 2-phenethylamine structure has been recognized by the drug discovery community, little attention has been given to the various ring-based rescaffolding procedures that can be conducted with this unit. In this regard, a review on the use of 2-heteroarylethylamines displaying pharmacological activity is reported. A detailed description of flexible, amine-opened motifs is provided, that describes therapeutic targets and other potent bioactive examples, which will be a valuable repository of phenyl, heteroaryl, and other replacement units of high value to the drug discovery community.
RESUMEN
A concise review covering updated presence and role of 2-phenethylamines in medicinal chemistry is presented. Open-chain, flexible alicyclic amine derivatives of this motif are enumerated in key therapeutic targets, listing medicinal chemistry hits and appealing screening compounds. Latest reports in discovering new bioactive 2-phenethylamines by research groups are covered too.
Asunto(s)
Química Farmacéutica , Receptores Acoplados a Proteínas G , Fenetilaminas/farmacología , Fenetilaminas/química , Receptores de Dopamina D2RESUMEN
Ezetimibe is a well-known drug that lowers blood cholesterol levels by reducing its absorption in the small intestine when joining to Niemann-Pick C1-like protein (NPC1L1). A ligand-based study on ezetimibe analogues is reported, together with one-hit synthesis, highlighted in the study. A convenient asymmetric synthesis of (2S,3S)-N-α-(R)-methylbenzyl-3-methoxycarbonylethyl-4-methoxyphenyl ß-lactam is described starting from Baylis-Hillman adducts. The route involves a domino process: allylic acetate rearrangement, stereoselective Ireland-Claisen rearrangement and asymmetric Michael addition, which provides a δ-amino acid derivative with full stereochemical control. A subsequent inversion of ester and acid functionality paves the way to the lactam core after monodebenzylation and lactam formation. It also shows interesting results when it comes to a pharmacophore study based on ezetimibe as the main ligand in lowering blood cholesterol levels, revealing which substituents on the azetidine-2-one ring are more similar to the ezetimibe skeleton and will more likely bind to NPC1L1 than ezetimibe.
Asunto(s)
Técnicas de Química Sintética , Diseño de Fármacos , Ezetimiba/análogos & derivados , Ezetimiba/síntesis química , Alelos , Amidas/química , Aminoácidos/química , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/síntesis química , Colesterol/sangre , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Proteínas de Transporte de Membrana/metabolismo , Simulación del Acoplamiento Molecular , Piridinas/química , EstereoisomerismoRESUMEN
The asymmetric synthesis of a compound with the cyclopentan[c]pyran core of iridoid natural products in four steps and 40% overall yield is reported. Our methodology includes a one-pot tandem domino reaction which provides a trisubstituted cyclopentane with five new completely determined stereocenters, which were determined through 2D homo and heteronuclear NMR and n.O.e. experiments on different compounds specially designed for this purpose, such as a dioxane obtained from a diol. Due to their pharmaceutical properties, including sedative, analgesic, anti-inflammatory, CNS depressor or anti-conceptive effects, this methodology to produce the abovementioned iridoid derivatives, is an interesting strategy in terms of new drug discovery as well as pharmaceutical development.
Asunto(s)
Productos Biológicos/síntesis química , Ciclopentanos/síntesis química , Iridoides/síntesis química , Piranos/síntesis química , Benzaldehídos/química , Productos Biológicos/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Ciclopentanos/química , Iridoides/química , Oxidación-Reducción , Espectroscopía de Protones por Resonancia Magnética , Piranos/química , EstereoisomerismoRESUMEN
The title compound, C22H25NO5, was prepared by CAN [cerium(IV) ammonium nitrate] oxidation of the corresponding ß-lactam. The dihedral angle between the benzene rings is 13.3â (4)° and the C-N-C(=O)-C torsion angle is 176.1â (6)°. In the crystal, amide-C(4) N-Hâ¯O and reinforcing C-Hâ¯O hydrogen bonds link the mol-ecules into infinite [010] chains. Further C-Hâ¯O hydrogen bonds cross-link the chains in the c-axis direction.