Stereoselective synthesis free radicals

The use of Lewis acids to impart chemoselectivity and stereoselectivity to free-radical polymerization and copolymerization is well documented [670]. Recent progress in radical reactions in organic synthesis has revealed the importance of Lewis acids in selective transformations [671,672]. Lewis acids have also been found to enhance the reactivity both of radical acceptors [673-675] and of radicals themselves [676], thus increasing the efficiency of radical reactions. 

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). 

The wide variety of methods available for the synthesis of orga-noselenides,36 and the observation that the carbon-selenium bond can be easily cleaved homolytically to give a carbon-centered radical creates interesting possibilities in organic synthesis. For example, Burke and coworkers have shown that phenylselenolactone 86 (see Scheme 16), produced by phenylselenolactonization of y,S-unsaturated acid 85, can be converted to free radical intermediate 87 with triphenyltin hydride. In the presence of excess methyl acrylate, 87 is trapped stereoselectively, affording compound 88 in 70% yield 37 it is noteworthy that the intramolecular carbon-carbon bond forming event takes place on the less hindered convex face of bicyclic radical 87. 

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. 

S. Velazquez, S. Huss, and M.-J. Camarasa, Stereoselective synthesis of [3.3.0] fused lactones (y-butyrolactones) of sugars and nucleosides by free radical intramolecular cyclization, J. Chem. Soc. Chem. Commun. p. 1263 (1991). 

Free-radical cyclization of phenyl selenide 15 to indolizidinone 16 represented a key step in the total synthesis of (—)-slaframine (equation 52). The two pairs of diastereomers were first separated and then hydrolyzed to the corresponding alcohols in 76% overall yield77. (TMS)3SiH-mediated acyl radical reactions from phenylseleno esters 17 have recently been utilized for the stereoselective synthesis of cyclic ethers78. In fact, the experimental conditions reported in equation 53 are particularly good for both improving cis diastereoselectivity and suppressing decarbonylation. 

Chapter 4 by J.J. Li reviews radical cyclization reactions in the total synthesis of indole alkaloids. The use of free radical chemistry in the synthesis of alkaloids has grown markedly because of the mild reaction conditions, tolerance of a wide variety of functional groups, and the good stereoselectivities. 

B. Giese, T. Gobel, B. Kopping, H. Zipse, Formation of C-C Bonds by Addition of Free Radicals to Ole-finic Double Bonds, in Stereoselective Synthesis (Houben-Weyl) 4th ed. 1996, (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), 1996, Vol. E 21 (Workbench Edition), 4,2203-2287, Georg Thieme Verlag, Stuttgart. 

Mechanistically, it was suggested [92] that this cyclization does not involve the free a-amino radical formed by cleavage of the C—Si bond of the trimethylsilylmethyl-amine radical cation. Instead, it was pointed out that cleavage of the C—Si a-bond from the delocalized trimethylsilylmethylamine radical cation, produced by a vertical overlap of the C—Si bond and empty p-orbital of nitrogen, is assisted by the 71-orbitals of the olefin. This strategy was applied to the stereoselective synthesis of pyrrolizidine and indolizidine ring systems [93]. The synthetic utility of this reaction is also demonstrated by the synthesis of ( )-iso-retronecanol [94]. 

Both intermolecular and intramolecular additions of carbon radicals to alkenes and alkynes continue to be a widely investigated method for carbon-carbon bond formation and has been the subject of a number of review articles. In particular, the inter- and intra-molecular additions of vinyl, heteroatomic and metal-centred radicals to alkynes have been reported and also the factors which influence the addition reactions of carbon radicals to unsaturated carbon-carbon bonds. The stereochemical outcome of such additions continues to attract interest. The generation and use of alkoxy radicals in both asymmetric cyclizations and skeletal rearrangements has been reviewed and the use of fi ee radical reactions in the stereoselective synthesis of a-amino acid derivatives has appeared in two reports." The stereochemical features and synthetic potential of the [1,2]-Wittig rearrangement has also been reviewed. In addition, a review of some recent applications of free radical chain reactions in organic and polymer synthesis has appeared. The effect of solvent upon the reactions of neutral fi ee radicals has also recently been reviewed. ... 

A two-step synthesis of modified 2 -C-nucleoside precursor, ethyl [2-(5-methyl-2,4-dioxo-3,4-dihydro-2i/-pyrimidin-l-yl)-4-hydroxyl-5-hydroxymethyltetra-hydrofuran-3-yl]fluoro-acetate 172, from protected glycal 170 and xanthate has been developed following the same idea, and a diastereomeric 1 1 mixture of 2,3-trans product 171 was obtained in 57% yield (O Scheme 46). The use of triethylborane as a free-radical initiator was less successful and a longer reaction time was also required. Interestingly, introducing th)miine at C-1 in the presence of silver triflate at 0°C was highly stereoselective, and only a C, C2-trans linked product was detected. 

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