Radical cyclization

Because many reagents exist for radical generation and trapping, establishing a single prevailing mechanism is not possible.

Cyclization of the homologous 6-heptenyl radical is still selective, but is much slower—as a result, competitive side reactions are an important problem when these intermediates are involved.

In 6-hexenyl radical substrates, polarization of the reactive double bond with electron-withdrawing functional groups is often necessary to achieve high yields.

[4] Stabilizing the initially formed radical with electron-withdrawing groups provides access to more stable 6-endo cyclization products preferentially.

In most all-carbon cases, selectivity can be rationalized according to Beckwith's guidelines, which invoke the reactant-like, exo transition state shown above.

[9] Placing substituents in pseudoequatorial positions in the transition state leads to cis products from simple secondary radicals.

[11] Small energy differences between early transition states constitute a profound barrier to success in this arena.

The products of fragmentation methods retain a double bond as a result, and extra synthetic steps are usually required to incorporate the chain-carrying group.

Atom-transfer methods rely on the movement of an atom from the acyclic starting material to the cyclic radical to generate the product.

[13][14] These methods use catalytic amounts of weak reagents, preventing problems associated with the presence of strong reducing agents (such as tin hydride).

Cyclic radicals are either oxidized or reduced and quenched with either external or internal nucleophiles or electrophiles, respectively.

[17] Macrocyclizations, which lack the FMO requirement of cyclizations of smaller substrates, have the unique property of exhibiting endo selectivity.

Metal-catalyzed cyclization reactions usually require mildly basic conditions, and substrates must be chosen to avoid β-hydride elimination.

Silicagel column chromatography of the crude product with hexane–EtOAc (92:8) as eluant gave tetrahydropyran 2 (395 mg, 97%) as an oily mixture of two diastereomers.