Barton radical method

A non-biomimetic synthesis of /J-(-)-horsfiline (57) has also been recently reported which was based on a thermal intermolecular 1,3-dipolar cycloaddition reaction as outlined in Scheme 7 [63J. The reaction of the optically active menthyl ester 67 acting as a dipolarophile, with the JV-methylazomethine ylide 68 (thermally generated in situ from sarcosine and formaldehyde) proceeded with n-facial diastereoselectivity to produce a chromatographically separable mixture of 69 and the unwanted diastereomer. Subsequent cleavage of the chiral auxiliary, followed by removal of the carboxylic acid group by the Barton radical method provided J7-(-)-horsfiline. 

Radicals formed by fragmentation of xanthate and related thiono esters can also be trapped by reactive alkenes.217 The mechanism of radical generation from thiono esters was discussed in connection with the Barton deoxygenation method in Section 5.4. 

Much more critical, however, is the introduction of the 2 -deoxy function. This can be achieved after selective 3 -0-benzoylation to 170, xanthation at the 2 position to 171 and reductive cleavage (Bu3SnH) to 172 following Barton s method [91]. Further radical ring opening by the Hullar-Hanessian procedure and final reduction leads to the D-C disaccharide 173 [92],... 

The chemistry of )9-(thiocarbonyloxy)alkyl radicals stands in complete contrast to that of the (acyloxy)alkyl radicals, with elimination, while not the rule, being the norm [I]. The difference between the acyloxy and thiocarbonyloxy series is likely a consequence of the much weaker thiocarbonyl bond and the related higher stability of sulfur-centered radicals. The method has been developed in combination with the Barton deoxygenation method (Volume 1, Chapter 1.6) as a means of converting a vicinal diol, via the dixanthate, into an alkene (Scheme 33) [60-62]. Tributyltin hydride has been the reagent of choice for this reaction but it may also be conducted with the triethylsilane/benzoyl peroxide couple [63] and, doubtless, tris(trimethylsilyl)silane. 

Boron trifluoride catalyses the 1,3-phosphotropic rearrangement of the a-phosphorylated imine (65) to give (66).35 This reaction takes place at room temperature, whereas the uncatalysed reaction requires heating to 150-2000C. High yields of the addition products (67) have been obtained from the reaction of carbon-centred radicals with diphenylvinylphosphine oxide.36 Radical addition to the chiral phosphine oxides (68) using Barton s method provides diastereomeric ratios of up to 9 1 in the case of (69). 

In contrast to the oxidative generation of radicals described above, reductions of alkyl iodides using tris(trimethylsilyl)silane also produces alkyl radicals under conditions suitable for Minisci-type substitution." Carboxylic acids (a-keto acids) are also useful precursors for alkyl (acyl ) radicals via silver-catalysed peroxide oxidation, or from their l-hydroxypyridine-2-thione derivatives using Barton s method,the latter in non-aqueous conditions. 

The last and the seventh synthesis of chaetomellic acid A was reported in 1997 by the Samadi group from CNRS, France [81]. This one step synthesis involves a Barton radical decarboxylation and gave 77% overall yield (Scheme 8). The method requires preparation of a thiohydroxamic ester of the corresponding alkyl acid followed by in-situ irradiation in the presence of citraconic anhydride and silica gel chromatography. The last intermediate in this synthesis is similar to the synthesis reported by Branchaud and Slate [75,76]. 

C-6-Allylated pyranoses and C-S-allylated fliranoses were prepared from the corresponding iodides by Keck radical coupling with allyltributyltin (e.g. 44->4S). The selective formation of product 47 in the chain-extension of the acetal-protected uronic acid derivative 46 by radical addition of methyl acrylate using Barton s method was ascribed to addition from the less hindered side to a conformationally stable radical intermediate the peracetate 48 furnished a 1 1 mixture of 49 and 50. ... 

Alkenyl boronic esters can also be used to trap nucleophilic carbon-centered radicals, which can be generated by the tin hydride method or by decomposition of an organomercurial derivative. The influence of the olefin and boron substituents on the reactivity and regioselectivity has been determined. Vinyl-9-BBN displayed significantly better reactivity than the boronic ester while the directing effect of the boronic ester group is weaker than that of an ester function. The Barton radical chain procedure furnished very stable adducts due to an intramolecular complexation between boron and nitrogen (Scheme 9.12) [29]. Radical additions of various xanthates also occurred smoothly in the presence of lauroyl peroxide [30]. Intermolecular ver-... 

Carbon-centered radicals generated by Barton s thiohydroxamate method can also participate in ring-forming reactions (see Scheme 26).52b,s3 For example, irradiation of 129 results in the formation of compound 130 (82% yield). The outcome of this transformation is reminiscent of Stork s elegant radical cyclization/trapping processes (see Schemes 7 and 8), in that/botn alkene carbon atoms have become functionalized. / I... 

The guanine radical cations (G +) are detected by their reactions with water, which leads after treatment with piperidine or ammonia to selective strand cleavage [14]. A similar charge detection method was used by J.K. Barton, G.B. Schuster and I. Saito as described in their articles in this volume. The cleavage products were separated and quantified by gel electrophoresis. A typical example is shown in Fig. 7 where the GGG unit acts as a thermodynamic sink for the positive charge, and the efficiency of the charge transfer can be measured by the product ratio Pggg/Pg-... 

The reduction of thiocarbonyl derivatives by EtsSiH can be described as a chain process under forced conditions (Reaction 4.50) [89,90]. Indeed, in Reaction (4.51) for example, the reduction of phenyl thiocarbonate in EtsSiD as the solvent needed 1 equiv of dibenzoyl peroxide as initiator at 110 °C, and afforded the desired product in 91 % yield, where the deuterium incorporation was only 48% [90]. Nevertheless, there are some interesting applications for these less reactive silanes in radical chain reactions. For example, this method was used as an efficient deoxygenation step (Reaction 4.52) in the synthesis of 4,4-difluoroglutamine [91]. 1,2-Diols can also be transformed into olefins using the Barton-McCombie methodology. Reaction (4.53) shows the olefination procedure of a bis-xanthate using EtsSiH [89]. 

Since its introduction by Barton and McCombie, the deoxygenation of thionocarbonyl derivatives of alcohols has become an important synthetic reaction and a valuable method for the generation of carbon-centered radicals.3-4 Xanthates, thionobenzotes, thionocarbonyl imidazolides, aryloxy thionocarbonate, N-phenylthionocarbamates and oxalate esters are conveniently deoxygenated with tin or silicon hydrides in boiling benzene or toluene.4-5... 

The Barton-McCombie deoxygenation reaction was invented for use in the manipulation of aminoglycoside antibiotics. It has become a popular method because of the mild conditions employed. Radical reactions have advantages over ionic reactions for carbohydrate chemistry. In this context, there is little neighboring group interference in cationic reactions and little elimination compared with normal nucleophilic displacement reactions. 

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