RESUMEN
Pin the amine on the gamma: A new method has been developed for the γ-addition of nitrogen nucleophiles to γ-substituted alkynoates or allenoates through intra- and intermolecular processes that are catalyzed by spirophosphine 1. An asymmetric version of this reaction affords enantioenriched pyrrolidines, indolines, and γ-amino-α,ß-unsaturated carbonyl compounds.
Asunto(s)
Alcadienos/química , Alquinos/química , Indoles/síntesis química , Fosfinas/química , Pirrolidinas/síntesis química , Amidas/síntesis química , Catálisis , Ciclización , EstereoisomerismoRESUMEN
Chiral phosphepine 1 catalyzes the transformation of an array of hydroxy-2-alkynoates into saturated oxygen heterocycles with good enantioselectivity. Phenols are also shown to participate in such phosphine-catalyzed cyclizations, including an asymmetric variant. This method provides a new approach to the enantioselective synthesis of tetrahydrofurans, tetrahydropyrans, and dihydrobenzopyrans.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Oxígeno/química , Fosfinas/química , Catálisis , Cromanos/síntesis química , Cromanos/química , Ciclización , Furanos/síntesis química , Furanos/química , Compuestos Heterocíclicos/química , Piranos/síntesis química , Piranos/química , EstereoisomerismoRESUMEN
Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced intramolecular cyclopropanation of unsaturated terminal epoxides provides an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols. Further elaboration of C-5 and C-6 stannyl-substituted bicyclo[3.1.0]hexan-2-ols via Sn-Li exchange/electrophile trapping or Stille coupling generates a range of substituted bicyclic cyclopropanes. An alternative straightforward cyclopropanation protocol using a catalytic amount of 2,2,6,6-tetramethylpiperidine (TMP) allows for a convenient (1 g-7.5 kg) synthesis of bicyclo[3.1.0]hexan-2-ol and other bicyclic adducts. The synthetic utility of this chemistry has been demonstrated in a concise asymmetric synthesis of (+)-beta-cuparenone. The related unsaturated chlorohydrins also undergo intramolecular cyclopropanation via in situ epoxide formation.
Asunto(s)
Clorhidrinas/química , Ciclopropanos/química , Compuestos Epoxi/química , Aldehídos/química , Compuestos Bicíclicos con Puentes/química , Catálisis , Heptanos/química , Hexanos/química , Isomerismo , Estructura Molecular , Sesquiterpenos/síntesis química , Sesquiterpenos/químicaRESUMEN
Starting from the high throughput screening hit (3), novel N-tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl carboxamides have been identified as potent antagonists of the ion channel TRPV1. The N-quinolinylnicotinamide (46) showed excellent potency at human, guinea pig and rat TRPV1, a favourable in vitro DMPK profile and activity in an in vivo model of inflammatory pain.
Asunto(s)
Benzamidas/química , Benzamidas/farmacología , Isoquinolinas/química , Isoquinolinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Benzamidas/síntesis química , Capsaicina/farmacología , Cobayas , Humanos , Isoquinolinas/síntesis química , Hígado/efectos de los fármacos , Hígado/metabolismo , Estructura Molecular , Quinolinas/síntesis química , Ratas , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
Efficient lithium amide-induced intramolecular cyclopropanation of bishomoallylic and trishomoallylic epoxides is described. The methodology is used in an asymmetric synthesis of sabina ketone.
Asunto(s)
Ciclopropanos/síntesis química , Compuestos Epoxi/síntesis química , Ciclopropanos/química , Compuestos Epoxi/química , Estructura MolecularRESUMEN
A strategy has been established for the synthesis of peptidomimetics derived from unsaturated carbohydrates, and exemplified by the use of methyl 2,6-anhydro-7-azido-3,7-deoxy-4,5-O-isopropylidene-D-lyxo-hept-2-enonate 9 as a dipeptide 'monomer' which can be elaborated from either end. Selective reduction of 9 gives a protected pseudodipeptide ester suitable for use as an amino component, and saponification gives an azido acid suitable for use as a carboxyl component. The 'dimer' product of coupling these two components with TBTU can be similarly elaborated at either end to give a 'trimer' and a further cycle of selective reduction and coupling gave a 'tetramer', 17, a pseudo-octapeptide.