2-Pyridones are aromatic molecules that readily undergo a photochemical dimerization.  This dimerization can be performed in almost any solvent, from benzene to water, and yields two head-to-tail products.  The cis isomer, with alkenes in close proximity, is thermally labile and undergoes a facile Cope rearrangement.  This rearrangement can be used to easily differentiate the cis and trans isomers.

The carbon skeleton of the photodimer has an intriguing overlap with eight-membered ring containing natural products, some of which are shown below, with a carbonyl group where one-carbon appendages are located and unsaturation where oxidation is required.Harnessing this photocycloaddition for total synthesis requires that the amide be reduced and in many cases,. and that the nitrogens be excised from the molecule.The strained, compact and highly functionalized photoproduct presents both advantages and challenges.

All of the natural products shown above have fused five or xix-membered rings that could be derived from three or four-carbon tethers.Initial investigations of intramolecular photoreaction of pyridones led to several important aspects.
 

In the case of a four-carbon tether, only the trans product is formed.It is likely that this simply results from the strain of the resulting molecule, coupled with the reactivity of the cis isomers.Part of the enhanced instability of these fused 6-8 rings, is seen in the conformation of the cyclohexane ring, which is held in a rigid boat conformation.In the case of taxol-related studies, the photoproduct was too unstable to chromatograph on silica gel, reverting to the starting bis-2-pyridone.

 

A three-carbon tether is more readily accomodated by the photoproduct, and so a three-carbon tether yields both cis and trans products very similar to the intermolecular reaction.The intramolecularity, in addition to bringing dissimilar pyridones together efficiently, allows for manipulations that are not readily accomplished intermolecularly.

Conversion of the cis isomer to the trans isomer, can be performed by taking the initial product mixture and heating.At 50 °C the cis isomer (only) undergoes a Cope rearrangement..This product, in contrast to the photoproducts, has a conjugated pi system and is photolabile. Irradiation of the mixture of the trans photoproduct and the Cope product, leads to photocleavage of the latter, which is then converted to the trans and cis [4+4] products.One cycle of heating and irradiation converts an initial 2:1 ratio into a 7:1 ratio.A second cycle results in a ratio fo nearly 20:1, with little decrease in the overall yield of [4+4] products.
 

Cis-selective photochemistry is more challenging, if only because the solution is not obvious.The motivation for developing such a transformation was application of the photochemistry to the fusicoccin (natural products and related natural products.With a cyclopentane fused starting bis-2-pyridone (a pyrindinone–pyridone), only the trans isomer was formed when any of the pyridones was N-methylated.When both pyridones were nitrogen-unsubstituted the stereochemistry of the reaction became solvent dependent, giving largely or only trans product in polar solvents. Nonpolar solvents like benzene and toluene gave only the cis isomer.A study of the effect of concentration in moderately polar solvents (like ethyl acetate) demonstrated that higher concentrations led to cis-selectivity.This is consistent with the intermediacy of a hydrogen bonded dimmer that folds bothmolecules into a cis-selective conformation.

N-Unusbtituted bis-2-pyridones in a nonpolar solvent leads to cis isomer formation.  Activation of the amide nitrogen leads to facile amide opening.

A complicating feature of this photoreaction was a pronounced instability of the cis photoproduct, which underwent a Cope rearrangement at room temperature.Fortunately, the photoreaction, when run at ice bath temperature (ca. 5 °C) can be followed up with dimethyldioxirane treatment.This epoxidation intercepts the cycloaddition product in 84% yield for the two steps, with the epoxide precisely where a trans-diol is needed for fusicoccin A.Activationof one amide by treatment with an isocyanate, followed by lithium borohydride reduction and reduction of the resulting primary alcohol by mesylation and zinc/iodide treatment converted one of the carbonyl groups to a methyl group.
 

Chlorination of the 2-pyridone photodimers stereoselectively lead to rearranged new strucrures.