RESUMO
Herein we describe our efforts on the Lewis acid catalyzed stereoselective ring-opening of pentafulvene derived diazabicyclic olefins using various ortho-functionalized aryl iodides such as 2-iodoanilines, 2-iodophenols and 2-iodobenzene thiols to access trans-1,2 disubstituted alkylidenecyclopentenes. The scope of the reaction was also explored with a range of easily available aromatic and aliphatic alcohols. Furthermore, the palladium catalyzed intramolecular Heck cyclization of trans-1,2 disubstituted alkylidenecyclopentenes would provide an easy approach for the synthesis of highly functionalized spiropentacyclic frameworks consisting of a cyclopentene fused to an indoline/benzothiophene and pyrazolidine.
RESUMO
The described titanium-catalyzed hydroalumination of conjugated dienes opens up a new way to allylaluminium reagents. The reaction is carried out by using diisobutylaluminium hydride (DIBAL-H) and a catalytic amount of [Cp2TiCl2] (Cp = cyclopentadienyl). When applied to mono- and disubstitued pentafulvenes, this reaction proceeds in a highly endocyclic manner. The formed allylaluminium compounds react regio- and stereoselectively with both aldehydes and ketones to afford homoallylic alcohols that are suitable synthons for functionalized cyclopentanones. An extension of this methodology to simple dienes was also investigated. In the proposed mechanism, the initially formed bimetallic species (Ti/Al) are involved in the two possible catalytic cycles with a direct hydroalumination or/and a hydrotitanation followed by a titanium to aluminium transmetallation.
RESUMO
A palladium/Lewis acid mediated stepwise and one-pot transformation of pentafulvene derived diazabicyclic olefins is described. The reaction offers a facile strategy for the synthesis of novel spiropentacyclic motifs with indoline and pyrazolidine fused to the cyclopentene core.
RESUMO
Mixtures of 2,4- and 2,5-disubstituted zirconacyclopentadienes were obtained by the reductive dimerisation of terminal alkynes using the Cp2ZrCl2/lanthanum system. Reactions of dihalophosphines with these mixtures afforded selectively the corresponding 2,4-disubstituted phospholes and 1,4-disubstituted butadienes. A new series of phospholes was characterized by multi-nuclear NMR spectroscopy and X-ray analysis. A possible explanation for the observed selectivity was obtained from X-ray studies and DFT analysis of the intermediate zirconacyclopentadienes.
RESUMO
Allyltitanocene complexes can be generated by reacting pentafulvenes with DIBAL-H and Cp2TiCl2. Their coupling with aldehydes affords homoallylic alcohols in a highly regio- and stereoselective manner. The potential of this method for the stereoselective synthesis of cyclopentane derivatives is illustrated.
Assuntos
Álcoois/síntese química , Ciclopentanos/química , Compostos Organometálicos/química , Titânio/química , Álcoois/química , Estrutura Molecular , Compostos Organometálicos/síntese química , EstereoisomerismoRESUMO
Conformational restrictions: Based on the pharmacophore model for 5-HT(6) receptor ligands (shown), tryptamine analogues bearing a cyclopropyl ring on the α-position of the tryptamine side chain were synthesized and evaluated against 5-HT receptors. N,N-Dimethyl-1-arylsulfonyltryptamine derivatives exhibited promising selectivity for 5-HT(6) over 5-HT(1a) and 5-HT(4) receptors and interesting activity against 5-HT(6) (K(i) =â¼0.15â µM; IC(50) =â¼0.20â µM).
Assuntos
Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Triptaminas/química , Triptaminas/farmacologia , Animais , Ciclopropanos/síntese química , Ciclopropanos/química , Ciclopropanos/farmacologia , Humanos , Antagonistas da Serotonina/síntese química , Relação Estrutura-Atividade , Triptaminas/síntese químicaRESUMO
A spectacular inversion of α- to γ-regioselectivity in the allylzincation of imines can be achieved by fine-tuning of the N-side chain. This approach allows easy preparation of regioisomeric amines, in racemic as well as enantiopure forms. The usefulness of the method is illustrated by the parallel asymmetric syntheses of 2,3- and 2,5-diphenylpyrrolidines.
Assuntos
Iminas/química , Aminas/química , Estrutura Molecular , Pirrolidinas/síntese química , EstereoisomerismoRESUMO
Access to nonracemic amino ketones via a hydrozirconation/transmetalation/acylation sequence applied to Boc-protected 1-aminobut-3-enes is presented. This method was applied to the stereoselective synthesis of cyclic imines (or iminiums) which were diastereoselectively converted into 2-cis-substituted and 2,6-cis-disubstituted piperidines. The potential of this approach in the field of alkaloid synthesis was illustrated by the synthesis of (-)-coniine and (-)-indolizidine 209D. Furthermore, access to indolizidines bearing a quaternary center could also be envisioned through this strategy.
Assuntos
Alcaloides/síntese química , Indolizidinas/síntese química , Indolizinas/síntese química , Piperidinas/síntese química , Acilação , Alcaloides/química , Indolizidinas/química , Indolizinas/química , Estrutura Molecular , Piperidinas/química , EstereoisomerismoRESUMO
An asymmetric variant of the hydrozirconation reaction has been established starting from Boc-protected chiral allylic amines. The resulting diastereoselectively formed N-functionalized organozirconiums can be considered as promising chirons. In this case, they have been transformed into enantiomerically enriched cis-2,3-disubstituted azetidines through a iodination/cyclization sequence.
Assuntos
Azetidinas/química , Hidrogênio/química , Silicatos/química , Zircônio/química , Ciclização , Iodo/química , Estrutura Molecular , Pirrolidinas/química , EstereoisomerismoRESUMO
A highly diastereoselective synthesis of trans-2-substituted cyclopentylamines via a tandem hydrozirconation/Lewis acid-mediated cyclization sequence applied to butenyl oxazolidines is described. The method allows an easy preparation of diversely substituted cyclopentylamines which appear to be useful synthetic intermediates. This was further illustrated by the syntheses of (±)-Rodocaine, (±)-trans-pentacin, and enantiomerically enriched trans-cyclopentane-1,2-diamine.
Assuntos
Aminas/síntese química , Anilidas/síntese química , Ciclopentanos/síntese química , Oxazóis/química , Aminas/química , Anilidas/química , Ciclização , Ciclopentanos/química , Ácidos de Lewis/química , Estrutura Molecular , EstereoisomerismoRESUMO
The synthesis of an optically pure proline-based tryptophan mimetic is described. The strategy involves the in situ generation of an unprecedented allylmetal species containing the indole moiety, and its coupling with a chiral imine. The construction of the 3-substituted proline skeleton is then achieved through a hydrozirconation/iodination sequence applied to the resulting homoallylic amine.
Assuntos
Materiais Biomiméticos/síntese química , Prolina/química , Triptofano/química , Iodo/química , Estrutura Molecular , EstereoisomerismoRESUMO
Nitrogen-in-the-ring analogues of l-fucose and l-rhamnose were prepared, which feature a spirocyclopropyl moiety in place of the methyl group of the natural sugar. The synthetic route involved a titanium-mediated aminocyclopropanation of a glycononitrile as the key step. Four new spirocyclopropyl iminosugar analogues were generated, which displayed some activity towards l-fucosidase and l-rhamnosidase.
Assuntos
Ciclopropanos/síntese química , Inibidores Enzimáticos/síntese química , Fucose/análogos & derivados , Ramnose/análogos & derivados , Compostos de Espiro/síntese química , Ciclopropanos/química , Ciclopropanos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fucose/síntese química , Fucose/química , Fucose/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Cinética , Espectroscopia de Ressonância Magnética , Rotação Ocular , Ramnose/síntese química , Ramnose/química , Ramnose/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Compostos de Espiro/química , Compostos de Espiro/farmacologia , alfa-L-Fucosidase/antagonistas & inibidores , alfa-L-Fucosidase/metabolismoRESUMO
The synthesis of carbohydrate-based glycogen phosphorylase inhibitors is attractive for potential applications in the treatment of type 2 diabetes. A titanium-mediated synthesis led to a benzoylated C-glucosylated cyclopropylamine intermediate, which underwent a benzoyl migration to afford the corresponding 2-hydroxy-C-glycoside. X-ray crystallographic studies revealed a unit cell composed of four molecules as pairs of dimers connected through two hydrogen bonds. The deprotection of the benzoate esters under Zemplén conditions afforded a glycogen phosphorylase inhibitor candidate displaying weak inhibition toward glycogen phosphorylase (16% at 2.5mM).
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Glicogênio Fosforilase Muscular/antagonistas & inibidores , Glicogênio/metabolismo , Animais , Cristalografia por Raios X , Dimerização , Avaliação Pré-Clínica de Medicamentos , Glucosídeos/síntese química , Glucosídeos/farmacologia , Glicogênio Fosforilase Hepática/antagonistas & inibidores , Glicogênio Fosforilase Hepática/metabolismo , Glicogênio Fosforilase Muscular/metabolismo , Glicosilação , CoelhosRESUMO
A simple synthesis of enantiomerically pure piperidine esters is described, offering a straightforward access to the trans-2,3-disubstituted piperidine skeleton which is present in a broad range of biologically active compounds.
Assuntos
Piperidinas/síntese química , Esparteína/análogos & derivados , Ciclização , Estrutura Molecular , Piperidinas/química , Esparteína/síntese química , Esparteína/química , EstereoisomerismoRESUMO
It has been shown that diene-titanium complexes exhibit substrate-dependent 1,2- or 1,4-dicarbanion reactivity. On this basis, 3-cyclopentenylamines and spiro-vinylcyclopropane lactams were easily prepared by using homoallylic Grignard reagents, Ti(O-i-Pr)4, and nitriles or cyanoesters, respectively.
RESUMO
We report a straightforward synthesis of 1-azaspirocyclopropane lactams from imides. Following the described procedure, polycyclic nitrogen heterocycles containing a cyclopropane unit could be obtained from unsaturated imides. [reaction: see text].
RESUMO
[reaction: see text] A "Cp(2)Zr" equivalent is generated under mild conditions (THF, room temperature) by reducing Cp(2)ZrCl(2) with cheap and readily available mischmetall (an alloy of Ce, La, Nd, and Pr). Coupling reactions, including those of terminal alkynes, can efficiently be achieved by using this reagent.
RESUMO
Polyhydroxy 4-azaspiro[2.4]heptane derivatives (spirocyclopropyl iminosugars) were prepared in four to six steps from readily available protected aldoses. The key step of the reaction sequence involves a titanium-mediated aminocyclopropanation of glycononitriles with subsequent cyclization. Five new polyhydroxypyrrolidines so-obtained have been evaluated for their ability to inhibit 16 glycosidases. One of them exhibits selective inhibition of alpha-L-fucosidase from bovine kidney (Ki=1.6 microM, competitive).
Assuntos
Inibidores Enzimáticos/farmacologia , Pirrolidinas/farmacologia , Compostos de Espiro/química , alfa-L-Fucosidase/antagonistas & inibidores , Animais , Bovinos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Rim/enzimologia , Conformação Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
[reaction: see text] A new diastereoselective synthesis of pyrrolidines from readily available chiral N-allyl oxazolidines is presented. The construction of the pyrrolidine ring is achieved via a tandem hydrozirconation-stereoselective Lewis acid mediated cyclization sequence.