RESUMEN
The origin of the stereoselectivity in the lithiation/trapping of 2-alkylideneaziridines bearing a chiral group as the nitrogen substituent was investigated. Optimal reaction conditions were discovered by in situ FT-IR monitoring. In addition, it has been found that the solvent and the alkene substitution pattern are important factors able to impart a switch in stereoselectivity. While lithiation of the alkylideneaziridine ring flanked by either a fully substituted or a Z-configured alkene pendant occurs stereoselectively in THF, in contrast unsubstituted 2-methyleneaziridine undergoes lithiation in toluene with the opposite sense of stereoinduction. Lithiation experiments, on deuterium labelled 2-alkylideneaziridines, confirmed the configurational stability of the lithiated intermediates. A model based on complexation and proximity effects was proposed to rationalize the reactivity. This model assumes that slowly equilibrating N-invertomers undergo deprotonation (lithiation) at different rates and that the stereochemical outcome is established during the deprotonation step.
Asunto(s)
Aziridinas/química , Litio/química , Nitrógeno/química , Espectroscopía Infrarroja por Transformada de Fourier , EstereoisomerismoRESUMEN
The reaction of ortho-lithiated aryloxiranes with various enaminones straightforwardly affords new functionalized isochromanes as mixtures of two epimeric stereoisomers in reasonable to very good yields (50-90%). The two diastereomers, which show a high structural variability, can be easily separated by column chromatography.
Asunto(s)
Cromanos/química , Cromanos/síntesis química , Compuestos Epoxi/química , Litio/química , Estructura Molecular , EstereoisomerismoRESUMEN
The employment of hexane/N,N,N',N'-tetramethylethylenediamine (TMEDA) dramatically hinders the racemization of those lithiated styrene oxides (trifluoromethyl-, chloro-, and phenylthio-substituted) that have been proven to be configurationally unstable in THF on the timescale of their reactions. The barriers to inversion and the activation parameters, calculated (Eyring equation) for reactions performed in THF, THF/TMEDA, and hexane/TMEDA, suggest the intervention of particular enantiomerization mechanisms for each case. The role of TMEDA in both coordinating and noncoordinating solvents has also been questioned and discussed in light of the kinetic data gathered and a model for deprotonation in hexane/TMEDA has also been proposed. The synthetic benefits of our results became apparent on establishing an asymmetric synthesis of an industrially important antifungal agent.
Asunto(s)
Compuestos Epoxi/química , Etilenodiaminas/química , Compuestos de Litio/química , Conformación Molecular , Solventes/química , EstereoisomerismoRESUMEN
Diastereomeric oxazolinylaziridines (R,R)-9 and (R,S)-9 have been regioselectively lithiated at the α-position with respect to the oxazolinyl ring. The resulting aziridinyllithium compounds proved to be chemically and configurationally stable under the experimental conditions used, thus furnishing, upon trapping with electrophiles, chiral 2,2-disubstituted aziridines, in contrast to the corresponding α-lithiated oxazolinyloxiranes that have been reported to be chemically stable but configurationally unstable. This peculiar behavior of the nitrogen-bearing heterocycle has been rationalized on the basis of DFT calculations and the observed dynamics of the aziridine nitrogen atom. The DFT analysis allowed the disclosure of a solvent-dependent differing stability of diastereomeric lithiated aziridines (R,R)-9-Li and (R,S)-9-Li, suggesting η(3)-coordinated oxazolinylaziridinyllithium compounds as likely intermediates. Such intermediates could be the result of a dynamically controlled lithiation that relies on the preliminary formation of a complex between the lithiating agent and the oxazolinyl ring. According to this model, the competing complexation of the lithiating agent by the lone pair of electrons on the aziridine nitrogen would cause addition to the oxazoline C=N bond, thus ending up with the formation of oxazolidines, which are precursors of useful chiral ketoaziridines. The proposed model has been also supported by estimating the nitrogen inversion barrier by dynamic NMR spectroscopic experiments.
Asunto(s)
Aziridinas/síntesis química , Litio/química , Nitrógeno/química , Compuestos Organometálicos/síntesis química , Oxazoles/síntesis química , Aziridinas/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/química , Oxazoles/química , EstereoisomerismoRESUMEN
A highly stereo- and regioselective functionalisation of chiral non-racemic aziridines is reported. By starting from a parent enantioenriched aziridine and finely tuning the reaction conditions, it is possible to address the regio- and stereoselectivity of the lithiation/electrophile trapping sequence, thereby allowing the preparation of highly enantioenriched functionalised aziridines. From chiral N-alkyl trans-2,3-diphenylaziridines (S,S)-1 a,b, two differently configured chiral aziridinyllithiums could be generated (trans-1 a,b-Li in toluene and cis-1 a,b-Li in THF), thus disclosing a solvent-dependent reactivity that is useful for the synthesis of chiral tri-substituted aziridines with different stereochemistry. In contrast, chiral aziridine (S,S)-1 c showed a temperature-dependent reactivity to give chiral ortho-lithiated aziridine 1 c-ortho-Li at -78 °C and α-lithiated aziridine 1 c-α-Li at 0 °C. Both lithiated intermediates react with electrophiles to give enantioenriched ortho- and α-functionalised aziridines. The reaction of all the lithiated aziridines with carbonyl compounds furnished useful chiral hydroxyalkylated derivatives, the stereochemistry of which was ascertained by X-ray and NMR spectroscopic analysis. The usefulness of chiral non-racemic functionalised aziridines has been demonstrated by reductive ring-opening reactions furnishing chiral amines that bear quaternary stereogenic centres and chiral 1,2-, 1,3- and 1,5-aminoalcohols. It is remarkable that the solvent-dependent reactivity observed with (S,S)-1 a,b permits the preparation of both the enantiomers of amines (11 and ent-11) and 1,2-aminoalcohols (13 and ent-13) starting from the same parent aziridine. Interestingly, for the first time, a configurationally stable chiral α-lithiated aziridine (1 c-α-Li) has been generated at 0 °C. In addition, ortho-hydroxyalkylated aziridines have been easily converted into chiral aminoalkyl phthalans, which are useful building blocks in medicinal chemistry.
Asunto(s)
Aminas/síntesis química , Amino Alcoholes/síntesis química , Aziridinas/química , Aminas/química , Amino Alcoholes/química , Litio/química , Estructura Molecular , Oxidación-Reducción , Solventes , EstereoisomerismoRESUMEN
After a long adolescence, the chemistry of lithium carbenoids has currently been entering its maturity bringing a dowry of a more in-depth and less empirical knowledge of the structure and configurational stability of such double-faced intermediates; this, thanks in particular to the synergistic and harmonic cooperation between calculations and the most modern NMR techniques now at our disposal. Such knowledge has stimulated the development of fruitful stereoselective applications in the field of organic synthesis, providing in addition a rationale to observed selectivities. Such aspects together with the role played by aggregation and solvation on the structure-reactivity relationship are highlighted throughout this Minireview with selected examples extracted from recent literature.
Asunto(s)
Alcanos/química , Alquenos/química , Compuestos de Litio/química , Química Orgánica , Espectroscopía de Resonancia Magnética , Estructura Molecular , Teoría Cuántica , Estereoisomerismo , TemperaturaRESUMEN
The configurational stability of some lithiated fluorinated styrene oxides has been investigated. Chemical studies have shown that in ethereal solvents alpha-lithiated ortho-, meta-, and para-fluorostyrene oxides (2-Li, alpha-5-Li, and alpha-6-Li) are all configurationally stable in the reaction time scale, whereas alpha-lithiated ortho-, meta-, and para-trifluoromethylstyrene oxides (9-Li, 13-Li, and 14-Li) are configurationally unstable. Optically active oxiranyllithiums 2-Li and 9-Li, could be stereospecifically generated and quenched with electrophiles. The corresponding derivatives were then successfully subjected to regiospecific ring-opening reactions with amines to give fluorinated beta-amino alcohols with a stereodefined quaternary carbinol center, which are useful synthons in medicinal chemistry. The barriers of inversion have been calculated (Eyring equation) for oxiranyllithiums 9-Li, 13-Li, and 14-Li by determining the enantiomeric ratios after electrophilic quenching on aging the enantioenriched organolithium for different times in THF; in the case of 9-Li, activation parameters have also been determined. Mechanisms that may be responsible of the racemization oxiranyllithiums 9-Li, 13-Li, and 14-Li undergo once generated are also discussed.
Asunto(s)
Amino Alcoholes/química , Compuestos Epoxi/química , Litio/química , Compuestos Organometálicos/química , Estirenos/química , Halogenación , Cinética , Estructura Molecular , EstereoisomerismoRESUMEN
A multinuclear magnetic resonance investigation, supported by density functional theory calculations, has been synergically used to investigate the configurational stability, reactivity and aggregation states of alpha-lithiated styrene oxide in THF at 173 K. NMR studies on alpha-lithiated [alpha,beta-(13)C(2)]styrene oxide (also in an enantiomerically enriched form) proved that in THF this oxiranyllithium is mainly present as a solvated monomeric species in equilibrium with a complex mixture of stereoisomeric dimeric aggregates, as well as with bridged and tetrameric aggregates. The fact that some C(alpha)-Li bonds are partially broken in some stereoisomers reduces their symmetry and complicates the NMR spectra: two diastereoisomers each having a pair of diastereotopic carbon atoms slowly inverting at the lithium atom in absence of tetramethylethylenediamine (TMEDA) have been detected. A ((13)C,(7)Li)-HMQC experiment to correlate (7)Li and (13)C resonances of the various aggregates has been performed for the first time. From natural bond analysis, the monomeric aggregate was proven to have a lower carbenoid character with respect to bridged O-coordinated dimeric aggregates. The employment of suitable experimental conditions in terms of concentration, temperature and the presence or not of TMEDA are crucial to mitigate at the best the "carbene-like" reactivity of lithiated styrene oxide toward intermolecular C-Li insertions, eliminative dimerisation reactions and ring-opening reactions. A two-step mechanism for the deprotonation of styrene oxide by sBuLi in THF has been proposed and discussed as well as competitive side reactions.
Asunto(s)
Compuestos Epoxi/química , Litio/química , Metano/análogos & derivados , Espectroscopía de Resonancia Magnética , Metano/química , Estructura Molecular , EstereoisomerismoRESUMEN
The lithiation reaction of o-tolylaziridine 1 has been investigated by using the aziridine ring capability to act as a directing metalation group. Trapped with electrophiles, the resulting o-aziridinyl benzyllithium 1-Li gives access to several functionalized aziridines 2a-j. The hydroxyalkylated derivatives 2d-j were converted into important scaffolds such as isochromans 3a-d. A stereoselective preparation of isochromans (R)-3b, (1R,3S)-3d, and (1R,3R)-3d has been developed starting from enantioenriched o-tolylaziridine.
Asunto(s)
Aziridinas/química , Cromanos/química , Cromanos/síntesis química , Litio/química , Alquilación , EstereoisomerismoRESUMEN
A short and efficient synthesis of tetrahydroindenofuranones based on the Michael addition of ortho-lithiated aryloxiranes to alkylidene malonates followed by the nucleophilic oxirane ring-opening and subsequent lactonization is described. The methodology has been applied to the synthesis of a structural analogue of epipodophyllotoxins.
Asunto(s)
Compuestos Epoxi/química , Furanos/síntesis química , Indenos/síntesis química , Litio/química , Malonatos/química , Compuestos Organometálicos/química , Ciclización , Furanos/química , Indenos/química , Estructura Molecular , EstereoisomerismoRESUMEN
The lithiation reaction of monophenyl- and diphenylaziridines has been investigated in detail in an effort to understand why the former undergo exclusively or mainly ortho-lithiation while the latter are lithiated exclusively at the alpha-position. Evidence is reported that ruled out the possibility that the alpha-lithiation, observed for the diphenylaziridines, is the result of an ortho- to alpha-translocation phenomenon, thus substantiating a direct alpha-deprotonation process. The role of the aziridine nitrogen lone-pair has been considered: dynamics at the aziridine nitrogen as well as complex-induced proximity effects seem to be responsible for the observed regioselectivity in both monophenyl and diphenylaziridines. It turns out that, by tuning the reaction conditions for the lithiation of trans-1-alkyl-2-methyl-3-phenylaziridines, it is possible to generate with high regioselectivity alpha- and/or ortho-lithiated aziridines, which can be stereoselectively functionalized by electrophilic trapping. A regioselective ortho-functionalization of diphenylaziridines is made possible by halogen- or tin-lithium exchange and by deprotonation of bis-deuterated aziridines.
Asunto(s)
Aziridinas/química , Química Orgánica/métodos , Nitrógeno/química , Electroquímica/métodos , Cromatografía de Gases y Espectrometría de Masas/métodos , Cinética , Espectroscopía de Resonancia Magnética , Modelos Químicos , TemperaturaRESUMEN
Chemical studies have shown that, in ethereal solvents, oxiranyllithium Li-1 is configurationally unstable either on the macroscopic (Hoffmann's text) or microscopic time scale at low temperature (175 K). An optically pure sample of oxazolinyloxirane 1, once deprotonated, racemized within 1 min at -130 degrees C in THF/Et(2)O (3:2) (t(1/2) = 6.05 s); the application of the Eyring equation suggested a barrier to inversion for Li-1 of 8.8 kcal/mol at -130 degrees C. Despite this, Li-1 exhibited an unusual thermal stability undergoing a successfully deuterium incorporation (>98%) also at 25 degrees C with a little decomposition. The structure, configurational stability, and stereodynamics in solution of alpha-lithiated oxazolinyloxirane Li-1 have been also synergically investigated by means of in situ IR and NMR spectroscopy. IR spectroscopic studies showed that lithiation of 1 is complete at -98 degrees C within 1 min and is accompanied by a decrease of the CN wavenumber by only 60 cm(-1), so supporting the idea that the structure of Li-1 may be more similar to that of an "organolithium" rather than an "azaenolate". In addition to this, multinuclear magnetic resonance studies suggested that at least in a range of concentration of 0.08-0.3 M, Li-1 mainly exists in THF as a monomeric eta(3)-aza-allyl coordinated species rapidly equilibrating, on the NMR time scale, with a complex mixture of diastereomeric oxazoline-bridged dimeric species variously intraaggregated. An exchange mechanism by which monomers would interchange their Li atoms via one of the above dimeric species and which may be responsible for the fast racemization Li-1 undergoes as soon as is generated has been proposed.
Asunto(s)
Compuestos Aza/química , Óxido de Etileno/análogos & derivados , Compuestos Organometálicos/química , Aniones/química , Éteres , Óxido de Etileno/química , Litio/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Solventes , Espectrofotometría Infrarroja , Estereoisomerismo , TemperaturaRESUMEN
Human Rhinovirus (HRV) is the most important aetiologic agent of common cold in adults and children. HRV is a single-stranded, positive sense RNA virus and, despite the high level of conservation among different serotypes, sequence alignment of viral protease 3C with mammalian protease reveals no homology. Thus, protease 3C is an optimal target for the development of anti-HRV agents. In the present work we investigated the design, the synthesis and the development of new potential reversible inhibitors against HRV protease 3C. Docking studies on the crystallized structure of HRV2 protease 3C led us to the design and the synthesis of a series of 3,5 disubstituted benzamides able to act as analogues of the substrate. We also developed 1,3,5 trisubstituted benzamides where aromatic substitutions on the aryl ring led us to investigate the importance of pi-pi interaction on the stabilization of protease 3C-inhibitor complex. All structures were tested for enzymatic inhibition on HRV14 protease 3C. Results highlighted the inhibitory activity of compounds 13, 14, and 20 (91%, 81%, and 85% at 10 microM, respectively), with the latter exhibiting an ID(50) (dose that inhibits 50% of the viral cytopathic effect) on HRV-14=25 microg/ml.
Asunto(s)
Antivirales/química , Benzamidas/química , Benzamidas/farmacología , Resfriado Común/tratamiento farmacológico , Cisteína Endopeptidasas/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/química , Rhinovirus/enzimología , Proteínas Virales/efectos de los fármacos , Proteasas Virales 3C , Humanos , Concentración 50 Inhibidora , Relación Estructura-Actividad , Proteínas Virales/antagonistas & inhibidoresRESUMEN
[structure: see text]. The lithiation reaction of cis- and trans-N-alkyl-2,3-diphenylaziridines has been investigated. While cis-diphenylaziridines do not undergo any lithiation upon treatment with organolithiums, the lithiation reaction of the trans counterparts is completely alpha-regioselective and the stereochemical course of the lithiation-trapping sequence is solvent dependent: inversion of configuration in coordinating solvents (THF or toluene/crown ether) and retention in hexane, ether, or toluene. The preparation of stereodefined functionalized N-alkyl-2,3-diphenylaziridines is described.
Asunto(s)
Aziridinas/química , Litio/química , Compuestos Organometálicos/química , Solventes/química , Electroquímica , Estructura Molecular , EstereoisomerismoRESUMEN
The regioselective lithiation of terminal oxazolinylaziridines has been investigated. The steric hindrance of the nitrogen substituent in 1-trityl-2-oxazolinylaziridine 3a, combined with the coordinating ability of the oxazolinyl group, causes beta-lithiation, whereas a completely regioselective alpha-lithiation is observed with the much less sterically demanding 1-benzyl-2-oxazolinylaziridine 3c and a competition between alpha- and beta-lithiation occurs with 1-cumyl-2-oxazolinylaziridine 3b in which the N-substituent has a steric hindrance in between the trityl and the benzyl groups. The application of the lithiation-trapping sequence for the preparation of enantioenriched 2,3-cis-disubstituted oxazolinylaziridines and aziridino-gamma-lactones is also reported.
Asunto(s)
Aziridinas/química , Litio/química , Lactonas/química , Oxazoles/química , EstereoisomerismoAsunto(s)
Aniones/química , Aziridinas/química , Aziridinas/síntesis química , Dimerización , Nitrógeno/química , ProtonesRESUMEN
[reaction: see text] A stereoselective synthesis of 9,10-epoxy-1,6-dioxa-4,7-diazaspiro[4,5]decanes has been developed on the basis of the addition of beta-lithiated oxazolinyloxiranes to nitrones. Conversion of these spirocyclic derivatives into 4,5-epoxy-1,2-oxazin-6-ones and successively into alpha,beta-epoxy-gamma-amino acids, alpha-hydroxy-gamma-amino acids, and gamma-butyrolactams is described.
Asunto(s)
Aminoácidos/síntesis química , Compuestos Epoxi/síntesis química , Litio/química , Óxidos de Nitrógeno/química , Oxazinas/síntesis química , Oxazoles/química , Aminoácidos/química , Compuestos Epoxi/química , Oxazinas/química , EstereoisomerismoRESUMEN
A simple and efficient stereoselective synthesis of polysubstituted beta,gamma-epoxyhydroxylamines and 4-hydroxyalkyl-1,2-oxazetidines, based on the addition of alpha-lithiated aryloxiranes to nitrones and subsequent cyclization of the corresponding intermediates in a 4-exo-tet mode, is described.
RESUMEN
It has always been a firm conviction of the scientific community that the employment of both anhydrous conditions and water-free reaction media is required for the successful handling of organometallic compounds with highly polarised metal-carbon bonds. Herein, we describe how, under heterogeneous conditions, Grignard and organolithium reagents can smoothly undergo nucleophilic additions to γ-chloroketones, on the way to 2,2-disubstituted tetrahydrofurans, "on water", competitively with protonolysis, under batch conditions, at room temperature and under air. The reactivity of the above organometallic reagents has also been investigated in conventional anhydrous organic solvents and in bio-based eutectic and low melting mixtures for comparison. The scope and limitations of this kind of reaction are discussed.
RESUMEN
The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCL8-induced human PMNs chemotaxis. We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1. The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity. Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.