The Radical-Polar Crossover Reaction

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... 

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. 

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. 

Having prepared simple indolines using the radical-polar crossover reaction, more complex targets were undertaken (Scheme 7). Diazonium salt 31 reacted very ste-reoselectively to afford 33 [10]. The ring-junction was cis as expected, but the bonus was that the alcohol 33 was detected and isolated as a single diastereoisomer. This... 

To probe this, model compounds were prepared and subjected to the reaction. Firstly, formation of the ABE ring system was modeled [14]. Diazotization of the amine 35 and reaction of the resulting diazonium salt afforded the spirocyclic product 36 in an acceptable 57% yield from the amine. This marked the first example where the radical-polar crossover reaction was terminated in an intramolecular manner. Modeling the ABCE tetracycle also worked well in preparing products 40 42. Importantly, the relative stereochemistry of 42, and by implication that of the other tetracycles, was verified by X-ray crystal structure analysis... 

The discovery and development of the radical-polar crossover reaction is due to the enthusiasm, skill and hard work of the students and research associates who have worked on this project and whose names are cited in the references. I also thank the EPSRC both for funding and for providing high resolution mass spectra for this project, and SmithKline Beecham, in particular Dr. Norman Lewis, for constant support of this work. 

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