Temporary tethering strategies

Table 3 shows the application of these intramolecular biaryl-forming conditions to the indirect synthesis of acyclic biaryls using a temporary tether strategy (Scheme 9). Silaketal tethers (Y = SiR2 and X = O, 31a-f) react efficiently to give the biaryl unit. A sulfide derivative (Y — S, X = CH2, 31g) led to many oxidized products, but sulfoxides (Y = SO,... 

Temporary Tethering Strategies in Radical Cyclization Reactions... 

Scheme 8.1 Temporary tethered strategy in organic synthesis.

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. ... 

Using an interesting catalytic tethering strategy wherein simple aldehydes are employed to bring temporary intramolecularity to two reacting sites, an hydroxyl-amine and a well-positioned olefin, the synthesis of enantioenriched 1,2-diamines has been achieved by Beauchemin and co-workers [143]. By this trick, otherwise difficult to realize intermolecular hydroamination of olefins is accomplished, although at present only a few enantioselective examples have been reported (Scheme 11.55). 

Temporary Silicon-tethered RCM (TST-RCM) of Enyne and Dienyne Temporary silicon-tethered strategies of enyne and dienyne metathesis have been studied to demonstrate the stereoselective formation of acyclic tri- and tet-rasubstituted 1,3-dienes to circumvent the problems with controlling chemo-, regio-, and stereoselectivity in the CM... 

For a direct comparison of the temporary silicon tethered strategy to enzyme catalyzed reaction, see Xin, Y.C., Mallet, J.-M., and Sinay, P. (1993) J. Chem. Soc., Chem. Commun., 864-865. 

Among special chemical methods that facilitate the Diels-Alder reaction can be included the temporary metal connection strategy [101] that is illustrated in Table 4.27. Si, Mg and A1 are used as temporary connectors of diene and dienophile moieties. The cycloaddition occurs easily due to its intramolecular nature and because the dienophilic component of reagent is now formally a vinyl carbon ion (i.e. a vinyl carbanion in 154 with M = AlEt ). Thus the metal-tethered 154, prepared from lithium alkoxide of 153 with the suitable metal vinyl halide, gives, by heating, the cycloadducts 156 and 157, through the... 

A remarkable extension of this strategy achieves the stereospecilic introduction of a C-C bond at the anomeric center by the cyclization of an acceptor group tethered to a suitable hydroxyl group of the sugar moiety through a temporary function. Table 2... 

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. 

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. 

The tether directing strategies for C- and O-glycosylation are one subset of a much wider area of using the temporary connection for controlling the regio- and stereochemical outcome in the reaction of nucleophiles with an electrophilic substrate. Some examples of this form of tether-mediated S3mthesis will be illustrated with some applications to natural product synthesis [109]. 

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