Organic Chemistry: Synthesis, Structure, and Application
P1-0230
Duration: 1.1.2022 - 31.12.2027
Head:
prof. dr.
Košmrlj Janez
Chemical synthesis and the resulting synthetic compounds provide untold benefits to society, in every aspect of our existence. The challenge of synthesis today, however, is not whether a molecule can be made, but whether it is beneficial and can be made efficiently and sustainably. Our research programme is driven by this challenge, and lies at the interface of organic, inorganic, coordination, pharmaceutical and medicinal chemistry.
We focus on the discovery and application of new, and more efficient and sustainable methods for the synthesis of catalysts, functional molecules and bioactive compounds. This includes the study of chemical reaction mechanisms, a cornerstone of chemical science, enabling the rational design of reaction conditions, improving the scope and yields of products, and reducing the cost of starting materials and problematic waste.
There are three major research themes within the programme: mechanistic insights, synthesis and catalysis, and practical applications
Mechanistic insights are crucial to the fundamental understanding of chemical processes, including their discovery, rational design, and optimization. We are addressing critical mechanistic questions of various reactions including classical, (organo)catalytic, redox-triggered, and cross-coupling reactions [PCCP 2021]. A recent example is the mechanism of the copper-free Sonogashira reaction, which had been unsolved for nearly five decades [NatChem 2018]. Regarding cross-coupling reactions, our goal is to extend the chemistry to other metal-metal manifolds, possibly leading to the discovery of new reactions, similar to our recent discovery of the palladium-palladium catalytic system [ChemComm 2016, OL 2020]. We have also addressed the issues of the fully catalytic Mitsunobu reaction [OL 2016, Chem Sci 2016] and the challenge of isolating highly reactive and unstable intermediate species, such as hydrogen trioxide (HOOOH) and its derivatives [ACIE 2015]. These are ubiquitous in oxidation reactions and are gaining interest in the scientific community as key intermediates in many chemical, biochemical, atmospheric, and environmental processes [ChemRev 2013]. Many fundamental mechanistic questions about the above molecules, processes, and beyond remain unanswered and are of interest to our research programme [J Chem Inf Model 2021, PCCP 2021].
Green synthesis, for a safer and healthier planet, is another major focus of our research. A challenge is to replace volatile organic solvents and harmful reagents with more environmentally friendly alternatives. We are interested in the conversion of thiols to sulfonyl halides using atmospheric oxygen as a terminal oxidant, the oxidation of neat sulfides to sulfones using hydrogen peroxide solution under solvent- and catalyst-free conditions, and the reduction of neat sulfoxides to sulfides without organic solvent, to name a few examples [Green Chem 2017, GCLR 2020]. We are also exploring the recycling and reuse of catalysts, reagents, and precious metals [ACIE 2022, ACIE 2022, Wiley 2009]. For example, we have developed recyclable azo reagents for the Mitsunobu reaction [Chem Sci 2016].
Similarly, reaction efficiency can be achieved through catalysis. Catalysis is now involved in the production of over 80% of the chemicals we encounter in our daily lives and is associated with about 30% of the total GDP of European economies. As a contribution to homogeneous catalysis, we have recently developed new N-heterocyclic carbenes (NHCs) based on pyridine-appended triazoles with a mesoionic (MIC) structure (PyMIC) which possess metal-stabilising properties superior to those of other ligands [ChemComm 2016]. PyMICs, which belong to a new class of SMART (Switchable, Multifunctional, Adaptable, oR Tuneable) ligands, have allowed us to develop highly active transition metal catalysts [OL 2020, OL 2020]. These include Ru-, Os-, and Ir-based catalysts for selective oxidations and reductions, as well as Pd complexes for Suzuki-Miyaura and Sonogashira cross-couplings that operate in water (solvent) and air. The Pd-PyMIC complex exhibits enzyme-like behaviour in the catalytic hydroamination of alkynes. The unique properties of metal complexes with PyMICs and some other ligands, including azocarboxamides, have potential for other catalytic reactions and form a major focus of our research efforts [Organometallics 2021].
One of our advanced research topics associated with practical applications deals with the development of molecular probes for the early detection of Alzheimer disease. Alzheimer disease, one of the biggest challenges to modern medicine, affects the lives of patients and their families and strains national health budgets worldwide. We have contributed to this field by developing the radiotracer [18F]FDDNP for in vivo positron emission tomography (PET) imaging of pathological protein aggregates [PNAS 2012]. As an alternative to in vivo imaging, which requires extremely expensive specialized infrastructure and poses a high health risk to patients, our current efforts are focused on developing smart molecular probes for predicting Alzheimer disease based on ex vivo detection of specific biomarkers in bodily fluids [JMC 2017]. In addition, we are focusing on the development of new molecules of biological relevance, e.g. with cytotoxic [Chem Eur J 2014, Organometallics 2019] and antibacterial properties [EJMC 2017, Chem Biol Drug Des 2017]. In collaboration with Sandoz Austria GmbH and Sandoz Development Centre Slovenia, we have developed a fully stereocontrolled aldol reaction of chiral β‑amino acids [OL 2015] and a lactone pathway to statins using the Wittig reaction [JOC 2010].
The development of new techniques, methods, catalysts, intermediates, and useful compounds is central to the sustainable development of the research-based chemical industry and, by extension, modern society. In this context, the contributions of our program group include the development of new knowledge, the establishment of a broad network of collaborations with domestic and foreign institutions, the transfer of knowledge from academia to industry (and vice versa), and the training of highly qualified young scientists. Read more at Košmrlj Group and follow the latest news on the group's Twitter profile @KosmrljGroup. We warmly invite interested community to contact us and join our efforts.
