Free-radical cascade

UV-induced ROS are extremely toxic to cells by causing oxidative damage to all biomolecules (Sies 1991). For instance, lipids, which are major compounds of all biological membranes, may be destroyed by ROS. After a first initiation reaction an unsaturated fatty acid is converted to a peroxyl radical, which in turn attacks another unsaturated fatty acid finally leading to free radical cascades. This photochemical peroxidation of unsaturated fatty acids may be particularly damaging for membrane structure and function (Bischof et al 2006a). 

Figure 12.9 Block copolymers by one-pot enzymatic ROP and nitroxide-mediated living free-radical cascade polymerization [24].

Design and management of organic syntheses through free-radical cascade processes 01AG(E)2224. 

McCarroll, A.J. Walton. J.C. Programming organic molecules Design and management of organic syntheses through free-radical cascade processes. Angew. Chem. Int. Ed. 2001. 40, 2224-2248. 

Recently, a practical and expedient synthesis of racemic as well as optically pure antipodes of tetracyclic amines 174 was developed by Khan et involving a stereoselective C7nC5x free-radical cascade protocol from bis-allyl amine 172 starting material as key step (Scheme 2.85). Using 20 mol.% of the optically pure amine 174 along with -nitrobenzaldehyde and methyl acrylate in MeOH under sonication conditions afforded the corresponding adduct in comparable yield,albeit with the low asymmetric induction (8% ee). 

Chiral azolium salts 52 and 53 have been used in the intramolecular vinylogous Stetter reaction of oxygen substrates 54 to provide 3-substituted chromanones (Scheme 77) (13CEJ15852). Other examples are obtained from the free-radical cascade reaction of O-allyl acylphosphonate with various functionalized P-ketoxanthates in the presence of dilauroyl peroxide, with moderate to good yields (130L4818). A series of 2,3-disubstituted chromanones are synthesized from the reaction of acrylic acids with arynes in the presence of CsF (13T2789). 

Fig. 12 Left. One-Pot enzymatic ring opening and iiving free radical cascade polymerization [44], Right. Block copolymers by combination of enzymatic ROP and carbene-catalyzed ROP [120]...

The complex cascades that comprise the inflammatory reaction are designed primarily to limit tissue damage and prevent or inhibit infection. ROMs play a critical role in both these beneficial processes. However, high level fluxes of toxic free radicals are capable of causing damage to diverse biomolecules, including lipids, proteins, DNA and carbohydrates (discussed below). 

Normally, the cascade from oxygen to water is well controlled by SOD, catalase and endogenous antioxidants such as glutathione, ascorbate and vitamin E. Vitamin E is the most important membrane-bound antioxidant. However, during ischaemia, the local control of ROS is lost, thus reactive free radicals can attack the membranes and lipid peroxidation begins. Endogenous antioxidants can be supplemented. This section describes this supplementation strategy. 

An excellent review by Walton and McCarroll has recapitulated the various processes which can be featured during a radical cascade [2]. Moreover, these authors have elaborated a compilation of classes of unimolecular free-radical rearrangements, as illustrated in Scheme 3.4. 

As mentioned above, PAF and PAF-like molecules are rapidly synthesized by keratinocytes following UV exposure. We suggest that two mechanisms are involved. UV-induced free radical formation leads to membrane oxidation and the formation of oxidized phosphatidylcholine. The PAF-like molecules bind to PAF receptors in either a paracrine or autocrine fashion. This induces the release of arachidonic acid from the membrane, activates PI.A2 and promotes the synthesis of bona fide PAF.55 The newly synthesized PAF then binds to PAF receptors, which upregulates the production of more PAF and downstream biological modifiers such as eicosanoids and cytokines. Ultimately this activates the cascade of events that leads to immune suppression. 

Many pyridine-indole compounds are biologically active. A growing number of methods for the preparation of indolylstannanes have been developed. 2-Trialkylstannylindoles, for example, have been synthesized via directed metalation followed by reaction with tin chloride [91-93]. The latest indolylstannane syntheses include Fukuyama s free radical approach to 2-trialkylstannylindoles from novel isonitrile-alkenes [94], and its extension to an isonitrile-alkyne cascade [95]. Assisted by the chelating effect of the SEM group oxygen atom, direct metalation of 1-SEM-indole and transmetalation with BujSnCl afforded 2-(tributylstannyl)-l//-indole 108, which was then coupled with 2,6-dibromopyridine to give adduct 109. 

A number of new resist materials which provide very high sensitivities have been developed in recent years [1-3]. In general, these systems owe their high sensitivity to the achievement of chemical amplification, a process which ensures that each photoevent is used in a multiplicative fashion to generate a cascade of successive reactions. Examples of such systems include the electron-beam induced [4] ringopening polymerization of oxacyclobutanes, the acid-catalyzed thermolysis of polymer side-chains [5-6] or the acid-catalyzed thermolytic fragmentation of polymer main-chains [7], Other important examples of the chemical amplification process are found in resist systems based on the free-radical photocrosslinking of acrylated polyols [8]. 

Apart from ATRP, the concept of dual initiation was also applied to other (controlled) polymerization techniques. Nitroxide-mediated living free radical polymerization (LFRP) is one example reported by van As et al. and has the advantage that no further metal catalyst is required [43], Employing initiator NMP-1, a PCL macroinitiator was obtained and subsequent polymerization of styrene produced a block copolymer (Scheme 4). With this system, it was for the first time possible to successfully conduct a one-pot chemoenzymatic cascade polymerization from a mixture containing NMP-1, CL, and styrene. Since the activation temperature of NMP is around 100 °C, no radical polymerization will occur at the reaction temperature of the enzymatic ROP. The two reactions could thus be thermally separated by first carrying out the enzymatic polymerization at low temperature and then raising the temperature to around 100 °C to initiate the NMP. Moreover, it was shown that this approach is compatible with the stereoselective polymerization of 4-MeCL for the synthesis of chiral block copolymers. 

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