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.

When a mixture of a pyroglutamate and an isocyanate in THF is treated with NaH, a ring transformation occurs leading to functionalised hydantoins. The novel reaction involves a ring‐closing ring‐opening sequence providing a new and straightforward access to an interesting class of heterocyclic compounds. Furthermore, starting from pyroglutamates allows the synthesis of highly substituted hydantoins under very mild conditions. This ring transformation in combination with ring‐closing metathesis is used in a four‐step reaction sequence for the synthesis of multi‐functionalised bicyclic hydantoin derivatives.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

[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.

Structural analysis of modified DNA with NMR is becoming ever more difficult with increasingly complex\ud compounds under scrutiny for use in medical diagnosis, therapeutics, material science and chemical\ud synthesis. To facilitate this process, we developed a molecular modeling approach to predict proton\ud chemical shifts in sufficient agreement with experimental NMR measurements to guide structure\ud elucidation. It relies on a QM/MM partitioning scheme and first principle calculations to predict the spatial\ud structure and calculate corresponding proton chemical shifts. It is shown that molecular dynamics\ud simulations that take into account solvent and temperature effects properly are of utmost importance to\ud sample the conformational space sufficiently. The proposed computational procedure is applicable to\ud modified oligonucleotides and DNA, attaining a mean error for the proton chemical shifts of less than 0.2\ud ppm. Here, it is applied on the Drew–Dickerson d(CGCGAATTCGCG)2 dodecamer as a benchmark system\ud and the mispair-aligned N3T-ethyl-N3T cross-linked d(CGAAAT*TTTCG)2 undecamer, illustrating its use as\ud computational tool to assist in structure elucidation. For the proton chemical shifts in the cross-linked\ud system our methodology yields a strikingly superior description, surpassing the predictive power of (semi-)\ud empirical methods. In addition, our methodology is the only one available to make an accurate prediction\ud for the protons in the actual cross-link. To the best of our knowledge, this is the first computational study\ud that attempts to determine the chemical shifts of oligonucleotides of this size and at this level of\ud complexity