Radical-polar-crossover

Scheme 16. Application of radical-polar crossover reaction in the total synthesis of ( )-aspidospermidine...

In all the following examples, the targeted double bonds were activated by suitable substituents to increase the efficacy of the desired cyclization mode. For the total synthesis of acutumine (26), an activated a,p-unsaturated ketone 27 was chosen as precursor (Scheme 10) [74, 75], Aryl radical additions to this type of alkenes are known to proceed about ten times faster than to comparable allylic alcohols. In a radical-polar crossover reaction, the spirocyclic product 28 was obtained in the presence of triethylaluminum as promoter and an oxaziridine as hydroxylating agent. The fact that even the efficient hydrogen donor tetrahydrofuran could be used as solvent nicely demonstrates the high efficacy of the cyclization step. 

Narasaka and coworkers reported radical-polar crossover addition/cyclization reactions of phenacyl bromides 204 and electron-rich alkenes such as (silyl) enol ethers 205, catalyzed by the rhenium(I) complex 206 (Fig. 57) [302], The active catalyst 206A formed after thermal nitrogen elimination from 206 reduced 204 either directly or by oxidative addition/homolysis via rhenium enolate 204A to... 

Fig. 57 Rhenium(I)-catalyzed radical-polar crossover addition/cyclization reactions...

Scheme 9. Application of the radical/polar crossover reaction to the total synthesis of aspidospermidine.

To effect the radical-polar crossover reaction, it is clear that the sulfide must be easily oxidized. To give the best chance of success, our first experiments in 1993 used tetrathiafiilvalene (TTF). TTF had been extensively used in materials chemistry, and so the oxidation... 

On reacting the diazonium salt la with TTF, immediate evolution of nitrogen occurred at room temperature in undried acetone as solvent. Monitoring by TLC indicated complete consumption of the diazonium salt and the appearance of a new product, the alcohol 4a. Since 4a cannot arise by interaction of radical 2a with water, this suggests that a radical-polar crossover process had occurred with the intermediate sulfonium salt undergoing facile hydrolysis in the undried acetone solvent. Repeating the experiment with lb similarly afforded the tertiary alcohol 4b, whereas, in contrast, diazonium salt Ic afforded no primary alcohol. Further investigation indicated that the sulfonium salt 3c had formed in this reaction. NMR spectra confirmed that this... 

The alkyne substrate 12 was set up to perform two rapid radical cyclizations, to show that tandem radical cyclization can be followed by interception by TTP. The tandem cyclization occurred, but the cyclopropanes 13 were the unexpected products. The formation of the cyclopropanes could occur either by cyclization of 14 followed by radical-polar crossover or by cationic cyclization of 15 15 would form by radical-polar crossover of 14. 

Cyclization of diazonium salts using iodide ion had been well developed by Beckwith s group, but the iodide corresponding to 50 is a secondary neopentyl iodide, which would be impossible to convert by S 2 chemistry into an alcohol. Our efforts to convert similar iodides to acetate esters with silver acetate by S l have also not met with success. Even if such conversions were possible, they would still be much less direct than with the new radical-polar crossover methodology. 

Having reviewed the latest developments in synthetic chemistry, several other aspects of the radical-polar crossover reaction have been investigated. One of these concerns attempts to effect S, 2 substitutions at the hitherto unreactive primary tetrathiafulvalenium salts. Three potential nucleophiles have been examined, and whereas each has afforded a facile reaction, none effected a simple S 2 displacement. First, attack by sodium azide on a series of primary tetrathiafulvalenium salts led to formation of TTF, but not by direct displacement. The route shown in Scheme 10 for (3c) could explain the observed products although the thioketene (59) was never isolated in these reactions. 

If this were the case, then the C-C coupling could in principle be possible but kinetically uncompetitive for nucleophilic radicals. If the C-C coupling were relatively slow for all radicals, then electrophilic radicals ought to be able to perform other radical cyclizations prior to this trapping. Support for Uiis idea came from substrate 68, where the intermediate electrophilic radical undergoes cyclization to form a new nucleophilic radical 69 which in turn undergoes radical-polar crossover reaction affording lactone 70. 

The past 5 years study of the radical-polar crossover reaction has led to a rich vein of new chemistry and intriguing reactions. This type of reaction is still in its infancy, and many facets remain to be explored. However, the use of radical-polar crossover chemistry as the key reaction in the synthesis of aspidospermidine demonstrates the utility of the process in a challenging molecular setting. 

REACTIONS OF ARENEDIAZONIUM SALTS WITH TETRATHIAFULVALENE AND RELATED ELECTRON DONORS A STUDY OF "RADICAL-POLAR CROSSOVER" REACTIONS Nadeem Bashir, Balaram Patro, and John A. Murphy... 

Scheme 74 Ferrocenium-mediated radical-polar crossover TEMPO-trapping...

Den s et al. reported an interesting example of a radical tandem 1,4-addition/carbocyclization reaction initiated by oxidation of dialkylzinc by dissolved oxygen in the solvent [213]. Reduction of the final radical with dialkylzinc through a radical/polar crossover reaction afforded a new organo-zinc derivative that could be further fimctionahzed. 

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