Stereoselectivity of Radical Reactions: Cyclic Systems

Abstract

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. The anti RuleCyclic 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 [ l , 21, the anti rule could be applied with great success to many cases of cyclic radicals: reactions occur preferentially in unti 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.

Free-Radical Hydroxylation Reactions of Alkylboronates

“…Primary and tertiary alkylcatecholboranes generated from β-pinene and 2,3-dimethyl-2-butene afforded the corresponding alkoxyamines with slightly lower yields (<65% yield) than secondary alkylcatecholboranes (Table , Entries 4 and 5). The stereochemical outcome of these reactions corresponds very well to expectations for radical processes . Indeed, reaction of phenylcyclopentene 16 afforded the trans alkoxyamine 21 (71% yield) with good diastereoselectivity ( trans / cis 89:11, Entry 2) .…”

“…The stereochemical outcome of these reactions corresponds very well to expectations for radical processes . Indeed, reaction of phenylcyclopentene 16 afforded the trans alkoxyamine 21 (71% yield) with good diastereoselectivity ( trans / cis 89:11, Entry 2) . In turn, α-pinene 17 was hydroborated with complete stereoselectivity from the less hindered face, and the subsequent radical reaction occurred with complete stereocontrol, anti to the neighboring methyl group and to the gem -dimethyl moiety .…”

A Convenient Tin-Free Procedure for Radical Carboazidation and Azidation

“…We recently reported a useful radical carboazidation of alkenes and its application toward concise synthesis of the core of different alkaloids. , This efficient procedure uses hexabutylditin as the chain transfer reagent. Organotin reagents are widely used in radical chemistry, especially because they are known to sustain efficiently radical chains . However, their toxicity and the difficulties encountered to remove traces of tin byproducts greatly limit their use for preparative purposes.…”

Stereoselective Synthesis of 1‘-C-Branched Arabinofuranosyl Nucleosides via Anomeric Radicals Generated by 1,2-Acyloxy Migration

“…The present radical migration (from C-2‘ to the anomeric position) is unique in that it is the reverse pathway to that observed in carbohydrate systems (from the anomeric position to C-2). Reaction of the nucleoside anomeric radical with radical acceptors proceeded stereoselectively, due to the steric repulsion exerted by the 2‘-“up”-pivaloyloxy group (the anti -rule) . It is noteworthy that a radical acceptor, which reacts through an addition−elimination mechanism such as styryl(tributyl)tin and 3-bromo-2-methylacrylonitrile, is a suitable choice of reagent for this tandem 1,2-acyloxy migration/intermolecular C−C bond formation methodology.…”