Group of Catalysis in Organic Synthesis

Department of Organic and Nuclear Chemistry
Faculty of Science
CHARLES UNIVERSITY


Outline of the current research and future projects

Our group is currently engaged in several projects that encompass different areas of organic chemistry involving transition metal compound catalysis such (C-C bond activation, [2+2+2]cyclotrimerizations, cross-metathesis), Lewis base organocatalysis, synthesis of natural compounds (estrone) and biologically active substances (ligands for estrogenic receptors), ferrocene and carborane chemistry. (For the full account, see the list of papers section.)

1. Development of New Transition Metal-Catalyzed Reactions

Carbon-carbon bond forming and cleavage reactions are essential operations for organic synthesis. In view of the aforementioned it is of a general interest to develop new procedures for catalytic cleavage of the C-C bonds under mild reaction conditions by using inexpensive transition metal compounds, e.g. Fe, Ni, and Co. In this regard we have developed an iron-complex catalyzed alkylative cyclization of 2-chlorodienes to alkyl(methylidene)cycloalkanes in the presence of trialkylaluminums. Outcome of these early studies was also the discovery of a new C-C bond cleavage reaction: Ni-catalyzed deallylation of diallylmalonates and related compounds. This reaction could also be carried with compounds where the allylic moiety is a part of a cyclic system. In this instance cleavage of unstarined 5- and 6-membered rings could be easily achieved. In addition we found that the course of the reaction the C-C cleavage or formation can be controlled by Ni/organoaluminum ratio. We have recently also utilized the C-C bond cleavage in biphenylene compounds catalyzed by a simple [RhCl(cod)]2/dppe catalytic system followed by the subsequent reaction with alkynes yielding selectively substituted phenanthrene and picene derivatives.

Scheme_1

Selected papers:
Eur. J. Org. Chem. 2004, 1280;
J. Am. Chem. Soc. 2004, 126, 10222;
Organometallics 2006, 25, 901;
New. J. Chem.2006, 30, 671;
Org. Lett. 2008, 10, 5261.

2. Synthesis of isoprenoid compounds

The aim of this project is to develop new methods for the construction of the steroid framework by using transition-metal based methodologies. We have developed so far two new diastereoselective approaches for the construction of estrone intermediate with core tetracyclic steroid skeleton. The first is based on three-fold use of Cp2ZrBu2 (Negishi reagent) and Ru-catalyzed ring closing metathesis. The second approach is based on two zirconium reactions (oxidative addition, cycloisomerization), followed by cobalt-mediated cyclocarbonylation (Pauson-Khand reaction). These early studies led to the development of a new enantioselective approach to stroid skeleton based on asymmetric conjugated addition. This methodology was used to synthesize (-)-estrone. The zirconocene–mediated cyclization was the cucial step in the synthesis of sesquiterpenoid derivatives bearing protoilludane, illudane and marasmane skeletons.

Scheme_2

Selected papers:
J. Org. Chem. 2012, 29 (review);
Eur. J. Org. Chem. 2011, 3279;
Eur. J. Org. Chem. 2010, 646;
Synlett 2009, 2445;
J. Org. Chem. 2008, 73, 6202.

3. Synthesis and Application of Lewis Base Catalysts in Organic Synthesis

This project is focused on synthesis of axially chiral N,N’-dixodes with bipyridine framework and their application in organic synthesis. The underlying synthetic strategy is based on [2+2+2]-cyclotrimerization of suitably substituted diynes with nitriles catalyzed by Co-complexes that gave rise to the desired bipyridines. Subsequent oxidation and resolution furnished the corresponding chiral N,N’-dioxides. The prepared compound 1 was used in catalytic allylation of aromatic and alfa,beta-unsaturated aldehydes to homoallyl alcohols with high enantioselectivity (up to 99% ee). The reaction mechanism of the allylation reaction as well as the asymmetric induction was crucially influenced by solvent effects.

Scheme_3

The prepared chiral homoallyl alcohols were used as building blocks for the synthesis of simple natural compounds such as goniothalamin etc. Further applications of the enantioselective allylation reaction are currently pursued. As potential targets have been chosen compounds such as biologically active flavonoids (e.g. liquiritigenin), pharmaceutically active substances (e.g. Ezetimibe and Duloxetine), and other natural compounds (papulacandine D).

Scheme_4

Selected papers:
Chem. Eur. J. 2011, 17, 7162–7166;
Eur. J. Org. Chem. 2010, 7040;
Chem. Eur. J. 2010, 16, 9442;
J. Am. Chem. Soc. 2010, 132, 12660;
Pure Appl. Chem. 2010, 82, 1813;
Adv. Synth. Catal. 2009, 351, 1279;
J. Am.Chem. Soc. 2008, 130, 5341;
Chem. Commun. 2009, 2314.

4. Dewar benzenes

Dewar benzenes (DB) are fascinating compounds worth of study. The substituted DBs are often remarkably stable compounds under ambient conditions and undergo rearrangement to benzenes only at elevated temperatures. This makes them not only attractive targets for various experimental and theoretical physical-organic studies but also interesting candidates for application in organic synthesis such as intermediates for synthesis polyaryl compounds and others.

Scheme_5

Selected papers:
Synlett 2011, 396;
J. Org. Chem. 2010, 75, 576;
Dalton Trans. 2009, 3137;
Eur. J. Org. Chem. 2008, 47.

5. Ferrocene chemistry

The aims of this project are syntheses of various compounds that bear the ferrocene moiety. The spectrum of compound encompasses a study of cycloadditions with sterically hindered ferrocenylalkynes resulting in compounds that could be otherwise difficult to access such as ferrocene-substituted polyaromatic compounds (e.g. bis(ferrocenyl)phenanthrene), synthesis of ferrocenylcarboranes, synthesis of ferrocenestrone as the first example of steroid analogue with integrated metallocene unit in the steroid skeleton.

Selected papers: manuscripts are in preparation.

6. Synthesis of perfluoroalkylated compounds

The aim if his project is to use cross-metathesis reation between perfluoroalkylpropenes with various terminal alkenes to synthesize perfluroalkylated compounds. Since the presence of fluorinated side-chains in many biologically relevant substances can modify and improve their properties, further synthesis of other of other analogues or derivatives represents worthy goal. This methodlogy was used for synthesis of perfluroalkylted carboranes, brassinosteroids or estradiol derivatives.

Scheme_7

Selected papers:
Eur. J. Org. Chem. 2010, 6256;
J. Med. Chem. 2010,53, 6947;
Synlett 2010, 885;
J. Med. Chem. 2009, 52, 5753;
Eur. J. Org. Chem. 2008, 4493.

7. Synthesis of new ligands for estrogenic receptors

The aim of this project is to synthsize new and selective ligands for estrogenic receptors alfa and beta. The main startegz fo achieving this purpose is moification of esrradiol skeleton, namely in positions 17 and 15. So far we have several types of modified estradiols have been prepared possessing various level of selective binding to the aforementioned receptors. The corresponding ligands have been prepared by using ransition metal catalyzed methodlogies such as [2+2+2]-cyclotrimerization, alkene-alkene cross-metathesis, etc.

Scheme_8

Selected papers:
J. Med. Chem. 2010, 53, 4290;
J. Med. Chem. 2010, 53, 6947.

Our research is carried out also in collaboration with several groups:
Prof. P. Kočovský (University of Glasgow, UK)
Prof. M. Hocek (IOCB, Czech Republic)
Prof. I. Valterová (IOCB, Czech Republic), etc.