RESUMO
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.
Assuntos
Alcadienos/química , Alcinos/química , Indóis/síntese química , Fosfinas/química , Pirrolidinas/síntese química , Amidas/síntese química , Catálise , Ciclização , EstereoisomerismoRESUMO
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.
Assuntos
Compostos Heterocíclicos/síntese química , Oxigênio/química , Fosfinas/química , Catálise , Cromanos/síntese química , Cromanos/química , Ciclização , Furanos/síntese química , Furanos/química , Compostos Heterocíclicos/química , Piranos/síntese química , Piranos/química , EstereoisomerismoRESUMO
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.
Assuntos
Cloridrinas/química , Ciclopropanos/química , Compostos de Epóxi/química , Aldeídos/química , Compostos Bicíclicos com Pontes/química , Catálise , Heptanos/química , Hexanos/química , Isomerismo , Estrutura Molecular , Sesquiterpenos/síntese química , Sesquiterpenos/químicaRESUMO
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.
Assuntos
Benzamidas/química , Benzamidas/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Benzamidas/síntese química , Capsaicina/farmacologia , Cobaias , Humanos , Isoquinolinas/síntese química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estrutura Molecular , Quinolinas/síntese química , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
Efficient lithium amide-induced intramolecular cyclopropanation of bishomoallylic and trishomoallylic epoxides is described. The methodology is used in an asymmetric synthesis of sabina ketone.
Assuntos
Ciclopropanos/síntese química , Compostos de Epóxi/síntese química , Ciclopropanos/química , Compostos de Epóxi/química , Estrutura MolecularRESUMO
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.