Tether-directed radical cyclization

Scheme 10-61 A tether-directed radical cyclization provided the key step in the formal synthesis of statine 189 by Hiemstra, Speckamp, and co-workers.

Tether-directed Radical Cyclization Approaches to the Synthesis of C-Glycosides... 

Controlled radical cyclization directly onto a ring junction is less easy. Lejeune and Lallemand envisaged that a tethered radical cyclization of a (bromomethyl)dimethylsilyl ether onto an allylic double bond could be used to incorporate a hydroxymethyl functionality into an angular position at the ring junction of a decalin system [53]. This would then provide an interesting entry into a variety of natural products containing this skeletal functionality, such as the insect antifeedant clerodin 132 (Scheme 10-45). 

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). 

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. 

Cycloadditions only proceeding after electron transfer activation via the radical cation of one partner are illustrated by the final examples. According to K. Mizono various bis-enolethers tethered by long chains (polyether or alkyl) can be cyclisized to bicyclic cyclobutanes using electron transfer sensitizer like dicyanonaphthalene or dicyano-anthracene. Note that this type of dimerization starting from enol ethers are not possible under triplet sensitization or by direct irradiation. Only the intramolecular cyclization ci the silane-bridged 2>. s-styrene can be carried out under direct photolysis. E. Steckhan made use of this procedure to perform an intermolecular [4+2] cycloaddition of indole to a chiral 1,3-cyclohexadiene. He has used successfully the sensitizer triphenylpyrylium salt in many examples. Here, the reaction follows a general course which has been developed Bauld and which may be called "hole catalyzed Diels-Alder reaction". 

Scheme 51), Weavers utilized direct formation of the a-iodomethylene-y-butyrolactone 148 from the propiolate 147 via atom transfer cyclization. Alke-noyloxymethyl iodides and selenides were converted into lactones upon treatment with tributylstannane or tributylgermane [101], In the (—)-zearalenone (152) synthesis reported by Pattenden [102] (Scheme 52), the ester tether is a bystander in the radical macrocyclization. 

---