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Research on Chemicals and Custom Synthesis

The Georganics research department is actively engaged in organic chemistry research at an academic/university level. Our interest lies in fundamental research on new reaction cascades involving C-H activation/carbonylation, total syntheses of natural products, and flow chemistry.

Flow chemistry is utilized in the synthesis of natural products and in the optimisation of various reaction steps in the preparation of a range of different products.

The active participation of our research group members in problem solving current research challenges ensures that our knowledge expands for our custom synthesis/research programs or our customers.

A Universal Strategy for Synthesis of Agropyrenol Family. Total Synthesis of Agropyrenol, Sordarial, and Heterocornol A and B

Martin Markovič, Peter Koóš, Saskia Sokoliová, Nikola Boháčiková, Tomáš Vyskočil, Ján Moncoľ, Tibor GraczaJ. Org. Chem. 2022, 87(23), 15947-15962.Published: 12 November 2022
A divergent strategy for natural polyketides synthesis has been designed. This synthetic route allowed chemical alterations leading to all stereoisomers of the natural agropyrenol 1, sordarial 2, and heterocornol B 4. Key steps involve desymmetrization of divinylcarbinol using asymmetric Sharpless epoxidation and Heck coupling of an easily available aromatic partner and prepared chiral alkene. The versatility of the synthetic method was demonstrated on the preparation of heterocornol A 3 and sordariol 5. The absolute and relative configurations of prepared natural compounds 2·1/3C6H12 and 4 were confirmed and assigned by single-crystal X-ray analysis.

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Flow Pd(II)-Catalysed Carbonylative Cyclisation in the Total Synthesis of Jaspine B

Pavol Lopatka, Michal Gavenda, Martin Markovič, Peter Koóš and Tibor GraczaCatalysts 2021, 11(12), 1513Published: 12 December 2021
This work describes the total synthesis of jaspine B involving the highly diastereoselective Pd(II)-catalysed carbonylative cyclisation in the preparation of crucial intermediates. New conditions for this transformation were developed and involved the pBQ/LiCl as a reoxidation system and Fe(CO)5 as an in situ source of stoichiometric amount of carbon monoxide (1.5 molar equivalent). In addition, we have demonstrated the use of a flow reactor adopting proposed conditions in the large-scale preparation of key lactones.

Keywords: Jaspine B; flow chemistry; palladium catalysis; cyclisation; carbonylation
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Recent advances in the construction of isoindolo[2,1-a]indol/indolin-6-ones via C-C cross-coupling reactions

Martin Markovič, Peter Koóš, Tomáš Čarný and Tibor GraczaTetrahedron Letters Volume 61, Issue 40Publication Date: 20 August 2020.

The review summaries the most recent synthetic methodologies for assembly of the 6H-isoindolo[2,1-a]indol-6-one and 10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one scaffolds, the structural motifs present in many natural and biologically interesting compounds. The literature covered in this overview dates from January 2015 to April 2020, and presented strategies are based on transition metal-catalysed C-C cross coupling reactions.

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Recent Applications of Continuous Flow in Homogeneous Palladium Catalysis

Martin Markovič, Pavol Lopatka, Tibor Gracza and Peter KoóšSynthesis 2020; 52(23): 3511-3529Publication Date: Jan 1, 2020

Considerable advances have been made using continuous flow chemistry as an enabling tool in organic synthesis. Consequently, the number of articles reporting continuous flow methods has increased significantly in recent years. This review covers the progress achieved in homogeneous palladium catalysis using continuous flow conditions over the last five years, including C–C/C–N cross-coupling reactions, carbonylations and reductive/oxidative transformations.

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Continuous Pd-Catalyzed Carbonylative Cyclization Using Iron Pentacarbonyl as a CO Source

Pavol Lopatka, Martin Markovič, Peter Koóš, Steven V. Ley and Tibor GraczaJ. Org. Chem. 2019, 84, 22, 14394–14406Publication Date:October 24, 2019

This work discloses a continuous flow carbonylation reaction using iron pentacarbonyl as source of CO. The described transformation using this surrogate was designed for use in commonly accessible flow equipment. Optimized conditions were applied to a scalable synthesis of the natural compound isolated from perianal glandular pheromone secretion of the African civet cat. In addition, a flow Pd-catalyzed carbonylation of aryl halides is successfully reported.

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One-Step Synthesis of Isoindolo[2,1-a]indol-6-ones via Tandem Pd-Catalyzed Aminocarbonylation and C–H Activation

Tomáš Čarný, Martin Markovič, Tibor Gracza and Peter KoóšJ. Org. Chem. 2019, 84, 19, 12499–12507Publication Date:September 11, 2019

A unified catalytic system for tandem Pd-catalyzed carbonylation and C–C cross-coupling via C–H activation was designed. The proposed cascade reaction allows a facile one-step construction of a tetracyclic isoindoloindole skeleton, in which three new C–C/C–N bonds are simultaneously formed. In detail, the carbonylation of aryl dibromides with indoles and C–H activation of in situ formed N-(2’-bromoaroyl)-indole provide biologically relevant 6H-isoindolo[2,1-a]indol-6-ones from commercially available substrates. The aminocarbonylation step in the proposed tandem reaction utilizes glyoxylic acid monohydrate as an environmentally friendly CO surrogate.

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A Short Asymmetric Synthesis of Sauropunols A–D

Martin Markovič, Peter Koóš and Tibor GraczaSynthesis 2017; 49(13): 2939-2942Publication Date: Jan 1, 2017

A short and efficient asymmetric synthesis of natural sauropunols A, B, and C/D has been accomplished in 6 steps from divinylcarbinol with overall yield of 19%, 7% and 32%, respectively. The key synthetic steps include effective Sharpless asymmetric epoxidation of penta-1,4-dien-3-ol and a highly diastereoselective Pd-catalysed oxycarbonylation of pentene-1,2,3-triol. The structures of sauropunols A and B have been confirmed.

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Glyoxylic Acid as a Carbon Monoxide Source for Carbonylation Reactions

Martin Markovič, Pavol Lopatka, Peter Koóš and Tibor GraczaChemistrySelect 2016, 1, 2454-2457Publication Date: 12 July 2016

A new protocol for the generation of carbon monoxide by the dehydration of glyoxylic acid has been developed. Glyoxylic acid was applied as an environmentally friendly and cheap substitute for toxic and gaseous CO in the palladium-catalyzed carbonylation reactions providing industrially interesting products in good to excellent yields.

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Zn-Mediated Reduction of Oxalyl Chloride Forming CO and Its Application in Carbonylation Reactions

Martin Markovič, Pavol Lopatka, Peter Koóš and Tibor GraczaOrg. Lett. 2015, 17, 22, 5618–5621Publication Date:November 10, 2015

An efficient protocol for the generation of carbon monoxide by Zn-mediated reduction of oxalyl chloride has been developed. Oxalyl chloride was applied as an extremely effective substitute for toxic gaseous CO in the palladium-catalyzed alkoxy-/amino-/hydrogen-/hydroxycarbonylation processes providing industrially interesting esters, amides, aldehydes, and carboxylic acids in good to excellent yields. This new procedure can be applied to various carbonylation reactions in the presence of a transition metal catalyst under mild conditions and with a stoichiometric amount of CO source.

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Palladium-catalysed cyclisation of alkenols: Synthesis of oxaheterocycles as core intermediates of natural compounds

Miroslav Palík, Jozef Kožíšek, Peter Koóš and Tibor GraczaBeilstein J. Org. Chem. 2014, 10, 2077–2086.Publication Date: 03 Sep 2014

The study of Pd-catalysed cyclisation reactions of alkenols using different catalytic systems is reported. These transformations affect the stereoselective construction of mono- and/or bicyclic oxaheterocyclic derivatives depending on a starting alkenol. The substrate scope and proposed mechanism of Pd-catalysed cyclisation reactions are also discussed. Moreover, the diastereoselective Pd-catalysed cyclisation of appropriate alkenols to tetrahydrofurans and subsequent cyclisation provided properly substituted 2,5-dioxabicyclo[2.2.1]heptane and 2,6-dioxabicyclo[3.2.1]octane, respectively. Such bicyclic ring subunits are found in many natural products including ocellenynes and aurovertines.

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