Radicals, reduction selectivity

Scheme 16 summarizes the results obtained by enantioselective radical reduction of a-bromoester by chiral binaphthyl-derived tin hydride. The reactions were generally performed at - 78 °C. An increase in the temperature resulted in the lowering of the selectivity. All reactions mediated by (S)-configured chiral tin hydride showed an (R)-selective preference in the product. The use of the opposite enantiomer of the chiral stannane resulted in a quantitative reversal of the selectivity (not shown). The selectivity remained modest on addition of magnesium Lewis acids. These reductions were also feasible when a catalytic amount of chiral tin hydride (1 mol %) was employed in combination with an excess of achiral hydride NaCNBH3, providing similar results. 

Cyclization reactions can be conducted by methods that remove cyclic radicals by selective radi-cal/radical coupling, oxidation, or reduction. The usual selectivity concerns are operative initial radicals must cyclize, and cyclic radicals must be productively removed. 

The radical reductive cyclisation of diesters to acyloins (see also Section 5.9.1, p. 628) is an important method of synthesis for ring sizes from four-membered upwards. The example selected here is 2-hydroxy-3-methylcyclopent-2-enone ( corylone ) (29) (Expt 7.10), which is an important perfumery and flavouring material.53 In the first step (i), methyl acrylate is converted into its dimer with tris(cyclohexyl)phosphine in pyridine solution.5b Step (ii) is the protection of the double bond by conversion into the dimethylamino adduct. The acyloin reaction is step (iii), and the product is trapped as its bis(trimethylsilyl)ether. Finally, in step (iv), the protecting dimethylamino and trimethylsilyl groups are removed by passage down a column of silica gel. 

Ethylenic cation radicals are also capable of rotating around the double bond. At the same time, the main specificity of ethylenic cation radical reduction consists of the high selectivity of the reaction. One-electron oxidation was developed as a strategy for selective and efficient reduction of relatively ionizable functionalities, including conjugated dienes, styrenes, and vinyl sulfides (Mirafzal et al. 1993). Reduction is highly sensitive to substrate ionizability and permits selective reduction of the more ionizable function in a difunctional compound. 

Table 5.2. Compilation of the reduction potentials of some inorganic radicals values selected by Wardman (1989). For further data, see also Das et al. (1999)...

Tandem radical additions have also been utilized for the synthesis of nitrogen containing heterocycles. These reactions have the same requirements as those discussed for the oxygen heterocycles. The reductive addition of phenylsulfanyl radicals to the unsaturated amide 153 has been investigated [95JCS(P1)19], The nucleophilic radical adds selectively to the enamide followed by 5-exo-cyclization to give 154 in excellent yield with high trans selectivity. 

As a result of the limited configurational stability of optically active organotin compounds, in which the chirality is on the tin atom, most advances in enantioselective free-radical reductions involve organostannanes where the elements of chirality are contained in the organic substituents. Selected... 

To study their properties, the easiest way is to form them by one-electron reduction of disulfide bonds. Among radicals from water radiolysis, hydrated electron is the most powerful reductant. It reacts with almost all amino acids and especially with the disulfide groups. Using less powerful reductants such as COO radicals, some selectivity in the attack appears. An example is displayed in Figure 3. 

The radical reduction of l-acetoxy-l-bromo-2-/ 7-butylpropane proceeds via acyloxy radical intermediates37. Similar levels of 1.2-asymmetric induction are obtained with different deuterium donors, thus indicating that the deuterium donor has little influence on the selectivity. 

Synthesis from o-xylose Clavalanine (2) was synthesized from D-xylose by conversion to 1,2-0-isopropylidene-D-xylofuranose (98), which was selectively acetylated followed by treatment with l,T-thiocarbonyldimidazole (TCDl) to furnish 99 in 85% overall yield (Scheme 11). Radical reduction of 99 followed by acid hydrolysis of the... 

Steric factors slow the rate of intermolecular addition of radicals to non-terminal alkenes such as 1, 2 and 10-12. In the absence of a Lewis acid additive, radical additions to the cinnamate 16 or the crotonate 17 are inefficient at —78 °C because radical reduction is faster than radical addition [21, 22, 25]. The reaction is also nonselective in the absence of Lewis acid. When stoichiometric amounts of Lewis acids are added to the reaction of isopropyl radical with 16, however, both the yield and the diastereoselectivity increase significantly. Thus, Yb(OTf)3 gives a product yield of 90% in a ratio of 18a/19a of 45 1. This record P diastereoselectivity in radical addition is comparable to or better than that obtained under ionic conditions. Use of catalytic Yb(OTf)3 (10 mol%) gives only a slight reduction in selectivity. Addition to the crotonate 17 promoted by Yb(OTf)3 gives a product ratio of 18b/ 19b of 25 1. 

Rychnovsky has systematically examined 5-, 6-, 7-, and 8-membered a-oxygenated radicals as intermediates in reductive decyanations and the diastereoselectivities associated with their reactions (Scheme 18) [27]. In eaeh case, reductive decyanation with lithium in ammonia proceeds in good yield, but the selectivity varies from >20 1 in the case of the 2,6-disubstituted tetrahydropyran to 1 1 in the case of the 2,5-disubstituted tetrahydrofuran. The observed stereoselectivities in these anomeric radical reductions correlate with the conformational rigidity of the parent ring systems. 

Radical reduction was also shown to be competitive with ring inversion under classical radical-forming conditions (Scheme 20) [28]. Photolysis of thiohydrox-amate ester 4ax at -78 °C generates initially the intermediate radical 2ax after Barton decarboxylation [17], At low thiol concentration (entry 1, 0.1 M t-BuSH), lax completely equilibrates to give a mixture of lax and leq, leading to the observed 3ax 3eq ratio. However, at high thiol concentration (entry 3, 1.0 M t-BuSH), the selectivity is increased to attain non-equilibrium product ratios of 3ax 3eq (compare with entries 1 and 3, Scheme 19). Importantly, when acrylonitrile is present as a radical acceptor, one observes diastereoselective C-C bond formation by nonequilibrium radical processes (Scheme 20). 

The DCNB-sensitized addition of ammonia to the 1-arylbutadiene 29 occurs selectively to afford the allylamine 29a (Scheme 18). The locus of amine addition is determined, as expected, by formation of the most stable radical intermediate, in this case the 1-phenylallyl radical. Reduction of this radical by DCNB-yields the 1-phenylaUyl anion, which is selectively protonated at the locus of highest charge density, adjacent to the phenyl ring. The nonsymmetric 1,4-diphenylbutadiene 30 affords a 5 1 mixture of the adducts 30a and 30b. 

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