Focus
The main focus of the organic synthesis research group is the chemical synthesis and derivatisation of organic compounds with non-trivial carbon connectivities, such as those found in polycyclic Natural Products. The design and selection of target structures is guided by a specific interest in reactivity patterns and/or a specific interest in biological phenomena. This research often follows a substrate-driven approach which relies on the use of highly modular synthetic intermediates as versatile building blocks or chemical platforms for various applications.
- The chemical synthesis research mainly involves the development of novel strategies and methods to assemble complex polycyclic scaffolds found in Nature, focusing on multiple bond forming steps such as cycloadditions and cascade reactions. [1], [2]
- The chemical derivatisation research focuses on the development of application-oriented versatile covalent ligation reactions (such as click-type reactions) to generate multiple functional derivatives from simple substrates or synthetic intermediates. [3]
- A major recent theme, which encompasses both of the above general topics, consists of research directed at the design and synthesis of highly modular synthetic building blocks that allow a rapid exploration of Natural Product-like chemical space using simple and orthogonal functional group transformations. [4]
- The concepts of versatile ligation/functionalisation reactions and modular building blocks in organic synthesis are also explored and applied in various collaborative research projects ranging from macromolecular and materials science to chemical biology. [5], [6]
Latest publications
The latest independent publications are given below, for all independent publications and collaborations, see publications
Stereoselective De Novo Synthesis of Substituted Cyclopentanes via a Gold(I)-Catalyzed (3 + 2) Cycloaddition of Enamides
A general and stereoselective synthesis of highly substituted cyclopentylamine scaffolds is reported starting from various N-alkenyl-amides. The reaction involves the generation of an aurated dithioallyl cation which undergoes a classical stepwise (3 + 2) allyl cation cycloaddition with a range of enamide substrates. The close coordination of the reactive intermediates with the well-defined gold(I)-catalyst results in a reactivity and selectivity profile that can be readily rationalized on the basis of a nonconcerted carbocationic cycloaddition reaction, and some remarkable counterion effects are seen to effect the chemoselectivity of the overall process.
1,4-Dithianes in Synthesis: Rapid Assembly of Indolizidine Alkaloid-Type Scaffolds Through Cationic Polyene Cyclization
We report a synthetic approach to the indolizidine scaffold, fused to a 1,4-dithiane. In a straightforward three-step protocol, the commercially available building block 5,6-dihydro-1,4-dithiin-2,3-dicarboximide undergoes two consecutive alkenylations, followed by a cationic cyclization mediated by an α,β-unsaturated N-acyliminium ion, affording a small range of substituted indolizidine scaffolds. The reaction was originally observed as an unexpected side reaction, but offers an attractive entry into this class of biologically active alkaloids.
Thiol-thiol cross-clicking using bromo-ynone reagents
Thiols are used in many click reactions, and are also excellent platforms for biomolecular click or bioconjugation reactions. The direct cross-coupling of two thiols is an attractive biomimetic concept for click chemistry, but leads to statistical mixtures of homo- and heterodimers. Here, we introduce a novel class of thiol-click reagents, bromo-ynones, where the kinetic differentiation between the first and second thiol addition onto these reagents facilitates a stepwise one-pot cross-clicking of two distinct thiols in aqueous media, without the need for intermediate isolation or purification. The two thiols are linked through a single carbon atom, mimicking a disulfide bridge. We demonstrate the use of bromo-ynones in the synthesis of various cross-coupled thiols, including small molecule drugs, fluorophores, carbohydrates, peptides and proteins, including an example of a protein-protein heterodimer. The resulting adducts are robust under physiological conditions and by judicious choice of the bromo-ynone reagent, the adducts can be stable even in the presence of excess free thiols.
Phenylpropynones as Selective Disulfide Rebridging Bioconjugation Reagents
Simple 1-phenylpropynones undergo a selective double thia-Michael addition with thiols in buffered media, yielding an interesting dithioacetal linkage joining two thiols. The reactivity of various Michael-alkyne reagents is compared in this chemoselective, atom economical, and non-oxidative cross-linking of two thiols. The stability and chemical reactivity of the dithioacetal links are studied, and the utility of the disulfide targeting bioconjugation methodology is shown by the selective rebridging of native cyclic peptides after the reductive cleavage of their disulfide bridge.
