Charles B. de Koning

Metathesis in the Synthesis of Aromatic Compounds

The importance of aromatic structures in organic chemistry can never be underestimated. Nature uses compounds containing aromatic or heteroaromatic nuclei extensively as the skeletal core for compounds involved in many important biological processes. In addition, modern medicinal and pharmaceutical chemists have found that aromatic cores are indeed “privileged structures” for the discovery of molecules with novel medicinal characteristics.2 Ring-closing metathesis (RCM) also needs little introduction; the explosion of applications of this useful methodology ultimately culminated in the award of the 2005 Nobel Prize in Chemistry to its discoverers and primary developers. One just has to look at the numbers of recent reviews highlighting this area of chemistry to realize the impact of ene-ene and ene-yne metathesis on modern synthetic chemistry, as well * E-mail: Willem.vanOtterlo@wits.ac.za and Charles.deKoning@wits.ac.za. † This review is dedicated to Prof. Dr. H.-G. (Hagga) Schmalz, Institute of Organic Chemistry, University of Cologne, Cologne, Germanysa scientist, mentor, and friend who wrote one of the first reviews on the emerging field of metathesis in synthesis in 1995. Chem. Rev. 2009, 109, 3743–3782 3743

Sequential isomerization and ring-closing metathesis: masked styryl and vinyloxyaryl groups for the synthesis of benzo-fused heterocycles

The use of an aryl allyl ether and an arylallyl group as masked vinyl ether and 1-propenylphenyl groups for ring-closing metathesis (RCM) leading to the synthesis of benzo-fused heterocycles was demonstrated by using a ruthenium-mediated isomerization followed by a ruthenium-mediated RCM reaction. This resulted in the syntheses of a variety of products including two substituted benzo[1,4]dioxins, a naphtho[2,3-b][1,4]dioxin, a 2H-chromene and a benzo[b]furan.

Reformatsky reactions with N-arylpyrrolidine-2-thiones: synthesis of tricyclic analogues of quinolone antibacterial agents

Abstract A convenient synthesis of 5-oxo-1,2,3,5-tetrahydropyrrolo[1,2- a ]quinoline-4-carboxylic acids, tricyclic analogues of the quinolone antibiotics, is described. Key steps in the route are a novel zinc-mediated Reformatsky reaction between diethyl bromomalonate and N -arylpyrrolidine-2-thiones 18 , and cyclisation of the resulting diethyl pyrrolidinylidenemalonate intermediates 19 in polyphosphoric acid. The products proved to be devoid of biological activity.

Ring-closing metathesis for the synthesis of benzo-fused bicyclic compounds

Ring-closing metathesis (RCM) was used to synthesise five 4H-chromenes, a naphthol and an indenol. These are the first examples of RCM applied to the synthesis of such benzo-fused bicyclic compounds.

The synthesis of 2- and 3-aryl indoles and 1,3,4,5-tetrahydropyrano[4,3-b]indoles and their antibacterial and antifungal activity.

A series of 2- and 3-aryl substituted indoles and two 1,3,4,5-tetrahydropyrano[4,3-b]indoles were synthesized from indole and 5-methoxyindole. The 2-aryl indoles were synthesized from the 1-(phenylsulfonyl)indole derivatives using magnesiation followed by iodination. The 2-iodinated compounds were then subjected to Suzuki-Miyaura reactions. In addition, the 3-aryl indoles were made from the corresponding 3-bromoindoles using Suzuki-Miyaura reactions. The 1,3,4,5-tetrahydropyrano[4,3-b]indoles were also synthesized from 1-(phenylsulfonyl)indole by magnesiation followed by treatment with allylbromide. The product was then converted into [2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl]methanol which upon exposure to Hg(OAc)(2) and NaBH(4) afforded tetrahydropyrano[4,3-b]indoles. A number of the 2- and 3-aryl indoles displayed noteworthy antimicrobial activity, with compound 13a displaying the most significant activity (3.9 microg/mL) against the Gram-positive micro-organism Bacillus cereus.

6-Substituted imidazo[1,2-a]pyridines: synthesis and biological activity against colon cancer cell lines HT-29 and Caco-2.

A range of 6-substituted imidazo[1,2-a]pyridines were synthesized using a multicomponent coupling reaction. Most of these compounds were found to exhibit excellent activity against the colon cancer cell lines HT-29 and Caco-2, whilst not showing significant toxicity against white blood cells. Our studies have shown that the proteolytic phase of apoptosis was initiated 2 h after treatment with these imidazo-[1,2-a]pyridines. The data suggests that the imidazo[1,2-a]pyridine-induced cell death in HT-29 and Caco-2 cells is mediated via pathway(s) that include the release of cytochrome c from the mitochondria to the cytosol and the activation of caspase 3 and caspase 8.

In search of a treatment for HIV – current therapies and the role of non-nucleoside reverse transcriptase inhibitors (NNRTIs)

The human immunodeficiency virus (HIV) causes AIDS (acquired immune deficiency syndrome), a disease in which the immune system progressively deteriorates, making sufferers vulnerable to all manner of opportunistic infections. Currently, world-wide there are estimated to be 34 million people living with HIV, with the vast majority of these living in sub-Saharan Africa. Therefore, an important research focus is development of new drugs that can be used in the treatment of HIV/AIDS. This review gives an overview of the disease and addresses the drugs currently used for treatment, with specific emphasis on new developments within the class of allosteric non-nucleoside reverse transcriptase inhibitors (NNRTIs).

MEMORY OF CHIRALITY IN ELECTRON TRANSFER MEDIATED BENZYLIC UMPOLUNG REACTIONS OF ARENE-CR(CO)3 COMPLEXES

As density functional calculations suggest, Cr(CO)3 -complexed benzylic radicals (such as 2) exhibit a significant degree of configurational stablility. This was exploited in an efficient method for the electron transfer mediated transformations of readily available 1-arylalkanol-Cr(CO)3 derivatives 1 to afford alkylated products 3 in good yields and with a high degree of stereochemical retention.

Nitroalkenes as precursors to the aromatic spiroketal skeleton of γ-rubromycin. A Nef-type reaction mediated by Pearlman's catalyst

Abstract The first synthesis of the benzannelated spiroketal core of γ-rubromycin using Henry condensations and a novel Nef-type reaction induced by Pearlmans catalyst is described.

Zirconium bis-indenyl compounds. Synthesis and X-ray crystallography study of 1- and 2-substituted bis(R-indenyl)zirconium dichloride metallocenes

Abstract A series of 1- and 2-substituted indenyl ligands were prepared and used in the synthesis of [1-R-Ind]2ZrCl2 [R=Me (2b), Et (4b), iPr (5b), tBu (6b), SiMe3 (8b), Ph (10b), Bz (12b), 1-Naph (14b)] and [2-R-Ind]2ZrCl2 [R=Me (1b), Et (3b), SiMe3 (7b), Ph (9b), Bz (11b), 1-Naph (13b)] metallocenes. An X-ray crystallographic study of 4b and 10b showed the complexes to be the racemic diastereomers (4b, both the R,R and S,S-enantiomers and 10b, the S,S-enantiomer). The X-ray data together with NMR spectral data revealed that the size of the substituent influenced the orientation the two indenyl ligands of the metallocenes. The 4b diastereomers are both found to crystallize with their ethyl groups syn (bis-central) with respect to each other whereas the larger phenyl groups in 10b results in an anti (bis-lateral) orientation of the indenyl ligands.