Cyclization radical-mediated

Selenides are more readily cleaved by tin radicals than are thioethers. Two examples of the tin radical mediated cleavage of selenides are listed in Table 3.48 (Entries 8 and 9) more examples have been reported [768,773,821-823], The carbon-centered radicals initially formed by homolytic C-Se bond cleavage can either be directly reduced to the alkane by treatment with a tin hydride, or may add to multiple bonds before reduction. Entry 10 in Table 3.48 is an example of the formation of a polycyclic indoline through radical cyclization. Radical-mediated cleavage proceeds under mild,... 

Other degradation products of the cytosine moiety were isolated and characterized. These include 5-hydroxy-2 -deoxycytidine (5-OHdCyd) (22) and 5-hydroxy-2 -deoxyuridine (5-OHdUrd) (23) that are produced from dehydration reactions of 5,6-dihydroxy-5,6-dihydro-2 -deoxycytidine (20) and 5,6-dihydroxy-5,6-dihydro-2 -deoxyuridine (21), respectively. MQ-photosen-sitized oxidation of dCyd also results in the formation of six minor nucleoside photoproducts, which include the two trans diastereomers of AT-(2-de-oxy-/j-D-eryf/iro-pentofuranosyl)-l-carbamoyl-4 5-dihydroxy-imidazolidin-2-one, h/1-(2-deoxy-J8-D-crythro-pentofuranosyl)-N4-ureidocarboxylic acid and the a and [5 anomers of N-(2-deoxy-D-eryfhro-pentosyl)-biuret [32, 53]. In contrast, formation of the latter compounds predominates in OH radical-mediated oxidation of the pyrimidine ring of dCyd, which involves preferential addition of OH radicals at C-5 followed by intramolecular cyclization of 6-hydroperoxy-5-hydroxy-5,6-dihydro-2 -deoxycytidine and subsequent generation of the 4,6-endoperoxides [53]. 

Interestingly, the nucleophilic addition of water in the sequence of events giving rise to 41 represents a relevant model system for investigating the mechanism of the generation of DNA-protein cross-links under radical-mediated oxidative conditions [80, 81]. Thus, it was shown that lysine tethered to dGuo via the 5 -hydroxyl group is able to participate in an intramolecular cyclization reaction with the purine base at C-8, subsequent to one electron oxidation [81]. 

The chemistry and utility of zinc-based Lewis acids are similar to those of their magnesium analogs. Their mild Lewis acidity promotes several synthetic reactions, such as Diels-Alder reactions, hetero Diels-Alder reactions,229 radical-mediated reactions,230 ene-type cyclization, and Simmons-Smith reactions. 

In an additional application of fluorous chemistry, radical-mediated cyclizations were performed in benzotrifluoride using microwave irradiation [70]. In the pre-... 

Tributyl tin radical mediated cyclization of the glucose derived exo-methylene furanose derivatives led to highly functionalized cA-fused bicyclic ethers. The product could subsequently be transformed into optically active tricyclic nucleoside analogue or oxepine derivative (Fig. 51).67... 

Allenes have also been used as substrates in free radical cyclizations. Dener and Hart demonstrated that such entries are valuable in constructing pyrrolizidine and indolizidine ring systems [71]. In a total synthesis of pyrrolizidine base (+)-heliotri-dine (340), compound 338 possessing an allene functionality was used as a key intermediate (Scheme 19.62). Tri-n-butyltin radical-mediated carbon-selenium bond homolysis of 338 followed by the addition of the free radical to the allene moiety... 

Over the last few years, silicon hydrides have been introduced as the radical mediators and the intramolecular C — C bond formation (or cyclization) by these reagents has been the subject of numerous publications. 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic 2-bromo-2-deoxysugars, in the presence of 1,1,2,2-tetraphenyldisilane as the radical mediator and AIBN in refluxing ethyl acetate. The corresponding cis-fused bicyclic sugars have been prepared in moderate to good yields (Reaction 7.28) [39]. 

An example of the influence of structure and geometry on radical cyclization is shown by the stereoselectivity of the 5-enJo-tng cyclization in compound 52 and 5-exo-trig cyclization in 53 using (TMS)3SiH as radical mediators [66]. In system52 a mixture of cA-fused and trans-imtd rings are obtained, whereas in system 53 the reaction proceeds in a stereoselective manner to give only the cw-fused product. 

Rhode and Hoffmann have investigated sequential radical-mediated cyclizations of enynes as a method for the stereocontrolled synthesis of heteroannular acetals. The sequence generally followed a S-exo-trigfi-endo-dig-patlmay and gave the products in a stereocontrolled manner <2000T6479>. 

Radical-mediated intramolecular tandem cyclization of the precursor 154 gives the cycloadduct in low yield but does provide a concise route to the indole alkaloid skeleton of pseudocopsinine (Equation 54) <1996T647>. 

In this case, the intermediate vinyl radical (cf Scheme 9) underwent a remarkable [1,51-hydrogen abstraction from the non-activated C—H bond of the proximal isopropyl group. Furthermore, the resulting primary alkyl radical underwent a unique, stereoselective 5-endo-trig cyclization onto the adjacent double bond to generate a tertiary radical, which is a precursor of the highly substituted cyclopentanols 22 and 23. The reaction with Bu3SnH as radical mediator totally reversed the products ratio obtained in 88% yield, i.e. 22 23 = 19 81. 

The intramolecular, radical-mediated cyclization of oj-halo-/ -alkoxyacrylates (formed from propiolates and >-halo alcohols) gives nearly quantitative yields of THF and tetrahy-dropyran ring systems (equation 184)660. The reaction is performed in refluxing benzene in the presence of BusSnH and AIBN. The functionalization in the 2-positions allows for further structural elaboration. Other similar radical cyclizations have also been performed as the key step in natural product synthesis661-663. 

Reduction of the reaction time was achieved by the use of microwave dielectric heating in synthesis of 2-cyanobenzothiazoles from anilines and 4,5-dichloro-l,2,3-dithiazolium chloride [84,85]. Mn(OAc)3 promoted the radical-mediated cyclization of aryl- and benzoyl-thioformanilides. The re-... 

S. Handa, G. Pattenden, Free Radical-Mediated Macrocyclizations and Transannular Cyclizations in Synthesis, Contemp. Org. Synth. 1997, 4, 196-215. 

Inspired by Nature, hydroxocobalamine 247 (X=OH) itself or modified vitamin B12 derivatives (review [331]) were probed as catalysts for radical cyclizations. This methodology is mediated by light and electrochemical or chemical reduction to close the catalytic cycle. It was applied to total syntheses of forskolin 280 by Pattenden [325] (Fig. 67, entry 13) as well as of jasmonate 284 and prostaglandin precursors 287 by Scheffold (entry 14) [326, 327], Starting materials were bromoacetaldehyde cyclohexenyl or cyclopentenyl acetals 278, 281, or 285, which cyclized in the presence of 247 to annulated butyrolactols 279, 283, or 287. In the forskolin synthesis the cyclized radical was reduced directly, while a radical addition ensued in the presence of acetoxyacrylonitrile 282 or ynone 286 in... 

Dichloroindium hydride HlnCla, prepared from indium(m) chloride and DIBAL-H, works as a radical mediator. This compound reduces aryl iodides and bromides in the presence of Et3B as a radical initiator. Reduction of iodoacetals provides cyclized products in good yields (Equation (99)).385 Only a catalytic amount of InCl3 is necessary for complete consumption of the starting compound with stoichiometric DIBAL-H as a hydride source (Equation (100)). 

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