Temporary Tethering Strategies in Radical Cyclization Reactions

3 Temporary Tethering Strategies in Radical Cyclization Reactions 

The following discussion on the application of the temporary connection to radical cyclizations will be divided into five sections. In the first, a silyl ether is used as the tether in which one of the alkyl groups attached to the silicon possesses the radical precursor (usually a halogen). In the second section, it is the radical acceptor which is introduced on silyl ether formation. The third section concerns the use of silyl acetals as a temporary connection and in the fourth other templating strategies which do not fall into any of the aforementioned areas will be discussed. The final section is a discussion of the use of some of these strategies in C-glycosylation. 

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Despite the development of various intermolecular radical addition methods, those studies have rarely accommodated additional functionality, our discovery of the manganese-mediated photolysis conditions notwithstanding. Prior to that discovery, we began to elaborate an alternative strategy which employs temporary tethers ([115, 116] reviews of silicon-tethered reactions [117-120]) (silyl ether or acetal linkages) linking radical and acceptor. In this scenario the C-C bond is constructed via cyclization, in which internal conformational constraints can control diaster-eoselectivity. The tether itself would be converted to useful functionality upon cleavage, and once the tether is cleaved the net result may be considered as formal acyclic stereocontrol. ... 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

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