Peroxyl Radicals in Synthesis

Schuchmann MN, Naumov S, Schuchmann H-P, von Sonntag J, von Sonntag C (2005) 4-Amino-3Ff-pyrimidin-2-one ("isocytosine") is a short-lived non-radical intermediate formed in the pulse radiolysis of cytosine in aqueous solution. Radiat Phys Chem 72 243-250 Schulte-Frohlinde D, Hildenbrand K (1989) Electron spin resonance studies of the reactions of OH and SO4 radicals with DNA, polynucleotides and single base model compounds. In Minisci F (ed) Free radicals in synthesis and biology. Kluwer, Dordrecht, pp 335-359 Schulte-Frohlinde D, Behrens G, Onal A (1986) Lifetime of peroxyl radicals of poly(U), poly(A) and single- and double-stranded DNA and the rate of their reaction with thiols. Int J Radiat Biol 50 103-110... 

Mouse peritoneal macrophages that have been activated to produce nitric oxide by 7-interferon and lipopolysac-charide were shown to oxidize LDL less readily than unactivated macrophages. Inhibition of nitric oxide synthesis in the same model was shown to enhance LDL oxidation (Jessup etal., 1992 Yates a al., 1992). It has recently been demonstrated that nitric oxide is able to inhibit lipid peroxidation directly within LDL (Ho etal., 1993c). Nitric oxide probably reacts with the propagating peroxyl radicals thus terminating the chain of lipid peroxidation. The rate constant for the reaction between nitric oxide and peroxyl radicals has recently been determined to be 1-3 X10 M" s (Padmaja and Huie, 1993). This... 

The human lens is rich in ascorbate, which is required for normal collagen synthesis and acts as a water-soluble antioxidant, reacting rapidly with superoxide, hydroxyl and peroxyl radicals. However, ascorbic acid can undergo auto-oxidation and, at certain concentrations, can form hydroxyl radicals with hydrogen peroxide in the presence of light and riboflavin as described above (Delaye and Tardieu, 1983 Ueno et al., 1987). 

Hi. Lysine. Gamma radiolysis of aerated aqueous solution of lysine (94) has been shown, as inferred from iodometric measurements, to give rise to hydroperoxides in a similar yield to that observed for valine and leucine. However, attempts to isolate by HPLC the peroxidic derivatives using the post-column derivatization chemiluminescence detection approach were unsuccessful. This was assumed to be due to the instability of the lysine hydroperoxides under the conditions of HPLC analysis. Indirect evidence for the OH-mediated formation of hydroperoxides was provided by the isolation of four hydroxylated derivatives of lysine as 9-fluoromethyl chloroformate (FMOC) derivatives . Interestingly, NaBILj reduction of the irradiated lysine solutions before FMOC derivatization is accompanied by a notable increase in the yields of hydroxylysine isomers. Among the latter oxidized compounds, 3-hydroxy lysine was characterized by extensive H NMR and ESI-MS measurements whereas one diastereomer of 4-hydroxylysine and the two isomeric forms of 5-hydroxylysine were identified by comparison of their HPLC features as FMOC derivatives with those of authentic samples prepared by chemical synthesis. A reasonable mechanism for the formation of the four different hydroxylysines and, therefore, of related hydroperoxides 98-100, involves initial OH-mediated hydrogen abstraction followed by O2 addition to the carbon-centered radicals 95-97 thus formed and subsequent reduction of the resulting peroxyl radicals (equation 55). 

With the increasing frequency of isolation of cyclic peroxides from natural sources [39] and the demonstrable antiparasitic and many other biological properties possessed by both the natural products and their analogs, there is currently considerable interest in the synthesis of such compounds [5]. In particular, the opportunity of exploiting the facile conversion of enols or enolates into peroxyl radicals and then inducing cyclization of the peroxyl radical (or hydroperoxide) by addition to a distal carbonyl group is apparent. 

Dussault has reported a remarkable example of stereocontrolled peroxyl radical rearrangement (cf. 35 36) in the context of his asymmetric total synthesis of the marine natural product plakortin and its C6-epimer, c t-chondrillin (Scheme 50) [89]. A systematic study of initiators and reaction conditions revealed that the yield of rearranged products can be substantially improved by using DTBN in conjunction with an excess of TBHP [89]. Equilibration of 35 under these conditions provided a 1 1.2 mixture of 35 and 36, which were obtained as single diastereoisomers after separation on silica gel in yields of 29 and 36%, respectively. The synthesis of c t-chondrillin allowed the assignment of absolute stereochemistry to the natural product chondrillin [89]. 

On the other hand, the coaddition of thiyl radicals and oxygen to olefins, a process termed cooxidation [41], is an attractive method to obtain access to peroxyl radicals, that is, the thiyl radical adduct is captured by oxygen. The final products depend on the nature of the starting materials. Selected examples of the addition of PhSH and O2 to alkenes are given in equations (11)-(15). The first two are used as entry to a-phenylthiocarbonyl compounds starting either from alkenyl sulfides [42] or alkenyl silanes (electroinitiation) [43]. Equations (13) and (14) are used for the synthesis of )5-hydroxysulfoxides [44,45] and equation (15) is an example of synthesis of five- and six-membered cyclic peroxides [46,47]. 

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