RESUMEN
The reactivity of 3-oxo-ß-lactams with respect to primary amines was investigated in depth. Depending on the specific azetidin-2-one C4 substituent, this reaction was shown to selectively produce 3-imino-ß-lactams (through dehydration), α-aminoamides (through CO elimination), or ethanediamides (through an unprecedented C3-C4 ring opening). In addition to the experimental results, the mechanisms and factors governing these peculiar transformations were also examined and elucidated by means of DFT calculations.
RESUMEN
cis-3-Acetoxy-4-(3-aryloxiran-2-yl)azetidin-2-ones were prepared through a Staudinger [2+2]-cyclocondensation between acetoxyketene and the appropriate epoxyimines in a highly diastereoselective way. Subsequent potassium carbonate-mediated acetate hydrolysis, followed by intramolecular ring closure through epoxide ring opening, afforded stereodefined 3-aryl-4-hydroxy-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones as a novel class of C-fused bicyclic ß-lactams. Selective benzylic oxidation of bicyclic N-(4-methoxybenzyl)-ß-lactams with potassium persulfate and potassium dihydrogen phosphate provided the corresponding N-aroyl derivatives as interesting leads for further ß-lactamase inhibitor development.
Asunto(s)
Azetidinas/química , Azetidinas/síntesis química , beta-Lactamas/química , Técnicas de Química Sintética , Diseño de Fármacos , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
Trans- and cis-2-aryl-3-(2-cyanoethyl)aziridines, prepared via alkylation of the corresponding 2-aryl-3-(tosyloxymethyl)aziridines with the sodium salt of trimethylsilylacetonitrile, were transformed into variable mixtures of 4-[aryl(alkylamino)methyl]butyrolactones and 5-[aryl(hydroxy)methyl]pyrrolidin-2-ones via KOH-mediated hydrolysis of the cyano group, followed by ring expansion. In addition, next to this chemical approach, enzymatic hydrolysis of the former aziridinyl nitriles by means of a nitrilase was performed as well, interestingly providing a selective route towards the above-mentioned functionalized γ-lactams.
Asunto(s)
Aminohidrolasas/metabolismo , Aziridinas/síntesis química , Aziridinas/metabolismo , Lactamas/metabolismo , Lactonas/metabolismo , Aminohidrolasas/química , Aziridinas/química , Hidrólisis , Lactamas/síntesis química , Lactamas/química , Lactonas/síntesis química , Lactonas/química , Estructura Molecular , EstereoisomerismoRESUMEN
The reactivity of 3-hydroxy-4-(1,2-dihydroxyethyl)-ß-lactams with regard to the oxidant sodium periodate was evaluated, unexpectedly resulting in the exclusive formation of new 2-hydroxy-1,4-oxazin-3-ones through a C3C4 bond cleavage of the intermediate 4-formyl-3-hydroxy-ß-lactams followed by a ring expansion. This peculiar transformation stands in sharp contrast with the known NaIO(4)-mediated oxidation of 3-alkoxy- and 3-phenoxy-4-(1,2-dihydroxyethyl)-ß-lactams, which exclusively leads to the corresponding 4-formyl-ß-lactams without a subsequent ring enlargement. In addition, this new class of functionalized oxazin-3-ones was further evaluated for its potential use as building blocks in the synthesis of a variety of differently substituted oxazin-3-ones, morpholin-3-ones and pyrazinones. Furthermore, additional insights into the mechanism and the factors governing this new ring-expansion reaction were provided by means of density functional theory calculations.
Asunto(s)
Azetidinas/química , Oxazinas/síntesis química , beta-Lactamas/síntesis química , Estructura Molecular , Oxazinas/química , Oxidación-Reducción , Ácido Peryódico/química , Estereoisomerismo , beta-Lactamas/químicaAsunto(s)
Técnicas de Química Sintética/métodos , Epiclorhidrina/química , Compuestos Heterocíclicos/síntesis química , Carbono/química , Compuestos Epoxi/química , Hidrocarburos Bromados/química , Hidrocarburos Fluorados/química , Hidrocarburos Yodados/química , Nitrógeno/química , Fósforo/química , Selenio/química , Estereoisomerismo , Azufre/químicaRESUMEN
Purine-ß-lactam chimera were prepared as a novel class of hybrid systems through N-alkylation of 6-benzylamino- or 6-benzyloxypurine with (ω-haloalkyl)-ß-lactams, followed by reductive ring opening of the ß-lactam ring by LiEt(3)BH to provide an entry into the class of purine-aminopropanol hybrids. Both new types of hybrid systems were assessed for their antiviral activity and cytotoxicity, resulting in the identification of eight purine-ß-lactam hybrids and two purine-aminopropanol hybrids as promising lead structures.
Asunto(s)
Antivirales/síntesis química , Lactamas/síntesis química , Propanolaminas/síntesis química , Purinas/síntesis química , Antivirales/química , Antivirales/farmacología , Diseño de Fármacos , Virus de Hepatitis/efectos de los fármacos , Humanos , Lactamas/química , Lactamas/farmacología , Orthomyxoviridae/efectos de los fármacos , Propanolaminas/química , Propanolaminas/farmacología , Purinas/química , Purinas/farmacología , Virus ARN/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The reactivity of 2-(2-mesyloxyethyl)azetidines, obtained through monochloroalane reduction and mesylation of the corresponding ß-lactams, with regard to different nucleophiles was evaluated for the first time, resulting in the stereoselective preparation of a variety of new 4-acetoxy-, 4-hydroxy-, 4-bromo-, and 4-formyloxypiperidines. During these reactions, transient 1-azoniabicyclo[2.2.0]hexanes were prone to undergo an S(N)2-type ring opening to afford the final azaheterocycles, which was rationalized by means of a detailed computational analysis. This approach constitutes a convenient alternative for the known preparation of 3,4-disubstituted 5,5-dimethylpiperidines, providing an easy access to the 5,5-nor-dimethyl analogues as valuable templates in medicinal chemistry. Furthermore, cis-4-bromo-3-(phenoxy or benzyloxy)piperidines were elaborated into the piperidin-3-one framework via dehydrobromination followed by acid hydrolysis.
Asunto(s)
Azetidinas/química , Química Farmacéutica/métodos , Mesilatos/química , Piperidinas/síntesis química , beta-Lactamas/química , Compuestos Aza , Halogenación , Hidrólisis , Espectroscopía de Resonancia Magnética , Modelos Químicos , Estructura Molecular , EstereoisomerismoRESUMEN
trans-4-Aryl-3-chloro-1-(2-chloroethyl)azetidin-2-ones, prepared through cyclocondensation of chloroketene and the appropriate imines in a diastereoselective way, were unexpectedly transformed into 3-aryl-2-(ethylamino)propan-1-ols using LiAlH(4) in THF under reflux. A stepwise analysis showed that the initially formed 1-(1-aryl-2-chloro-3-hydroxypropyl)aziridines were converted into trans-2-aryl-3-(hydroxymethyl)aziridines, most probably via N-spiro bis-aziridinium intermediates, which were subsequently prone to undergo ring opening by LiAlH(4) to afford 3-aryl-2-(ethylamino)propan-1-ols.
Asunto(s)
Azetidinas/química , Azetidinas/síntesis química , Aziridinas/química , Aziridinas/síntesis química , Iminas/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
A variety of 2-amino-3-arylpropan-1-ols, anti-2-amino-3-aryl-3-methoxypropan-1-ols and anti-2-amino-1-arylpropan-1,3-diols were prepared selectively through elaboration of trans-4-aryl-3-chloro-ß-lactams. In addition, a number of 2-(azidomethyl)aziridines was converted into novel 2-[(1,2,3-triazol-1-yl)methyl]aziridines by Cu(I)-catalyzed azide-alkyne cycloaddition, followed by microwave-assisted, regioselective ring opening by dialkylamine towards 1-(2,3-diaminopropyl)-1,2,3-triazoles. Although most of these compounds exhibited weak antiplasmodial activity, six representatives showed moderate antiplasmodial activity against both a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum with IC(50)-values of ≤25 µM.
RESUMEN
trans- and cis-1-Alkyl-4-aryl-3-chloroazetidin-2-ones, prepared through cyclocondensation of chloroketene and the appropriate imines in a diastereoselective way, were transformed into the corresponding non-activated trans- and cis-2-aryl-3-(hydroxymethyl)aziridines via reductive ring contraction using LiAlH(4) in Et(2)O. Furthermore, trans-2-aryl-3-(hydroxymethyl)aziridines were transformed into 2-amino-3-arylpropan-1-ols and anti-2-amino-3-aryl-3-methoxypropan-1-ols by means of an unprecedented ring opening by LiAlH(4) and by MeOH, respectively. cis-2-Aryl-3-(hydroxymethyl)aziridines were shown to be highly reluctant to undergo ring opening by LiAlH(4) and MeOH under similar reaction conditions.
Asunto(s)
Aziridinas/química , Aziridinas/síntesis química , Lactamas/química , Compuestos de Aluminio/química , Compuestos de Litio/química , Metanol/química , Estereoisomerismo , Especificidad por SustratoRESUMEN
A variety of novel syn-2-alkoxy-3-amino-3-arylpropan-1-ols was prepared through LiAlH(4)-promoted reductive ring-opening of cis-3-alkoxy-4-aryl-beta-lactams in Et(2)O. The latter gamma-aminoalcohols were easily converted into cis-5-alkoxy-4-aryl-1,3-oxazinanes using formaldehyde in THF. Both series of compounds were evaluated against a chloroquine sensitive strain of Plasmodium falciparum (D10), revealing micromolar potency for almost all representatives. Eleven compounds exhibited antimalarial activity with IC(50) values of Asunto(s)
Amino Alcoholes/síntesis química
, Oxazinas/síntesis química
, Amino Alcoholes/farmacología
, Animales
, Antimaláricos/síntesis química
, Antimaláricos/farmacología
, Concentración 50 Inhibidora
, Oxazinas/farmacología
, Pruebas de Sensibilidad Parasitaria
, Plasmodium falciparum/efectos de los fármacos
, Propanoles
, Relación Estructura-Actividad