RESUMO
The properties and stereochemical reactivity of cyclobutadiene, benzene, cyclooctatetraene, and the [10]- to [14]annulenes can be uniformly rationalized through the bent bond/antiperiplanar hypothesis (BBAH). This new orbital model considers electronic delocalization between pyramidal diradical resonance structures and associated bent bonds, as it applies to aromatic, nonaromatic, and antiaromatic molecules.
RESUMO
Glycosylation reactions were performed on a series of bicyclic C2-substituted pyranoside models to isolate and analyze factors that control the glycosylation stereoselectivities observed in carbohydrates. The bent bond/antiperiplanar hypothesis (BBAH) orbital model rationalizes all of these results by considering hyperconjugation interactions between groups at C2 and the two τ bonds (bent bonds) of oxocarbenium ion intermediates formed under the glycosylation conditions. According to the BBAH, nucleophiles add to oxocarbenium intermediates by SN2-like antiperiplanar displacement of the weaker of their two τ bonds.
RESUMO
The glycosylation stereoselectivities for a series of bicyclic furanoside models have been carried out in the presence of weak nucleophiles. These results were analyzed through the bent bond/antiperiplanar hypothesis (BBAH) orbital model to test its validity. According to the BBAH, incoming nucleophiles displace one of the two bent bonds of bicyclic oxocarbenium ion intermediates in an antiperiplanar fashion. The glycosylation stereoselectivity is then governed by the displacement of the weaker bent bond as determined by the presence of electron-withdrawing or -donating substituents at C2. Overall, the BBAH analysis expands Woerpel's "inside/outside attack" glycosylation model by considering the stereoelectronic influence of neighboring electron-withdrawing and -donating groups on the nucleophilic addition to oxocarbenium ion intermediates.
RESUMO
The thermolysis of an optically active tetradeuterated 2-methoxymethyl methylenecyclopropane produces a specific ratio of eight possible rearrangement stereoisomers. Despite numerous efforts, this reaction and other similar transformations have defied mechanistic interpretation until now. The direct application of the bent bond/antiperiplanar hypothesis (BBAH) to this reaction produces a mechanistic model that rationalizes all the observed reaction kinetics and products. The BBAH dictates that allyl diradical intermediates, produced during methylenecyclopropane thermolysis, retain pyramidal character due to antiperiplanar delocalization into their respective bent bond.
RESUMO
The bent bond/antiperiplanar hypothesis (BBAH) is used to propose a mechanism-based orbital model for the facial selectivity of sigmatropic hydrogen shifts under both thermal and photochemical conditions. The BBAH analysis of these concerted rearrangements invokes transient vibrationally excited singlet diradicals in both 4 n and 4 n+2 polyenes.
RESUMO
The bent bond/antiperiplanar hypothesis (BBAH) has been applied to the thermal rearrangements of cyclooctatetraene and related C8H8 isomers. This novel orbital model shows that pyramidal singlet diradical intermediates produced from thermal vibrational states of C8H8 isomers account for their chemical reactivity.
RESUMO
L. T. Scott has discovered the 1,2-swapping of carbon and hydrogen atoms which is known to take place on benzenoid aromatics (up to â¼1000 °C range). For example, 13C-1-naphthalene is specifically converted to 13C-2-naphthalene, and there is evidence that this occurs through the formation of benzofulvene and a naphthalene-carbene intermediate. Application of the bent bond/antiperiplanar hypothesis leads to the postulate that higher in energy pyramidal singlet diradical intermediates can be used to propose a mechanism that rationalizes various atom rearrangements on benzenoid aromatics and related isomeric compounds.
RESUMO
The stereoselectivity of nucleophilic addition on oxocarbenium ions derived from the bicyclic pyranoside model with or without a C2-OR group can be understood through the use of the bent-bond and the antiperiplanar hypothesis in conjunction with the concept of hyperconjugation as an alternative interpretive model of structure and reactivity.
RESUMO
The bent bond/antiperiplanar (BBA) hypothesis has been applied to the analysis of [1,3]-sigmatropic alkyl shifts. These thermal rearrangements, for which there is evidence that they proceed through diradical intermediates, can be interpreted by considering their transient allyl radical structures. For the thermolysis of cyclic molecules, the preferred generation of pyramidal allyl radicals in staggered conformations is postulated on the basis of the BBA hypothesis. This accounts for the preference of suprafacial rearrangement pathways as well as the extent of inversion or retention of configuration at the migrating carbons.
RESUMO
A full account of our anionic polycyclization approach to access highly functionalized tricycles related to quassinoids and terpenoids from several optically active bicyclic enone systems and Nazarov reagents is presented. (+)-Carvone is the only chiral source used to fix the entire stereochemistry of all of the tricycles, and the stereochemical outcome of this process was unambiguously determined by X-ray crystallographic analysis. The utility of this strategy was demonstrated by the stereocontrolled construction of advanced tricycles related to the highly potent anticancer natural product bruceantin, a member of quassinoid family, and the total synthesis of the cardioactive terpenoid (+)-cassaine, a nonsteroidal inhibitor of Na(+)-K(+)-ATPase.
Assuntos
Alcaloides/química , Alcaloides/síntese química , Ânions/química , Monoterpenos/química , Quassinas/química , Terpenos/química , Abietanos , Produtos Biológicos , Cristalografia por Raios X , Ciclização , Monoterpenos Cicloexânicos , Humanos , Quassinas/farmacologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/química , EstereoisomerismoRESUMO
An efficient synthesis of hippuristanol (1), a marine-derived highly potent antiproliferative steroidal natural product, and nine closely related analogues has been accomplished from the commercially available hydrocortisone utilizing Hg(II)-catalyzed spiroketalization of 3-alkyne-1,7-diol motif as a key strategy. This practical synthetic sequence furnished 1 in 11% overall yield from hydrocortisone in 15 linear steps. Modifications to the parent molecule 1 encompassed changing the functional groups on rings A and E. Each analogue was screened for their effects on inhibition of cap-dependent translation, and the assay results were used to establish structure-activity relationships. These results suggest that the stereochemistry and all substituents of spiroketal portion (rings E and F) and C3-α and C11-ß hydroxyl functional groups on rings A and C, respectively, are critical for the inhibitory activity of natural product 1.
Assuntos
Hidrocortisona/química , Mercúrio/química , Esteróis/síntese química , Esteróis/farmacologia , Animais , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , RNA Polimerases Dirigidas por DNA/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A stereoselective total synthesis of (+)-cassaine (1) via an anionic polycyclization methodology is described. Commercially available (+)-carvone (5), the only chiral source, was used to fix the entire stereochemistry of the natural product. Anionic polycyclization of a new substituted 2-(methoxycarbonyl)cyclohex-2-en-1-one (4) with known 1-phenylysulfinyl-3-penten-2-one (3) provided the versatile tricycle (2) with requisite stereochemistry. A sequence of functional group manipulations of tricycle (2) furnished the natural product 1.
Assuntos
Alcaloides/síntese química , Abietanos , Alcaloides/química , Ânions/síntese química , Ânions/química , Ciclização , Conformação Molecular , EstereoisomerismoRESUMO
BACKGROUND: Chemotherapy-induced hair loss (alopecia) (CIA) is one of the most feared side effects of chemotherapy among cancer patients. There is currently no pharmacological approach to minimize CIA, although one strategy that has been proposed involves protecting normal cells from chemotherapy by transiently inducing cell cycle arrest. Proof-of-concept for this approach, known as cyclotherapy, has been demonstrated in cell culture settings. METHODS: The eukaryotic initiation factor (eIF) 4E is a cap binding protein that stimulates ribosome recruitment to mRNA templates during the initiation phase of translation. Suppression of eIF4E is known to induce cell cycle arrest. Using a novel inducible and reversible transgenic mouse model that enables RNAi-mediated suppression of eIF4E in vivo, we assessed the consequences of temporal eIF4E suppression on CIA. RESULTS: Our results demonstrate that transient inhibition of eIF4E protects against cyclophosphamide-induced alopecia at the organismal level. At the cellular level, this protection is associated with an accumulation of cells in G1, reduced apoptotic indices, and was phenocopied using small molecule inhibitors targeting the process of translation initiation. CONCLUSIONS: Our data provide a rationale for exploring suppression of translation initiation as an approach to prevent or minimize cyclophosphamide-induced alopecia.
Assuntos
Alopecia/prevenção & controle , Antineoplásicos/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxiciclina/efeitos adversos , Fator de Iniciação 4E em Eucariotos/antagonistas & inibidores , Alopecia/induzido quimicamente , Alopecia/metabolismo , Animais , Antineoplásicos/administração & dosagem , Western Blotting , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Doxiciclina/administração & dosagem , Fator de Iniciação 4E em Eucariotos/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Interferente Pequeno/genéticaRESUMO
By taking into consideration bent bonds (τ-bonds, tau-bonds), the antiperiplanar hypothesis, the classic theory of resonance, and the preference for staggered bonds over eclipsed bonds in tetrahedral systems, a simple qualitative model is presented to rationalize the conformation and reactivity for a wide range of compounds containing double bonds and/or carbonyl groups. Alkenes, carbonyl and carboxyl derivatives, conjugated systems as well as other functional groups are revisited. This also leads to a simple model to understand aromaticity, and electrocyclic reactions. The bent bond model and the antiperiplanar hypothesis provide a qualitative model for better understanding the electron delocalization and the reactivity inherent to unsaturated organic systems by an alternative view of the classic resonance theory.
RESUMO
Hg(II) salts are identified as highly efficient catalysts for the versatile construction of spiroketals from alkyne diols in aqueous conditions. Monounsaturated spiroketals and furans were accessed with equal ease when propargylic triols (or propargylic diols) were subjected to similar conditions. Even the semiprotected alkyne diols gave the corresponding spiroketals with the same ease in a cascade manner. The reactions are instant and high yielding at ambient temperatures. Regioselectivity issues are well addressed.
Assuntos
Álcoois/química , Alcinos/química , Furanos/síntese química , Mercúrio/química , Compostos de Espiro/síntese química , Catálise , Ciclização , Furanos/química , Estrutura Molecular , Compostos de Espiro/químicaRESUMO
A full account of the synthesis of hippuristanol and its analogues is described. Hecogenin acetate was identified as a suitable and economical starting material for this work, and substrate-controlled stereoselection was obtained throughout the construction of the key spiroketal unit. Suárez cyclization was first used, but Hg(II)-catalyzed spiroketalization of the 3-alkyne-1,7-diol motif was finally identified as the most convenient strategy.
Assuntos
Furanos/química , Mercúrio/química , Reticulócitos/citologia , Reticulócitos/efeitos dos fármacos , Compostos de Espiro/química , Esteróis/síntese química , Esteróis/farmacologia , Animais , Catálise , Proliferação de Células/efeitos dos fármacos , Ciclização , Conformação Molecular , Coelhos , Estereoisomerismo , Esteróis/químicaRESUMO
The steroidal natural product hippuristanol targets eukaryotic translation initiation factor (eIF)4A which plays a pivotal role in translation in eukaryotic cells. Now an efficient synthesis of hippuristanol from 11-ketotigogenin is reported. The synthesis features a rapid construction of a spiroketal unit via Hg(OTf)(2)-catalyzed oxidation/spiroketalization of the 3-alkyn-1,7-diol motif.
Assuntos
Proliferação de Células/efeitos dos fármacos , Furanos/química , Mercúrio/química , Compostos de Espiro/química , Esteróis/síntese química , Catálise , Estrutura Molecular , Esteróis/farmacologiaRESUMO
The reactivity of two new bicyclic cyclohexenones (13 and 27) with several Nazarov reagents is presented. A flexible synthetic strategy is developed and provides access to highly substituted tricycles related to quassinoids and triterpenes.
Assuntos
Cicloexanonas/química , Quassinas/síntese química , Triterpenos/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise , Ciclização , Estrutura Molecular , Quassinas/química , Triterpenos/químicaRESUMO
A full account of the total synthesis of ouabagenin and ouabain is described. A highly stereocontrolled anionic cycloaddition for the rapid construction of the basic steroid skeleton is a pivotal conversion for the whole strategy. A careful study was needed to establish the order and the sequence of functional group manipulations. Specific conformational features of the ouabain skeleton allowed us to overcome a few stereochemical problems. Degradation studies on ouabain provided an ultimate proof for a key intermediate, which is used as a relay. Late stage butenolide formation and glycosidation yielded ouabain.
Assuntos
Ouabaína/análogos & derivados , Ouabaína/síntese química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , Cristalografia por Raios X , Ciclização , Ouabaína/química , Oxirredução , EstereoisomerismoRESUMO
Masked ortho-benzoquinones are very reactive as diene partners in Diels-Alder reactions. Careful exploration of the orbital factors that govern their surprising behavior shows that their LUMO is almost as electron demanding as that of o-benzoquinone itself. Methyl substituents at either end of their diene system influence the activation energy through modification of the reaction pathway being more or less asynchronous.