Radical cascades are those in which the
key step constitutes a radical reaction. The high reactivity of free radical
species renders radical-based synthetic approaches decidedly suitable for
cascade reactions.
One of the most widely recognized
examples of the synthetic utility of radical cascades is the cyclization
sequence employed in the total synthesis of (±)-hirsutene, in 1985 (Scheme 6). Herein, alkyl iodide 28 was converted to the primary radical
intermediate 29, which underwent a 5-exo-trig cyclization to afford reactive species 30. A subsequent 5-exo-dig radical cyclization lead to intermediate 31, which upon quenching gave the
target (±)-hirsutene (32) in 80%
overall yield.
A cascade radical process was also
used in one of the total syntheses of (–)-morphine (Scheme 7). Aryl bromide 33 was converted to the corresponding
radical species 34 by treatment with
tri-n-butyltin hydride. A 5-exo-trig cyclization then occurred to
give intermediate 35
stereoselectively in virtue of the stereochemistry of the ether linkage. In the
next step of the cascade, the geometric constraints of 35 forbid the kinetically favored 5-exo-trig cyclization pathway; instead secondary benzylic radical
species 36 was obtained via a
geometrically-allowed 6-endo-trig
cyclization. Subsequent elimination of the phenyl sulfinyl radical afforded
product 37 in 30% overall yield,
which was further elaborated to (–)-morphine (38).