STORK Radical cyclization

Formation of a tra 5-fused 5,6-ring junction can sometimes also be achieved selectively. In an early example from Stork, radical cyclization of silyl ether 126 proceeded in 36% yield but with complete stereoselectivity affording the frans-fused hydrindane system [51a]. In this case, the methyl and O Bu groups presumably reinforce the directing effect of the convex, newly formed silatricycle and H-abstraction is forced to occur from the sterically less hindered face (Scheme 10-43). 

Olefins andAlkynes. The increased scope of the silicon tether in radical chemistry, which is still the most important reactivity allowed by the (bromomethyl)dimethylsilane moiety, has been reviewed. Some authors have again illustrated the synthetic interest of Nishiyama-Stork radical cyclizations of allylic (bromomethyl)dimethylsilyl ethers. Jenkins achieved stereoselective cyclizations on a fused cyclopentanol, while Herdewijn prepared pyranosyl nucleosides. Starting from /-substituted... 

The Ueno-Stork reaction is a radical cyclization of the a-haloacetal of an aUylic alcohol that provides substituted tetrahydrofuran and y-lactone derivatives. The chiral center of the aUylic moiety can control the stereochemical outcome, and the stereoselectivity may also be affected by the conformational anomeric effect. The Ueno-Stork radical cyclization has been applied in the synthesis of (-l-)-eldanolide (Scheme 25.22)," the pheromone of the male African sugarcane stem borer Eldana saccharina, in which bromoacetal 49 evolves to 50. The stereochemical outcome of these reactions is rationalized by a chair-like transition state, in which the adopted conformation maximizes the anomeric effect of the acetal center. 

Villar F, Equey O, Renaud P. Desymmetrization of l,4-dien-3-ols and related compounds via Ueno-Stork radical cyclizations. Org. Lett. 2000 2(8) 1061-1064. 

Scheme 3. Selected vinyl radical cyclizations developed by Stork and coworkers.

Vinyl radicals can also participate in 6-exo cyclizations. In pioneering work, Stork and his group at Columbia University showed that stereoisomeric vinyl bromides 20 and 21 (see Scheme 3) can be converted to cyclohexene 22.7 The significance of this finding is twofold first, the stereochemistry of the vinyl bromide is inconsequential since both stereoisomers converge upon the same product and second, the radical cyclization process tolerates electrophilic methoxycarbonyl groups. The observation that the stereochemistry of the vinyl bromide is inconsequential is not surprising because the barrier for inversion of most vinyl radicals is very low.8 This important feature of vinyl radical cyclization chemistry is also exemplified in the conversion of vinyl bromide 23 to tricycle 24, the key step in Stork s synthesis of norseychellanone (25) (see Scheme 4).9 As in... 

Scheme 4. Stork s vinyl radical cyclization strategy for the synthesis of norseychellanone (25)...

Scheme 8. Stork s tandem radical cyclization/trapping strategy for the synthesis of (+)-prostaglan-din F2a (45).

Carbon-centered radicals generated by Barton s thiohydroxamate method can also participate in ring-forming reactions (see Scheme 26).52b,s3 For example, irradiation of 129 results in the formation of compound 130 (82% yield). The outcome of this transformation is reminiscent of Stork s elegant radical cyclization/trapping processes (see Schemes 7 and 8), in that/botn alkene carbon atoms have become functionalized. / I... 

Another possibility here is to use entropic acceleration. In this way, it is possible to use a substrate that first reacts in an intramolecular mode to give an intermediate, which then undergoes an intermolecular reaction with a second molecule. An impressive older example is a radical cyclization/trapping in the synthesis of prostaglandin F2a, as described by the Stork group [20]. A key step here is the radical transformation of the iodo compound 0-32 using uliu3Sril I formed in situ from... 

This strategy was later refined by Stork and co-workers142 who used silicon (e.g. 164) as the tethering atom [Scheme 55a)]. The latter strategy was adapted by Sinay and co-workers143 for the synthesis of C-disaccharides (e.g. 169) by employing 8- and 9-endo radical cyclizations with the readily prepared silaketal connectors [Scheme 55b)]. 

Skrydstrup, Beau and co-workers122 have adapted Stork s method to the SmI2-reduction of glycosyl pyridyl sulfones bearing a silicon-tethered unsaturated group at HO-C(2). An example is shown with the synthesis of methyl a-C-zso-maltoside 172 from alkyne 170 via the 5-exo-dig radical cyclization of 171 (Scheme 56).144... 

Free radical reactions are proving to be synthetically useful altern-atives for producing carbon-carbon bonds. Recently, Stork has shown that vinyl radicals are valuable in ring forming reactions since they place a double bond in a predictable position. Their compatibility with many unprotected functional groups and their ability to form quaternary centers are additional features which make vinyl radical cyclization an attractive synthetic method. 

G. Stork and M. J. Sofia, Stereospecific reductive methylation via a radical cyclization-desilylation process, J. Am. Chem. Soc. 708 6826 (1986). 

Each of the syntheses of seychellene summarized in Scheme 20 illustrates one of the two important methods for generating vinyl radicals. In the more common method, the cyclization of vinyl bromide (34) provides tricycle (35).93 Because of the strength of sjp- bonds to carbon, the only generally useful precursors of vinyl radicals in this standard tin hydride approach are bromides and iodides. Most vinyl radicals invert rapidly, and therefore the stereochemistry of the radical precursor is not important. The second method, illustrated by the conversion of (36) to (37),94 generates vinyl radicals by the addition of the tin radical to an alkyne.95-98 The overall transformation is a hydrostannylation, but a radical cyclization occurs between the addition of the stannyl radical and the hydrogen transfer. Concentration may be important in these reactions because direct hydrostannylation of die alkyne can compete with cyclization. Stork has demonstrated that the reversibility of the stannyl radical addition step confers great power on this method.93 For example, in the conversion of (38) to (39), the stannyl radical probably adds reversibly to all of the multiple bond sites. However, the radicals that are produced by additions to the alkene, or to the internal carbon of the alkyne, have no favorable cyclization pathways. Thus, all the product (39) derives from addition to the terminal alkyne carbon. Even when cyclic products might be derived from addition to the alkene, followed by cyclization to the alkyne, they often are not found because 0-stannyl alkyl radicals revert to alkenes so rapidly that they do not close. 

Scheme 23. Application of 6-exo-trig radical cyclization in Stork s approach to ( )-gelsemine...

A radical cascade reaction has been accompHshed by StaHnski and coworkers which converts dipeptide derivatives to nitrogen-containing heterocycles (Scheme 6) [9]. In this work, N-bromobenzyl-hf-propargyl-substituted dipeptides such as 10 were subjected to Stork s catalytic procedure with tributyltin hydride [10]. An aryl radical is formed followed by a 1,5-hydrogen shift, generating the a-centered carbon radical 11. 5-Fxo-dig radical cyclization... 

Recently, Nagashima and associates developed a new route to y-lactams by the ruthenium-catalyzed cyclization of /V-allyltrichloroacetamides [24], Also, Stork and Mah reported the radical cyclization of /V-protected haloacetamides to yield /V-protected lactams. The protecting groups can then be easily removed under a range of different conditions [25]. This efficient radical cyclization route to d.s-fused pyrrolidones and piperidones is interesting because of the widespread occurrence of related systems in natural products [26]. 

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