Programming Organic Molecules: Design and Management of Organic Syntheses through Free-Radical Cascade Processes

Abstract

Cascade, domino, or tandem processes, that link together two or more transformations in one pot, are increasing in popularity because they lead to improvements in synthetic efficiency and decreases in environmental impact. Not only do these cascades contain choice mechanistic gems but they also deliver compact and elegant syntheses of complex natural products. Longer cascades require more functional groups precisely configured within carefully designed initial molecular architectures. Such “purposeful” molecules can be thought of as chemical algorithms.This article surveys the phenomenal range of unimolecular free‐radical cascades. A convenient system for classifying free‐radical cascades is described that is useful for evaluating and comparing cascades and aids the design of synthetic routes to polycyclic structures.Double cyclization cascades lead to cyclopentylcyclopentane or bicyclo[3.3.0]octane derivatives. Precursors that contain a ring as a template have been used to control stereochemistry in syntheses of triquinanes and many related compounds. Of the cascades containing ring‐cleavage steps, the most useful are the ring expansions which have opened up new synthetic routes to medium ring polycycles.The key design features of three‐stage unimolecular free‐radical cascades that yielded steroid structures, are linear arrays of radical acceptor units associated with methyl groups distributed every fifth C‐atom in the precursor polyenes. Ring cleavage is the reverse of cyclization. In special, symmetrical structures, therefore, this led to sequences that were reversible, thus launching endlessly repeating cascades supported by delightfully fluxional structures. The science of “programming” organic molecules to achieve particular target structures is maturing rapidly. Coordination and classification of the welter of information in this area is intended to facilitate design and hence to extend the range and complexity of attainable structures.

Green chemistry: the emergence of a transformative framework

“…Intramolecular radical cascades are useful in streamlining synthesis of polycyclic natural products. With careful planning, cyclizations, 1,2-group migrations, hydrogen shifts, fragmentations, and substitutions can be ''programmed'' in a useful order (47) (Figure 7). …”

Recent developments in cyclization reactions of α-aminoalkyl radicals

“…29 For example, in the reaction of carbamate 29, the vinyl radical 31 resulting from 5-exo-dig cyclization of α-acylamino radical 30 is trapped intramolecularly by 1,5-H transfer from silicon to carbon, and the resulting silicon-centered radical 32 undergoes 5-endo-trig ring-closure to give the bicyclic product 34 stereoselectively (Scheme 9). In contrast to the number of applications found in the literature involving α-acylamino-type radicals generated using these methods, reports on the similar use of α-(dialkylamino)alkyl radicals do not abound.…”

Diels-Alder Reactions of 12-Hydroxy-9(10®20)-5aH-abeo-abieta-1(10),8(9),12(13)-triene-11,14-dione

“…One way for chemists to devise the most efficient synthetic route possible for a given compound is to recognize when two or more transformations can be achieved under the same reaction conditions without isolation of the intermediate product(s) [26][27][28][29][30][31][32]. Indeed, the more sequential transformations that can occur, the fewer the steps needed to achieve a given total synthesis, and hence the more efficient the synthesis is.…”