FKKT

P1-0230

Trajanje: 1.1.2022 - 31.12.2027

Raziskovalni program P1-0230 (Organska kemija: sinteza, struktura in aplikacija)

Kemijska sinteza in posledično dostopnost do najrazličnejših sintetičnih spojin je koristila družbi na številne načine v vseh obdobjih našega razvoja. Vendar pa izziv kemije danes ni več zgolj sinteza ciljnih molekul, ampak predvsem kakšne so možnosti njihove uporabe in kako te spojine pripraviti na praktičen, učinkovit in okolju prijazen način. Raziskovalno delo našega programa, ki vključuje področja organske, anorganske, koordinacijske, farmacevtske in medicinske kemije, sledi opisanim izzivom. Ukvarjamo se z odkrivanjem in uporabo novih, učinkovitejših in trajnejših reakcij ter sinteznih metodologij tako v smeri razvoja in priprave katalizatorjev, drugih funkcionalnih molekul in biološko pomembnih spojin. Nepogrešljivo izhodišče je poznavanje mehanizmov kemijskih reakcij, temelja kemijske znanosti, ki omogoča racionalno zasnovo reakcijskih pogojev, zmanjšanje stroškov izhodnih spojin ter zmanjšanje tvorbe problematičnih odpadkov.

Naš program obsega tri glavne raziskovalne tematike: študij mehanizmov kemijskih reakcij, sintezo in katalizo ter praktično uporabo pridobljenih znanj.

Razumevanje kemijskih reakcij na mehanističnem nivoju je ključnega pomena za obvladovanje in uporabo kemijskih procesov, saj je le tako možno racionalno načrtovanje in optimizacija sintez, kakor tudi odkrivanje novih reakcij. Ukvarjamo se z reševanjem ključnih mehanističnih vprašanj mnogih reakcij, vključno s tistimi, ki potekajo pod klasičnimi pogoji, kot tudi s takimi, ki potekajo pod pogoji (organo)katalize ter z redoks reakcijami in reakcijami spajanja [PCCP 2021]. Pred kratkim smo na novo definirali mehanizem Sonogashirove reakcije, ki poteka brez prisotnosti bakrovih zvrsti in je dotlej temeljil na napačni predpostavki uveljavljenega mehanizma izpred skoraj petih desetletij [NatChem 2018]. Na področju reakcij spajanja je naš cilj razširiti kemijo še na druge kovine, kar lahko privede do odkritja novih reakcij, podobno kot smo nedavno odkrili nov katalitski sistem paladij-paladij [ChemComm 2016, OL 2020]. Odgovorili smo tudi na izzive katalitske Mitsunobu reakcije [OL 2016, Chem Sci 2016] in sinteze zelo reaktivnih in nestabilnih zvrsti, kot so vodikov trioksid (HOOOH) in njegovi derivati [ACIE 2015]. Ti so pogosti intermediati pri oksidacijah in so vse bolj prepoznani v številnih kemijskih, biokemijskih, atmosferskih in okoljskih procesih [ChemRev 2013]. Posvečamo se tudi številnim drugim strukturnim, sinteznim in mehanističnim vprašanjem ter njimi povezanimi procesi in tehnikami [J Chem Inf Model 2021, PCCP 2021].

Pomemben del naših raziskav namenjamo zeleni kemiji, ki predstavlja eno bistvenih usmeritev k zdravju in okolju bolj prijaznim sintezam, s končnim ciljem doseči sonaravni in trajnostni razvoj. Številni izzivi na tem področju, s katerimi se ukvarjamo, so na primer zamenjava lahko hlapnih, vnetljivih ali strupenih organskih topil ter škodljivih reagentov z bolj prijaznimi alternativami. Primer je pretvorba tiolov v sulfonil halogenide z uporabo zračnega kisika kot končnega oksidanta, oksidacija sulfidov do sulfonov z vodikovim peroksidom brez uporabe topil in katalizatorjev ter redukcija sulfoksidov v sulfide v odsotnosti organskega topila [Green Chem 2017, GCLR 2020]. Drugo pomembno področje v okviru zelene kemije je recikliranje ter ponovna uporaba katalizatorjev in žlahtnih kovin [ACIE 2022, ACIE 2022]. Razvili smo katalitsko Mitsunobu reakcijo z azo reagenti, ki jih je mogoče reciklirati [Chem Sci 2016].

Na učinkovitost reakcije je mogoče vplivati s katalizo. Katalizirane reakcije so danes ključne pri proizvodnji več kot 80% spojin, s katerimi se srečujemo v vsakdanjem življenju. Katalizatorji in katalitski procesi so povezani s približno 30% celotnega BDP evropskega gospodarstva. Nedavno smo razvili N-heterociklični karbenski (NHC) ligand na osnovi triazola z mezoionsko (MIC) strukturo – PyMIC – z bistveno izboljšanimi lastnostmi glede na druge ligande [ChemComm 2016]. PyMIC spadajo med nove SMART (»Switchable, Multifunctional, Adaptable, oR Tuneable«) ligande, ki omogočajo razvoj izjemno aktivnih katalizatorjev na osnovi kovin prehoda [OL 2020, OL 2020]. Sem spadajo Ru-, Os- in Ir-katalizatorji za selektivne oksidacije in redukcije ter Pd-kompleksi za reakcije spajanja (npr. reakciji Suzuki-Miyaura in Sonogashira), ki delujejo v vodi kot edinem topilu in v prisotnosti zraka. Kompleks Pd-PyMIC kaže encimom podobno reaktivnost pri katalitskem hidroaminiranju alkinov. Edinstvene lastnosti kompleksov s PyMIC, pa tudi z drugimi ligandi, kot so npr. azokarboksamidi, imajo zato potencial tudi v mnogih drugih katalitskih reakcijah in so v središču našega raziskovalnega dela [Organometallics 2021].

Ena izmed naših aplikativnih raziskovalnih tem je povezana z razvojem molekularnih sond za zgodnje odkrivanje Alzheimerjeve bolezni. Alzheimerjeva bolezen postaja eden izmed vodilnih problemov sodobne medicine, saj ima izjemno negativen vpliv na kvaliteto življenja bolnikov in njihovih družin, znatno pa obremenjuje tudi nacionalne proračune za zdravstveno varstvo po vsem svetu. Naš zgodnji prispevek k diagnostiki Alzheimerjeve bolezni je povezan z razvojem radioaktivne sonde [18F]FDDNP za in vivo slikanje patoloških proteinskih agregatov s pozitronsko emisijsko tomografijo (PET) [PNAS 2012]. Kot alternativa in vivo slikanju, ki zahteva izjemno drago specializirano infrastrukturo in predstavlja veliko tveganje za zdravje bolnikov, so naša trenutna prizadevanja osredotočena na pametne molekularne sonde za zgodnje napovedovanje Alzheimerjeve bolezni na podlagi ex vivo detekcije ustreznih biomarkerjev v telesnih tekočinah [JMC 2017]. Poleg tega se ukvarjamo z razvojem novih biološko pomembnih molekul s citotoksičnimi [Chem Eur J 2014, Organometallics 2019] in antibakterijskimi lastnostmi [EJMC 2017, Chem Biol Drug Des 2017]. V sodelovanju z razvojnima centroma Sandoz Austria in Sandoz Slovenija smo razvili popolnoma stereokontrolirano aldolno reakcijo na kiralnih β-aminokislinah [OL 2015] in laktonsko pot do statinov z uporabo Wittigove reakcije [JOC 2010].

Razvoj novih tehnik, metod, katalizatorjev, intermediatov in uporabnih spojin je ključnega pomena za trajnostni napredek raziskovalno usmerjene kemijske industrije in s tem sodobne družbe. V tem okviru se v naši programski skupini trudimo za razvoj novih znanj, vzpostavitev čim širše mreže sodelovanj z domačimi in mednarodnimi inštitucijami, prenos znanja iz akademskega okolja v industrijo (in obratno), s čimer nenazadnje prispevamo tudi k razvoju visokokakovostnih mladih znanstvenikov. Več o delu naše programske skupine si lahko preberete na Košmrlj Group, najnovejšemu dogajanju pa sledite tudi na Twitter profilu skupine @KosmrljGroup. Prijazno vabimo vse zainteresirane, da nas kontaktirajo in se nam pridružijo pri našem delu.

Research programme P1-0230 (Organic Chemistry: Synthesis, Structure, and Application)

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.