Silicon-tethered radical cyclization

J. C. Lopez, A. M. Gomez, and B. Fraser-Reid, Silicon-tethered radical cyclization and intramolecular Diels-Alder strategies are combined to provide a ready route to highly functionalized decalins, J. Chem. Soc. Chem. Comtmm. p. 762 (1993). 

A highly general procedure relies on the use of a silicon tethered radical cyclization process to provide for introduction of a hydroxymethyl substituent using the Tamao conditions.33 38 Pioneered by Nishiyama39 the synthesis of regioisomeric diols, as in 33, from readily available ally silyl ethers, such as 31, was achieved via radical cyclization and oxidization. The predominance of the 5-exo cyclization is further demonstrated by the formation of 36 by this same process. 

Scheme 10-47 Crimmins and O Mahony used a silicon-tethered radical cyclization in a synthesis of talaromycin A.

The stereoselective branching of L-rhamnal at C-1 and C-2 via a silicon tethered radical cyclization is illustrated in Scheme 7, and allyl alcohol groups which are protected as their (bromomethyl)dimethylsilyl ethers undergo a radical-induced cyclization to give branched-chain sugars as shown in Scheme ZP... 

A synthetic method for the introduction of an ethynyl group in cyclic structures is based on an intramolecular silicon-tethered radical cyclization with iodine transfer (Scheme 25.8). For example, starting from alkyne 10, a triethyl borane-initiated process allows a radical formation and cyclization to give the alkenyl radical 11. An iodine atom is abstracted from the starting material to give the alkenyl iodide 12, thus, propagating the chain. Treatment of 12 with tetra-/j-butylammonium fluoride (TBAF) results in elimination to furnish 13 in good yields. 

In a related process, boron-tethered radical cyclizations are a useful alternative to the widely used silicon versions. In some cases, rearranged products were produced as a result of an intramolecular S i reaction of a carbon-centered radical at boron (Scheme 9.13) [31]. 

Predictable stereochemistry at Cl would be expected when applying 5-exo-cyclizations in silicon-tethered radical reactions for the construction of C-disaccharides. A sole example has been provided by Skrydstrup and Beau using glycosyl pyridyl sulfones for the generation of the anomeric radical [31]. This approach has been successfully exploited in the synthesis of peracetylated methyl C-isomaltoside 137 (Scheme 37). 

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... 

Hydroxymethylation by Radical Cyclization of Silicon-Containing Tether (84] 1) BrCH2S (CH3)j... 

Fraser-Reid s stereocontrolled synthesis of the Woodward reserpine precursor 195 relied upon a tandem 5-exol6-exo radical cyclization of pyranose-derived dienes [76-77]. As outlined in Scheme 36, a,P-unsaturated ester 188 was prepared by free radical coupling of iodide 187 with a tin acrylate. After hydrolysis of 188 (MeONa, MeOH, 100%) to give primary alcohol 189, the silicon tethered diene 190 was installed by silylation. Treatment of 190 with n-BujSnH led to the desired cage molecule 192 in high yield via a 5-exo-trig cyclization to intermediate 191 followed by a 6-exo cyclization. Tamao oxidation of tricycle 192 led to diol... 

Curran and co-workers have explored the use of silicon tethers to carry out these reactions. They have successfully demonstrated the 1,5 and 1,6 translocation of a radical that goes on to do intramolecular cyclization reactions. This method was used to synthesize natural product such as crinipellin A22 and 2-(o)-(2-bromoaryl)dimethylsilyl-a-methyl-D-mannopyranoside.24 One of the nice benefits to the use of silicon tethers is that they serve as a hydroxyl-protecting group before and after the reaction is performed. 

Once a chiral silane is synthesized, intramolecular reaction such as the Heck reaction and the radical cyclization reaction with transfer of chirality from the silicon center can be pursued. Other reactions of interest include the stereoselective hydrosilylation of aldehydes and ketones. Our method could be used to tether chiral silanes to solid support for uses in solid support... 

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. 

Our strategy for the Smij-promoted synthesis of l,2-cis-C-glycosides is illustrated in Figure 3. It was assumed that one-electron transfer to the LUMO of the aryl sulfone group in A would result in concomitant cleavage of the C1 -S bond liberating an anomeric radical intermediate, as previously observed in the reductive lithiation of glycosyl phenyl sulfones." If 5-exo cyclization onto the silicon-tethered alkene/alkyne is substantially favored over a second electron transfer from Smij, then the exocyclic carbon radical B would ultimately be formed. On the other hand, reduction of the Cl-radical by... 

Shuto s group has developed a highly versatile regio- and stereoselective method for introducing the C2 substituent via an intramolecular radical cyclization reaction, in which a silicon-containing group was applied as a temporary radical acceptor tether [59,60], as summarized in... 

Scheme 15. Preparation of C-disaccharides via Sm -induced radical cyclization using silicon tethering...

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. 

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... 

Vinyl groups have also been transferred to quaternary carbons using the vinyl silicon tether strategy. The vinylsiloxy ethers 21 were made by the reaction of the corresponding alcohols in DMF or DCM with chlorodimethylvinylsilane in the presence of pyridine or imidazole. They were subjected to radical reaction conditions using triethylborane to initiate the intramolecular cyclization followed by acid treatment to form the elimination products 22 favoring the 2,3-5 yw-diastereomer in good yields (eq 11). ... 

---