Mariella Mella

Quinone Methides Tethered to Naphthalene Diimides as Selective G-Quadruplex Alkylating Agents

We have developed novel G-quadruplex (G-4) ligand/alkylating hybrid structures, tethering the naphthalene diimide moiety to quaternary ammonium salts of Mannich bases, as quinone-methide precursors, activatable by mild thermal digestion (40 degrees C). The bis-substituted naphthalene diimides were efficiently synthesized, and their reactivity as activatable bis-alkylating agents was investigated in the presence of thiols and amines in aqueous buffered solutions. The electrophilic intermediate, quinone-methide, involved in the alkylation process was trapped, in the presence of ethyl vinyl ether, in a hetero Diels-Alder [4 + 2] cycloaddition reaction, yielding a substituted 2-ethoxychroman. The DNA recognition and alkylation properties of these new derivatives were investigated by gel electrophoresis, circular dichroism, and enzymatic assays. The alkylation process occurred preferentially on the G-4 structure in comparison to other DNA conformations. By dissecting reversible recognition and alkylation events, we found that the reversible process is a prerequisite to DNA alkylation, which in turn reinforces the G-quadruplex structural rearrangement.

A new and highly efficient catalyst for the enantioselective Mukaiyama–Michael reaction between ( E )-3-crotonoyl-1,3-oxazolidin-2-one and 2-trimethylsilyloxyfuran

Abstract The Mukaiyama–Michael reaction between 2-trimethylsilyloxyfuran and (E)-3-crotonoyl-1,3-oxazolidin-2-one has been stereoselectively catalysed by several optically active complexes based on bis(oxazoline) (box) or pyridine bis(oxazoline) (pybox) chiral ligands and metal cations. The catalysts derived from the newly synthesised 2,6-bis[(4′R,5′R)-diphenyl-1,3-oxazolin-2′-yl]pyridine and the triflates of EuIII, LaIII, CeIV were highly efficient: the diastereoselectivity was entirely anti and the enantioselectivity was excellent (ranging from 98 to >99%). A mechanistic insight into the nature of the activated substrate–catalyst complex was inferred studying the lanthanum complexes with 1H and 13C NMR spectroscopy. Based on these results and on the crystallographic structure of the complex between pybox and La(OTf)3, a stereochemical model is proposed to rationalise the crucial role of the substituent in position 5, suitably placed to blind the Si-face of the coordinated reagent.

Targeting Loop Adenines in G-Quadruplex by a Selective Oxirane

Caught in the oxirane: Naphthalene diimides conjugated to a quinone methide and an oxirane have been synthesized and investigated as selective DNA G-quadruplex alkylating agents. The oxirane derivative generates a stable adduct with a G-quadruplex and shows selective alkylation of the loop adenines, as illustrated.

Photochemistry of 1‐Cyclopropyl‐6‐fluoro‐1,4‐dihydro‐4‐oxo‐7‐ (piperazin‐1‐yl)quinoline‐3‐carboxylic Acid (=Ciprofloxacin) in Aqueous Solutions

The 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)quinoline-3-carboxylic acid (=ciprofloxacin; 1) undergoes low-efficiency (Φ=0.07) substitution of the 6-fluoro by an OH group on irradiation in H2O via the ππ* triplet (detected by flash photolysis, λmax 610 nm, τ 1.5 μs). Decarboxylation is a minor process (≤5%). The addition of sodium sulfite or phosphate changes the course of the reaction under neutral conditions. Reductive defluorination is the main process in the first case, while defluorination is accompanied by degradation of the piperazine moiety in the presence of phosphate. In both cases, the initial step is electron-transfer quenching of the triplet (kq=2.3⋅108M−1 s−1 and 2.2⋅107M−1 s−1, respectively). Oxoquinoline derivative 1 is much more photostable under acidic conditions, and in this case the F-atom is conserved, and the piperazine group is stepwise degraded (Φ=0.001).

Synthesis of monoprotected 1,4-diketones by photoinduced alkylation of enones with 2-substituted-1,3-dioxolanes

Abstract Photosensitized hydrogen abstraction from 2-alkyl-1,3-dioxolanes by triplet benzophenone gives the corresponding 1,3-dioxolan-2-yl radicals and these are trapped by α,β-unsatured ketones yielding monoprotected 1,4-diketones. With open chain ketones (3-buten-2-one and 4-penten-3-one) the yields are low and competitive pathways in part consume the radicals. With cyclic enones however, yields are good as tested with cyclopentenone, cyclohexenone and 4-hydroxy-cyclopentenone. More generally, this is a viable alternative for the synthesis of 1,4-diketones via radicals while the thermal initiation gives only low yield. The reaction cannot be extended to strongly stabilized radicals, such as the 2-phenyl-1,3-dioxolanyl radical.

New synthetic methods via radical cation fragmentation

Photoinduced single electron transfer followed by radical cation cleavage is a selective method for generating radicals and cations from unconventional substrates under unparalleled mild conditions. The versatility of the method and its synthetic significance are demonstrated through the discussion of selected examples involving alkyl radicals as the key species, such as nucleophilic aromatic substitution, addition to unsatured esters, nitriles and ketones, and reduction, as well as of an example of addition to cations.

Environment-friendly organic synthesis. The photochemical approach

Photochemical reactions are expected to have an increasing role in organic synthesis with the drive towards environment-friendly reactions. Some examples illustrating the scope and versatility of radical alkylation of electrophilic alkenes via photoinduced electron transfer are presented. A few applications in special fields are mentioned.

A PHOTOCHEMICAL GENERATION OF NITROSOCARBONYL INTERMEDIATES

Abstract Nitroscarbonyl intermediates are photochemically generated from 1,2,4-oxadiazole-4-oxides and efficiently trapped with enes and dienes.

TITANIUM DIOXIDE PHOTOCATALYSED ALKYLATION OF MALEIC ACID DERIVATIVES

Abstract The irradiation of a nitrogen-flushed acetonitrile suspension of titanium dioxide in the presence of benzyltrimethylsilane, its 4-methoxy derivative or 4-methoxyphenylacetic acid as the donors and maleic acid, maleic anhydride or related nitriles as the acceptors leads to the corresponding benzylsuccinic acid derivatives via electron, hole transfer and fragmentation of the benzyl radical cation (such a cleavage is too slow with 4-methoxytoluene). A rationale of the reaction and an evaluation of the synthetic significance of the method are given.

Cycloadditions of Nitrile Oxides to the Highly Reactive N-Acyl-2-oxa-3-azanorborn-5-enes Afford Versatile Cycloadducts and a Convenient Entry to Highly Functionalized Derivatives

N-Acyl-2-oxa-3-azanorborn-5-enes are highly reactive dipolarophiles in cycloadditions with nitrile oxides. The cycloadducts can be easily elaborated to various functionalized structures that are not directly accessible by 1,3-dipolar cycloadditions.