Stereoselectivity of Radical Reactions Cyclic Systems

Cyclic radicals are very often involved in the key step of a reaction sequence. They are particularly useful since the stereochemical outcome of their reactions can be easily predicted and in some cases directed. Selected examples from the recent literature have been chosen in order to illustrate the different factors governing the stereochemical outcome. The importance of steric effects, conformational effects, neighboring prochiral centers, pyramidalization, stereoelectronic effects and position of the transition states will be discussed based on examples of synthetic importance. 

Cyclic radicals can only exist in a reduced number of conformations relative to acyclic ones. Therefore, prediction of the stereochemistry is simplified. As nicely documented in two excellent review articles [1, 2], the anti rule could be applied with great success to many cases of cyclic radicals reactions occur preferentially in anti fashion to the substituents present in the cyclic moiety. This simple model is based on minimization of steric interactions in the transition state and is particularly efficient when the conformation of the radical intermediate is known. 

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Free-radical cyclizations using ethyl radicals generated by EtsB/air system or stannyl radicals systems provide a range of carbocyclic and heterocyclic hydroxylamines (equation 77). Stereoselectivity in these reactions is variable but can be semiquaUtatively predicted by Beckwith-Houk models . Depending on the substitution pattern of the emerging cyclic system, stereoselectivity can be very high, especially in fused polycyclic systems (equation... 

A more practical, atom-economic and environmentally benign aziridination protocol is the use of chloramine-T or bromamine-T as nitrene source, which leads to NaCl or NaBr as the sole reaction by-product. In 2001, Gross reported an iron corrole catalyzed aziridination of styrenes with chloramine-T [83]. With iron corrole as catalyst, the aziridination can be performed rmder air atmosphere conditions, affording aziridines in moderate product yields (48-60%). In 2004, Zhang described an aziridination with bromamine-T as nitrene source and [Fe(TTP)Cl] as catalyst [84]. This catalytic system is effective for a variety of alkenes, including aromatic, aliphatic, cyclic, and acyclic alkenes, as well as cx,p-unsaturated esters (Scheme 28). Moderate to low stereoselectivities for 1,2-disubstituted alkenes were observed indicating the involvement of radical intermediate. 

One of the main advantages of the anionic cyclizations is their regioespecificity and stereoselectivity when compared with radical or other types of reactions leading to cyclic systems. This is usually due to the formation of complexes involving the lithiated alkyl, vinyl or aryl substrate and an unsaturated, double or triple, C—C bond. In some cases, a heteroatom is involved in stabilizing the transition state for the reaction. In other cases, the stereoselectivity of the cyclization is determined by the presence of several functional groups in the substrate. 

Free-radical reactions have begun to find increasingly wide application in synthetic chemistry. Because of their high stereoselectivity, some of them are very appealing. At the same time, many such processes have serious limitations since they use iodine-containing systems as substrates. Nevertheless, radical cyclization has become a known technique of both cyclic and heterocyclic system design. 

Stereoselective hydrogen transfer reactions on oxacyclic radical intermediates are useful as shown in the synthesis of lauthisan (32) [126]. A key step in the total synthesis of brevetoxin B by Nicolaou [127] (Scheme 65) features conversion of the hydroxy dithioketal 189 into the oxoeene system 190 via cyclic hemithioketal formation and stereoselective radical-mediated desulfurization. More recently, Tachi-bana employed the same reaction sequence in the partial synthesis of ciguatoxin ]128]. 

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