Radical polar crossover reactions

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. 

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. 

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... 

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. 

Interestingly, the 3 chloro 1 iodopropane addition (Table 2.6, entry 9) led exclusively to pyrrolidine 37 (Scheme 2.4) none ofthe acyclic adducts was found [31]. Presumably, radical addition was followed by in situ Sn2 type cyclization. The same type ofcyclization, giving the epimeric pyrrolidine (epi 37), occurs upon ethyl addition to the 3 chlorobu tyraldehyde hydrazone (Table 2.6, entry 18). These reactions are hybrid radical ionic annulations of the C=N bond, a new class of radical polar crossover reactions [32]. 

The reactivity of tetrathiafulvalenes toward free radicals has been little studied. Nevertheless, a recent report has shown that 1 can act as a catalyst for radical-polar crossover reactions (93CC295) (Scheme 10). In fact, compound 17 has been isolated (cf. Section II.B.2) and its reactions with nucleophiles result in the displacement of the TTF moiety. 

Scheme 4. Radical-polar crossover reaction of an allyl sulfide...

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... 

---