Silyl-tethered radical cyclization

Scheme 10-45 A silyl-tethered radical cyclization could be used to incorporate angular hydroxymethyl functionality at a ring junction.

In most cases the radical generated after cyclization is quenched by H-abstraction. However, another possibility is to utilize the cyclized radical in another C-C bond-forming event. Fraser-Reid and co-workers utilized a silyl-tethered radical cyclization of the (L)-rhamnal-derived silyl ether 142 to generate the anomerically. stabilized radical 143, which could be trapped in the presence of an excess of acrylonitrile to generate acetate 144 after tether cleavage and peracetylation (Scheme 10-48) [55a]. This reaction sequence occurred with complete regio- and stereoselectivity. The same group has also used an acetal tether (vide infra) to effect similar transformations [55 b, 56]. 

Previous examples of silyl-tethered radical cyclizations have involved the incorporation of the radical precursor during the formation of the silyl ether tether. An alternative would be to incorporate the radical acceptor. A number of suitable silyl chlorides are commercially available which facilitate the preparation of such cyclization precursors. 

Scheme 10-63 The stereochemical outcome in the silyl-tethered radical cyclization of nucleosides is dictated by the configuration of the silyl ether group.

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. 

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... 

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. 

Temporary tethering of radical precursors has found other applications in natural product synthesis. Crimmins and O Mahony utilized a silyl ether temporary eonnection to direct a hydro-hydroxymethylation of enol ether 139 in their synthesis of talaromycin A, 140 [54]. Since talaromycin A is susceptible to acid-catalyzed isomerization to the thermodynamically more stable talaromycin B in which the hydroxymethyl substituent is equatorial, the use of the essentially neutral conditions of a radical cyclization to install the requisite axial hydroxymethyl group would avoid any potential isomerization problems. Formation of enol ether 139 was achieved in five steps from (4R)-4-ethylvalerolac-tone 141. Exposure of 139 to Bu3SnH in benzene at reflux in the presence of AIBN as initiator effected radical cyclization with delivery of the radical to the same face to whieh the ether tether was attached. Tamao oxidation proceeded uneventfully, furnishing the desired natural product (Scheme 10-47). 

Tamao et al. have investigated (dichloromethyl)dimethylsilyl ethers as radical cyclization precursors [69]. Silyl ether 174 was readily prepared from the commercially available silyl chloride and isophorol. 5- xo-trig cyclization could be effected under high-dilution conditions, affording the bicycle 175 as a 6 4 mixture of stereoisomers. Subsequent oxidative tether cleavage afforded 2-formyl alcohols 176 and 177 where unfortunately, the presence of base caused partial epimerization of the center a to the formyl group (Scheme 10-56). 

Scheme 10-57 Two radical cyclizations are possible with a (dichloromethyl)silyl ether tether.

Scheme 10-60 A silyl tether provides a more readily prepared radical precursor for effecting cyclization.

Chattopadhyaya and co-workers have also demonstrated that alkynyl groups can be used as radical acceptors when linked through a silyl ether [76c]. Radical cyclization and subsequent oxidative cleavage of the tether provided access to 2 - and 3 -C-branched a-keto-]3-D-ribonucleosides, usually in good to excellent yields. 

Silyl acetals have been investigated by Hutchinson and co-workers as tethers in radical cyclization reactions [78]. A number of commercially available dialkyldichlorosilanes were investigated as tether precursors although Pr2SiCl2 was found to be the most suit-... 

Although the (bromomethyl)silyl ether connection has been more extensively utilized in radical cyclizations, Stork also introduced, at a similar time, the use of a mixed acetal function [51a, 73b, 80], This tether differs in that a two-carbon unit is introduced on the proximal carbon atom of the olefin, whereas the silyl tether allows the incorporation of only one carbon atom. The chemistry of this tether is dominated by 5-exo-trig cyclizations onto allylic double bonds which proceed with the usual degree of high stereoselectivity. 

The silyl-tethered compound 69 undergoes a tandem radical cyclization followed by desilylation and oxidation of the sulfide and elimination to give bicyclic 70 further elaborations (by way of 71) convert this intermediate to cyclohexane derivative 72, transformed in five steps to 73, an intermediate in Woodward s reserpine synthesis (Scheme 13). PCC oxidation of the enol ether function of 72 yielded 74. 

Substrates containing an electron-rich double bond, such as enol ethers and enol acetates, are easily oxidized by means of PET to electron-deficient aromatic compounds, such as dicyanoanthracene (DCA) or dicyanonaphthalene (DCN), which act as photosensitizers. Cyclization reactions of the initially formed silyloxy radical cation in cyclic silyl enol ethers tethered to an olefinic or an electron-rich aromatic ring, can produce bicyclic and tricyclic ketones with definite stereochemistry (Scheme 9.14) [20, 21]. 

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. ... 

---