Uncommon Four-Membered Building Blocks - Cyclobutenes, Azetines and Thietes.

Strained ring systems have gained considerable importance over the last few years for their implication in natural product syntheses or in drug discovery programs. We present herein a recollection of our work on the construction and functionalization of unsaturated four-membered carbo- and heterocycles in the context of the literature, as well as their applications in further reactions.

Thiete Dioxides as Templates Towards Twisted Scaffolds and Macrocyclic Structures.

Thiete dioxide units have been employed as a template for further functionalization through C-H activation strategies. Using simple thiete dioxide building blocks, a new library of axially chiral molecules has been synthesized that owe their stability to electrostatic interactions in the solid state. Similar starting materials were further engaged in the formation of cyclic trimeric structures, opening the pathway to unprecedented macrocyclic ring systems.

Strain-release arylations for the bis-functionalization of azetidines.

The addition of nucleophilic organometallic species onto in situ generated azabicyclobutanes enables the selective formation of 3-arylated azetidine intermediates through strain-release. Single pot strategies were further developed for the N-arylation of resulting azetidines, employing either SNAr reactions or Buchwald-Hartwig couplings.

Terminal Terthiophenediones: Fast-Decay Fluorescent Dyes and Their Efficient Syntheses.

Terminally acylated terthiophenes, in particular, the bis-pivaloyl derivative, were synthesized by Friedel-Crafts acylation with sub-stoichiometric amounts of standard zinc oxide and exhibit strong fluorescence and an ultrafast fluorescence decay of 400 ps. Their high photostability and large Stokes' shifts are good prerequisites for applications in optical GBit fast data systems such as fiber optics in slip rings.

Stereoselective Access to Azetidine-Based α-Amino Acids and Applications to Small Peptide Synthesis.

Non-natural azetidine-based amino acids (Aze) present interesting features in protein engineering. A simple organometallic route toward unsaturated carboxylic acid precursors is presented. Subsequent metal-catalyzed asymmetric reduction allowed for the synthesis of a new library of 2-azetidinylcarboxylic acids, which were finally employed in the formation of small peptide chains.

Parallel Approaches for the Functionalization of Thietes: α-Metalation versus C-H Activation.

For the first time, an approach to 3,4-disubstituted thietes was developed through two complementary paths. While the first one relies on α-metalation, the second is based on direct C-H functionalization. A new library of sophisticated sulfur-containing four-membered rings is described, paving the way to new bioactive analogues and small heterocycle incorporation.

Chemodivergent and Stereoselective Access to Fused Isoxazoline Azetidines and Thietanes through [3 + 2]-Cycloadditions.

By combining efficient methodologies for the preparation of substituted azetines and thietes with a highly regio- and diastereoselective [3 + 2]-cycloaddition, a straightforward pathway for the synthesis of fused isoxazoline azetidines and thietanes has been designed. With minimal steps and starting from commercial sources, a new library of elaborated architectures was synthesized opening up a new class of molecules with large potential in pharmacology. Finally, a retro [2 + 2]-cycloaddition leading to substituted isoxazoles is described.