RESUMO
Oligodeoxynucleotides incorporating a reactive functionality can cause irreversible cross-linking to the target sequence and have been widely studied for their potential in inhibition of gene expression or development of diagnostic probes for gene analysis. Reactive oligonucleotides further show potential in a supramolecular context for the construction of nanometer-sized DNA-based objects. Inspired by the cytochrome P450 catalyzed transformation of furan into a reactive enal species, we recently introduced a furan-oxidation-based methodology for cross-linking of nucleic acids. Previous experiments using a simple acyclic building block equipped with a furan moiety for incorporation into oligodeoxynucleotides have shown that cross-linking occurs in a very fast and efficient way and that substantial amounts of stable, site-selectively cross-linked species can be isolated. Given the destabilization of duplexes observed upon introduction of the initially designed furan-modified building block into DNA duplexes, we explore here the potential benefits of two new building blocks featuring an extended aromatic system and a restored cyclic backbone. Thorough experimental analysis of cross-linking reactions in a series of contexts, combined with theoretical calculations, permit structural characterization of the formed species and allow assessment of the origin of the enhanced cross-link selectivity. Our experiments clearly show that the modular nature of the furan-modified building blocks used in the current cross-linking strategy allow for fine tuning of both yield and selectivity of the interstrand cross-linking reaction.
Assuntos
Reagentes de Ligações Cruzadas/química , DNA/química , DNA/metabolismo , Furanos/química , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/metabolismo , Oligonucleotídeos/química , Oligonucleotídeos/metabolismo , Sequência de Bases , Modelos Moleculares , Conformação de Ácido Nucleico , Oligodesoxirribonucleotídeos/síntese química , Oligonucleotídeos/síntese química , OxirreduçãoRESUMO
Phosphonylated azaheterocycles are an important class of compounds with high biological potential as conformationally restricted bioisosteres of amino acids. Therefore, it is of interest to synthesize conformationally constrained amino phosphonates. We wanted to investigate possible routes via ring opening of alpha-amino phosphonates with an oxanorbornene skeleton, as these can be synthesized with high stereoselectivity. This was achieved using different Lewis acids, leading to a range of products. The reaction with TiCl(4) and FeCl(3) was modelled at a DFT level of theory to get insight in the pathways towards the corresponding products. To ease the work up, the Fe(iii) catalyst was coated on montmorillonite clay, but this accelerated aromatization after ring opening. Quenching the FeCl(3) catalyzed reaction mixture on celite caused complete aromatization.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Isoindóis/química , Norbornanos/química , Organofosfonatos/síntese química , Oxigênio/química , Hidrogenação , Modelos Moleculares , Estrutura MolecularRESUMO
The properties and functions of (bio)molecules are closely related to their molecular conformations. A variety of methods are available to sample the conformational space at a relatively low level of theory. If a higher level of theory is required, the computational cost can be reduced by selecting a uniformly distributed set of conformations from the ensemble of conformations generated at a low level of theory and by optimizing this selected set at a higher level. The generation of conformers is performed using molecular dynamics runs which are analyzed using the MD-Tracks code [J. Chem. Inf. Model. 2008, 48, 2414]. This article presents a Kennard-Stone-based algorithm, with a distance measure based on the distance matrix, for the selection of the most diverse set of conformations. The method has been successfully applied to macrocyclic alkenes. The correct thermodynamic stability of the double-bond isomers of a flexible macrocyclic alkene containing two chiral centers is reproduced. The double-bond configuration has a limited effect on the conformation of the whole macrocycle. The chirality of the stereocenters has a larger effect on the molecular conformations.
Assuntos
Algoritmos , Alcenos/química , Compostos Macrocíclicos/química , Conformação Molecular , Estereoisomerismo , Temperatura , TermodinâmicaRESUMO
During the synthesis of tricyclic phosphonopyrrolidines via intramolecular Diels-Alder reactions of 1-acylamino(furan-2-yl)methyl phosphonates, two isomers are formed in most cases. The presence of a short three-atom tether together with spectroscopic data, including difference NOE, revealed that the cycloaddition occurred exo, but the phosphonate substituent on the tether had an exo or endo orientation. This was confirmed via X-ray analysis. A thermodynamic preference for the product with the phosphonate function in the endo position was observed experimentally and was confirmed theoretically. Density functional theory methods and several high-level post Hartree-Fock procedures were used to rationalize the observed isomer ratio of the IMDAF-reactions. This was done for two different types of reagents: with the activating carbonyl group in the tether or as a substituent on the tether. For the first type of molecules there is a large steric hindrance of the bulky tether substituents that disfavors the exo-isomer. In the latter case, there was a very small energy difference between the transition states causing a mixture of epimers being formed.
Assuntos
Pirrolidinas/síntese química , Cristalografia por Raios X , Modelos Moleculares , Organofosfonatos/química , Estereoisomerismo , TermodinâmicaRESUMO
[reaction: see text] Perhydro-1,3-diazepine-2,4-diones are rare and can only be prepared, up to now, by special methods. A new one-step protocol was developed, comprising N-carbamoylation using an isocyanate followed by intramolecular ring expansion. This new methodology provides a straightforward access to this interesting seven-membered skeleton.
Assuntos
Azepinas/síntese química , Técnicas de Química Combinatória , Ácido Pirrolidonocarboxílico/química , Isotiocianatos/química , Estrutura MolecularRESUMO
A short and elegant synthetic pathway was developed for the synthesis of 1,3-dioxo-hexahydropyrido[1,2-c][1,3]diazepine carboxylates, a new 1,3-diazepan-2,4-dione containing bicyclic moiety, starting from pyroglutamate esters.
RESUMO
An efficient and straightforward two-step approach toward N3,N'3-polymethylene-bis-hydantoins was developed. As a first step, a pyroglutamate is reacted with a diisocyanate to produce a bis-carbamoyllactam. The second step is a double-ring transformation by treatment of this bis-carbamoyllactam with KOtBu in ethanol. In this fashion N3,N'3-polymethylene-bis-hydantoins are produced in two quantitative steps and under very mild conditions. When properly derivatized, these compounds can be converted to their macrocyclic derivatives upon treatment with 5 mol % of second-generation Grubbs' catalyst. These macrocyclic derivatives are so far not described in the literature. It was proven that exclusively (E)-isomers are formed.