Acetal-Tethered Radical Cyclizations

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]. 

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. 

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. 

Scheme 10-72 Synthesis of the C(l)-C(9) fragment of rhizoxin in which Rama Rao used an acetal tether to direct a radical cyclization.

The same group used a ketal tether as an alternative connecting group in the synthesis of the 1,4-linked C-disaccharide 236 [85 b]. Tebbe methylenation of acetate 237 provided the corresponding enol ether 238, which upon treatment with alcohol 235 in the presence of CSA at -40°C in acetonitrile, furnished linked disaccharide 239 in 81% yield. Subsequent radical cyclization, acidic hydrolysis of the tether and peracetylation provided the D-mannose-containing C-disaccharide 236 as the major product in 35% yield from 239 (Scheme 10-75). Cyclization was not completely stereoselective and a small amount of the )8-C-manno isomer was also isolated (a/)3 10 1). This result is in contrast to similar studies on tether-directed /J-C-mannoside syntheses (vide infra) where a much shorter tether attached to the axial 2-hydroxyl group forces obtention of the desired P-configuration. 

Oxidative radical cyclization sequences have also been used to generate 1,2-fused indoles. Treatment of amides 152 and 154 with dimethyl methylmalonate in the presence of manganese(III) acetate and sodium acetate in acetic acid, gave the expected cyclized product in 63% and 40%, respectively [97]. The proposed mechanistic sequence involves the intermolecular addition of the dimethyl methylmalonate radical to the tethered exocyclic alkene followed by cyclization and finally rearomatization. Byers and coworkers also achieved a similar cyclization on the C-2 position of the indole when a 3-acylindole was subjected to these oxidative cyclization conditions. 

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. ... 

Baylis-Hillman adducts such as 55 and 56 derived from 2-nitrobenzaldehydes were shown to function as useful precursors to functionalized (1H)-quinol-2-ones and quinolines. Treatment of 55 and 56 with iron and acetic acid at 110 °C afforded 57 and 58, respectively <02T3693>. A variety of other cyclization reactions utilized in the preparation of the quinoline scaffold were also reported. An iridium-catalyzed oxidative cyclization of 3-(2-aminophenyl)propanols afforded 1,2,3,4-tetrahydroquinolines <02OL2691>. The intramolecular cyclization of aryl radicals to prepare pyrrolo[3,2-c]quinolines was studied <02T1453>. Additionally, photocyclization reactions of /rans-o-aminocinnamoyl derivatives were reported to provide 2-quinolones and quinolines <02JHC61>. Enolizable quinone and mono- and diimide intermediates were shown to provide quinolines via a thermal 6jt-electrocyclization <02OL4265>. Quinoline derivatives were also prepared from nitrogen-tethered 2-methoxyphenols. The corresponding 2-methoxyphenols were subjected to a iodine(III)-mediated acetoxylation which was followed by an intramolecular Michael addition to afford the quinoline OAc O... 

However, the most important applications of 0,Se-acetals are related to sugar and nucleotide derivatives [34-36]. For instance, the generation of anomeric radicals from 0,Se-acetals is a very popular approach. The preparation of C-disaccharides by an elegant 8-endo-trig cyclization involving two tethered monosaccharides has been reported [Eq. (15)] [37, 38]. In a related manner, a concise route to tunicamycin antibiotics has been developed the key feature of... 

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