From Marco Polo to chiral stannanes - radical chemistry for the new millennium

Over the past few decades, free-radicals have emerged as important intermediates in a large cross-section of disciplines ranging from chemical synthesis to biology and medicine. Free-radicals are now understood to be important in oxidative processes affecting areas that include materials science, DNA damage and heart disease, and are involved in many enzyme -mediated transformations. Significantly, radicals can be harnessed to provide powerful imaging tools and novel synthetic methodology with application to natural products and other chemistries. This review describes the author's involvement in the development of new free-radical technology useful for the preparation of compounds of biological importance. Examples include the use of carbon-centred radicals to prepare selenium-containing compounds that are then used as free-radical scavengers and antioxidants. Novel reagents have been developed to perform enantioselective free-radical chemistry with the aim of preparing novel pharmaceuticals. Examples are provided.


Introduction
There can be no doubt that selenium-containing organic molecules have played and continue to play an important role in biology and medicine. 1The mythology surrounding the "high toxicity" wasteland and guarded by a custodian called the Fisher King, who suffered from a wound that would not heal.His recovery and the renewal of the wastelands depended upon the successful completion of the quest.Equally, the self-realization of the questing knight was assured by finding the Grail.

Discussion
Ebselen and the quest for selenium-based radical scavengers Glutathione peroxidase (GSH-Px) is a mammalian selenoenzyme that catalyses the reduction of a wide variety of hydroperoxides which are known to generate highly-reactive oxygen radicals that destroy key biological molecules and cause damage to cell membranes. 11The activity of GSH-Px is principally due to the redox chemistry surrounding the selenocystine residue found in the active site of the enzyme. 11selen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), 4 and some of its derivatives mimic the action of GSH-Px. 11The sulfur analogue is completely inactive, an observation which highlights the importance of selenium in this redox chemistry. 12Ebselen has also been shown to be a nitric oxide synthase (NOS) inhibitor, 13 to induce cytokines such as interferons, tumour necrosis factor, interleukin-2 and gratunocytemacrophage colony stimulating factor. 14These properties combined with Ebselen's low toxicity have led to interest in its therapeutic potential for a number of diseases. 5ng demonstrated some time ago that Ebselen and analogues could be prepared in good yield through the use of free-radical homolytic substitution chemistry. 15Interestingly, attempts to prepare the N-acyl pyridinethiooxycarbonyl (PTOC) carbamate precursor resulted in the formation of the rare benzoselenazine-2,4-dione ring system 5 (Scheme 1). 16We reasoned that since compounds 5 resemble Ebselen, their pharmacology should be assessed.Indeed, Venn demonstrated that 5 is an NOS inhibitor, but less effective than either Ebselen 4 or nitro-Larginine, a commonly used (standard) inhibitor (Figure 1). 17

Scheme 1
The chemistry described above has also been applied to the preparation of thiophene analogues 6 of Ebselen which are expected to show improved solubility properties. 18tibiotics for the Fisher King † -toward selenium-containing penems and cephalosporins It is generally appreciated that β-lactam based antibiotics have a limited future given increased resistance demonstrated by many strains of bacteria.There is an urgent need for the development of new classes of antibiotic and many laboratories have made significant progress in this area, especially with the introduction of peptide-based agents.As part of ongoing work, Martin and Carland explored methods of incorporating selenium into the penem and cephalosporin nuclei. 19ce again, free-radical homolytic substitution was used to effect the required outcome; examples are given in Scheme 2.

Scheme 2 A crusade for start of the new millennium -novel antioxidant carbohydrates
There is a need for the development of improved, water-soluble antioxidants.As part of an ongoing collaboration with the Heart Research Institute in Sydney, we have been interested in selenium and tellurium containing carbohydrates.It is interesting to note that most organic selenides tested in vitro have proven to be effective antioxidants, while the few organic tellurides tested have proven to be more effective still. 20Zheng utilised samarium iodide mediated homolytic substitution chemistry to prepare selenium derivatives (eg. of Vitamin E. 22 The activity of 10 is most likely due to its ability to quench active peroxyl radicals in vivo through the rapid transfer of its phenolic hydrogen. 232,6-Di-tert-butyl-4methylphenol (BHT) 11 is a further example of a common antioxidant which finds application in the food industry. 24nzofuran 12 displays enhanced antioxidant activity when compared with 10; this enhanced activity has been explained in terms of the better overlap between the non-phenolic 2p-type lone pair and the aromatic π-system in 12 as compared to 10. 25 As part of ongoing collaboration with the research group of Engman in Sweden, we have been involved in the application of the novel free-radical chemistry developed in our laboratories at the University of Melbourne to the preparation of selenium-and tellurium-containing tocopherol analogues with enhanced antioxidant capacity.

Scheme 4
The serendipitous discovery by Laws and Zugaro that butyltelluroate is an effective electron transfer agent has been put to good use in the preparation of benzotellurophenes 13 and benzoselenophenes 14. 4 In addition, Malmström was able to show for the first time that tertiary carbon-centred radicals generated from PTOC oxalyl esters 15 undergo smooth homolytic substitution chemistry to provide antioxidants 16 in good yield (Scheme 4). 26Current efforts are directed toward the preparation of selenotocopherol 17 which effectively combines the antioxidant capacities of both hindered-phenol and selenide moieties into the same molecule.

Drinking from the Cup -enantioselective free-radical chemistry
More than 90% of biomolecules exhibit chirality.Many pharmaceutical products contain different chiral forms of drugs, some of which are harmful or ineffective.For example, one form of the drug naproxen has 28 times the anti-inflammatory activity of its enantiomer.In the synthetic form of dopamine used to treat Parkinson's disease one isomer acts on the nerve cells to control the patient's tremors whilst the other enantiomer is toxic.
The technology of chiral synthesis, known as chirotechnology, is an industry rapidly increasing in commercial importance.Growth continues in both the number and value of single enantiomer drugs.In 1992 chiral pharmaceuticals alone were estimated to have a market value of $US18 billion.This year they are worth over $US100 billion. 27The basis of the chirotechnology industry is the preparation of products in a single pure chiral form; 80 per cent of new drugs entering development are enantiomerically pure.The development of improved methods to provide single-enantiomer compounds is therefore a topical objective.
A significant challenge facing free-radical chemists is in the area of stereocontrol, specifically the ability to control the direction of reagent attack at a prochiral radical.Despite there being numerous reports of free-radical reactions proceeding with diastereocontrol, there are very few examples that proceed with genuine enantiocontrol. 28The majority of this small set of examples involve the use of chiral auxiliaries. 28Of the remaining few reports, the introduction of asymmetry in the substrate through the use of chiral Lewis acid mediation, 29 and in the reagent through the use of chiral ligands on the tin atom in suitably constructed stannanes, 30 have been the methods of choice for achieving enantioselectivity in radical chemistry.Our approach to the development of synthetically useful chiral stannanes primarily involves the judicious choice of ligand from the multitude of compounds available in the natural chiral pool.
Perchyonok also demonstrated that dimenthylphenyltin hydride 19 reacts with bromide 23 in toluene at -78° and in the presence of (S,S)-(+)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2cyclohexanediaminomanganese(III) chloride 24 to afford ethyl (S)-2-phenyl-2cyclopentylacetate 25 with 96% ee (Scheme 5). 34To the best of our knowledge, this result represents the highest-ever reported enantioselectivity observed during any organic free-radical transformation.More extensive enantioselectivity data can be found in our recent publication. 34lecular modelling has also played an important role in the design of novel reagents.
Skidmore showed recently that cholic acid 26 provides an excellent chiral template for stannanebased reagents.Indeed, computational data recommended 27 and 28 as the reagents of choice for enantioselective reduction; these stannanes were subsequently prepared from cholic acid and lithocholic acid (Scheme 6). 35

Scheme 6
In practice, the 7α-stannane 27 afforded enantioselectivities in excess of 90% in several reactions, 36 providing strong support for our approach involving the combination of molecular modelling and experimental techniques.

A renaissance in radical chemistry -concluding remarks
During the twenty year period 1970 -1990, free-radical chemistry underwent a series of remarkable transformations that effectively drew to a close the era in which free-radicals were considered to give rise only to intractable tars or polymers.The increased understanding of the factors which govern the reactivity, regio-and stereochemistry of radical addition chemistry led to the emergence of a maturity which saw the development of several impressive syntheses based on radical chemistry.While this period revolutionised synthetic chemists' attitudes toward freeradicals, in 1990 there were still some limitations confronting free-radical chemistry that required attention.These included, most notably, a lack of methods for the formation of bonds to higher heteroatoms, and the low levels of stereochemical control achievable in radical transformations.Work in the author's laboratories at The University of Melbourne over the last decade has seen significant inroads in both of these areas.New reagents and methods for the preparation of novel selenium and tellurium containing compounds of interest in biology and medicine have been developed and utilised, while novel reagents that control hydrogen transfer reactions (homolytic substitution at hydrogen) have been developed to the extent that single- enantiomer outcomes are now possible.These discoveries have been applied to the preparation of novel antioxidants, antibiotics, free-radical scavengers, nitric oxide synthase (NOS) inhibitors as well as enantiopure intermediates for use in the pharmaceutical industry.
In much the same way that a clearer understanding of the details of homolytic addition chemistry gave rise to a rapid increase in the use of that methodology in synthesis, recent increases in the understanding of homolytic substitution processes have the similar potential of providing chemists with yet further tools for their synthetic endeavours.